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TOLERANCE, DRUG ABUSE AND HABITUAL BEHAVIORS



A. MECHANISMS OF TOLERANCE


GENERAL FEATURES

The introduction of a drug into a biological system is far more complicated thanadding a compound into a test tube. The initial dosage of the drug, the route ofadministration, the rate of absorption, the rate of elimination and many otherfactors enter into this complex equation. Ultimately, the effectiveness of the drugis usually determined by the concentration of drug molecules in the plasma that arefree to interact with receptor sites (cf.,
Chapter 3).

The distribution of drug molecules to the receptor sites may be complicated, but itis only the tip of the iceberg in terms of the organism's overall response to thedrug. Early in the text, a somewhat loose distinction was made between a drug action(how the drug interacts with a specific receptor, e.g., mimickingacetylcholine at muscarinic receptors) and a drug effect (the physiological orbehavioral results of this drug action; e.g., a decrease in heart rate or anincrease in arousal level). There is yet another class of drug effects that may ormay not involve the specific receptors that mediate the drug action: The presenceof the drug may trigger any of several different responses that change the reactionto future encounters with the drug. This altered response to the drug is usually adecrease (tolerance), although increased response to the drug (sensitization) canalso occur.

The body has two general methods of increasing its tolerance to a drug. One ofthese is to reduce the opportunity of the drug to reach the receptors (i.e., reducethe drug action), the other is to launch a biological counterattack against the drugeffect (i.e., a compensatory reaction).

There are several different ways in which the receptors can be insulated from thedrug. The entry of free drug molecules into the bloodstream can be reduced bylowering the rate of absorption from the stomach and intestines. This might beaccomplished mechanically by a change in blood flow or peristaltic action, orbiochemically by a reduction of the transport mechanisms that may be required tocarry the drug molecules across the membranes and into the plasma compartment. Another possibility is to allow the drug to enter the bloodstream in exactly thesame way, but to reduce the final level that is reached by increasing the rate atwhich the drug is eliminated (e.g., by the kidneys or liver). Finally, it may bepossible to increase the binding of drug molecules into complexes with other, largermolecules to render them inert. Figure 9.1 summarizes these mechanisms oftolerance.

There are also several alternatives through which a compensatory response can bemade to drug effects. One of the most straightforward ways is to increase theactivity of an opposing system. For example, if a sympathetic agonist is increasingthe heart rate, this could be countered by an increase in parasympathetic activitythat reduces the heart rate. Although the contrapuntal relationship between thesympathetic and parasympathetic systems has been overrated, mutual feedback systemsdo tend to modulate and balance the activity of these systems, and some brainsystems may have comparable patterns of organization. The details of thiscompensatory response are usually not clear for any individual case, but the generalfeatures probably involve neuromodulation, which has already been discussed in othercontexts. If, for example, a drug reduces the amount of transmitter that isreleased, the postsynaptic cells may respond by increasing the number and orsensitivity of receptor sites to maximize the effect of the available transmittermolecules. (This process is basically the same as denervation supersensitivity, aphenomenon which can occur if the fibers coming into a cellular region have been cutand allowed to degenerate. Following the degeneration, the cells that have losttheir inputs frequently show an increase in the number of receptor sites and becomesupersensitive to even small amounts of the missing transmitter substance.) Alternatively, agonists may cause the postsynaptic cells to reduce the number ofreceptors to prevent excessive levels of stimulation. At a still more complicatedlevel, behavioral tolerance may enter into the picture, with the organism learningor otherwise adapting to the effects of the drug, such that the behavior isnormalized in spite of any prevailing physiological changes that the drug mayproduce. These compensatory mechanisms are summarized in Figure 9.2 (cf., Ellisonet al, 1978; Lee & Javitz, 1983; Schwartz & Keller, 1983).

The common feature of all of these mechanisms of tolerance is that the response tosubsequent drug administration is changed. Depending upon the nature of theparticular response, the tolerance might be evidenced by a change in the effectivedose, the lethal dose, the time course of the drug effect, the range of effects, orsome combination of these. Furthermore, the changes that occur within one systemcan even alter the future responses to drugs that are in a different pharmacologicalclass (cf., Glowa & Barrett, 1983). We turn now to some specific examples oftolerance to demonstrate some of these reactions to repeated drug injections.

Tachyphylaxis

The term tachyphylaxis literally means rapid protection and is exemplified by thetolerance that develops to the effects of indirect acting drugs. Ephedrine, a drugwhich stimulates the sympathetic nervous system, is such a drug. As shown in Figure9.3a, a standard dosage of ephedrine produces a rapid and short lived increase inblood pressure. If this same dosage is repeated at 10-minute intervals, the effectbecomes smaller and smaller until, after several dosages, there is virtually nochange in blood pressure. How could such a rapid tolerance develop?

The mechanism of this rapid tolerance can be inferred by the time course and by theeffects of other drugs. The tolerance does not represent a permanent change,because the change in blood pressure will return to its original level if aninterval of several hours is allowed between doses. This pattern of rapid tolerancethat goes away quickly could be the result of fatigue of the smooth muscles thatcause the vasoconstriction. However, the effects of epinephrine show that this isnot the case. Repeated dosages of epinephrine continue to produce large elevationsin blood pressure, and a single dosage of epinephrine given at a time when ephedrinehas no effect, will produce a full scale change in blood pressure (see Figure 9.3b).

The interaction of these drugs with a third drug, reserpine, provides furtherinformation about the mechanism of tachyphylaxis. Reserpine causes the gradualdepletion of norepinephrine from the sympathetic terminals. This results in adecline in blood pressure, which can be readily reversed by epinephrine. Bycontrast, ephedrine (even the first dosage) has no effect on blood pressure afterthe transmitter substance has been depleted (see Fig. 9.3c).

The conclusion is that the tachyphylaxis is the result of a rapid emptying of thetransmitter substance from the synaptic vesicles (see Figure 9.3d). Ephedrine perse has no direct effect on the smooth muscle receptors that mediate the change inblood pressure. Rather, the elevated blood pressure is produced indirectly bystimulating the release of the neurotransmitter from nerve terminals. Repeateddosages of the drug in rapid succession release the transmitter faster than it canbe replaced, and the effectiveness of the drug declines. These conclusions arefurther supported by the observations that norepinephrine administration not onlyproduces an increase in blood pressure, but it also partially restores theeffectiveness of ephedrine. The restoration occurs because the reuptake process(cf., Chapter 3) incorporates some of the norepinephrine into the vesicles where itcan be released by the next dosage of ephedrine.

This form of tachyphylaxis is a special case of tolerance that does not involve anyparticular reaction of the systems involved. It is a simple case of the drug effectbeing limited by the capacity of the system to respond. The remaining types oftolerance that will be discussed involve a much more dynamic and longer lastingreaction to the effects of drugs.

Changes in Receptor SensitivityTolerance can also be mediated by a change in the sensitivity of the relevant systemto the drug or transmitter. An example of this sort of tolerance can be seen in theresults of an experiment performed by
Brodeur and DuBois in 1964. They administereddaily dosages of an acetylcholinesterase inhibitor to rats. This blockade of theinactivation of acetylcholine allows the transmitter substance to accumulate. Initially, these drug injections produced a variety of parasympathetic symptoms,including tremor and convulsions. By the end of 60 days, however, tolerance haddeveloped and none of these effects was observed.

There are several possible ways that such tolerance could be developed. Forexample, the drug could lose its ability to block acetylcholinesterase. However,assays demonstrated that the degree of cholinesterase inhibition remained unchangedover the 60-day treatment period. This leaves open the possibility that theacetylcholine levels were brought under control by some other mechanism, butmeasures of acetylcholine showed the same high levels were produced by the drug onDay 60 as on Day 1. How could tolerance develop if the actions of the drug remainedconstant?

Suppose the observed tolerance occurred because the neural systems had becomerefractory to the high levels of acetylcholine. This notion was tested byadministering carbachol, a synthetic drug that acts on receptors for acetylcholine,but is immune to the inactivating effects of acetylcholinesterase. In animals thathad not received prior drug treatment, the LD-50 was 2 mg/kg. The rats that haddeveloped tolerance to the cholinesterase inhibitor were twice as resistant to theeffects of carbachol, showing an average lethal dose of 4 mg/kg. In other words,the drug continued to inhibit the action of acetylcholinesterase, the resultingincrease in acetylcholine levels were maintained, but the tremors and convulsionsdisappeared: The drug actions remained constant while the drug effects declined.

The most likely mechanism for this form of tolerance is a change in the sensitivityof the postsynaptic membrane. This can occur through the process of neuromodulation(see figure 9.4). Synaptic activity is a dynamic process, which can be controlledby either a change in the amount of transmitter substance that is released or achange in the response to the transmitter. In the example described above, it wouldappear that the neural systems responded to the high acetylcholine levels byreducing the number of receptors (cf., Schwartz and Keller, 1983).

Although it is not necessary to go through the details of a specific example, itshould be pointed out that the same mechanisms can result in tolerance to drugs thatproduce a decrease in transmitter substance. The initial effects of transmitterreduction are typically greater than the chronic effects. This type of tolerancecan be attributed to an increase in the number of postsynaptic receptors. Thiseffect has been described in earlier discussions as it applies to the phenomenon ofdenervation supersensitivity. The increased sensitivity that follows nerve damagecan be viewed as tolerance to the physical damage.

These changes in receptor populations involve some rather major commitments ofcellular metabolism. As such, they have the properties of both inertia andmomentum; it takes some time (perhaps days or weeks) for the tolerance to developand perhaps even more time for the system to return to initial levels when the drugis no longer present. These are very important considerations which will be seen inmore detail in the later discussion of rebound phenomena.

Enzyme InductionEnzymes are protein molecules that increase the speed of chemical reactions. Theytypically have a rather high affinity for a particular chemical structure (thesubstrate) and the enzyme-substrate complex proceeds through the chemical reactionfaster than the substrate alone. We already have seen several examples of enzymesthat are involved in neurotransmitter systems (e.g., AChE, MAO, COMT and tyrosinehydroxylase). The liver has a rather extensive library of enzymes that facilitatephysiological processes (especially digestion) and help to break down toxicsubstances from both internal and external sources.

The chemical specificity of enzymes allow for the precise control of chemicalreactions, but it also poses a problem. It would be very inefficient (not tomention impossible) for the body to produce and store all the enzymes that might beneeded. It would be much simpler to have a way to limit production to those thatactually are needed. This is what happens in the process known as enzyme induction(see Figure 9.5). When a new foodstuff or drug is encountered it may induce themetabolic machinery to produce an enzyme that has the specific ability to break itdown into simpler components that can be used by the body (in the case offoodstuffs) or inactivated and eliminated (in the case of drugs).

The induction of enzymes involves protein synthesis, a process that may requireseveral hours or more to take place. What this means in terms of the metabolic fateof drugs is that the drug molecules from the first injection may induce theformation of the appropriate enzyme (usually by liver cells), but undergo metabolismthrough the existing, sluggish pathways. Thus, the drug may stay in the system andproduce its effects for a long period of time. However, once the liver cells havebegun production of the enzyme, it is more readily available for encounters with thedrug molecules, and the breakdown reactions for subsequent dosages will proceed morerapidly. It should be noted that this is not an all or none process, but rather onewhich can be regulated by the number of times the inducing substance is encounteredand the amount that is presented. In any event, the induction of enzymes can resultin dramatically different rates of drug metabolism that are seen as examples oftolerance.

The barbiturate drugs provide a good example of tolerance that is at least partiallythe result of enzyme induction. Remmer (1962) administered high anesthetic doses ofpentobarbital to rats on three successive days. Rats in a control group receiveddaily injections of saline. Then all the rats received a lower test dosage todetermine if tolerance had developed. The rats that had been pre-treated withpentobarbital slept only half as long as the rats in the control group (30 min vs 67min). This change in sleeping time was paralleled by a change in the rate ofeliminating the drug from the system. The half-life of the drug (the time requiredto inactivate half of the injected drug) in the control group was twice as long asthat of rats that had been pre-treated with pentobarbital.

It could be postulated that the relevant brain cells became less responsive to theeffects of pentobarbital in the same way that the cells became less responsive toacetylcholine in the previous discussion. The evidence does not support this. Theconcentration of pentobarbital in the blood at the time of awakening can be used asan index of the sensitivity of the cells to the drug. As the concentrationgradually falls, it eventually reaches a level that is low enough to allow theanimal to awaken. The rats that had been pre-treated were at least as sensitive tothe drug as control rats, with waking levels of the drug that were even slightlylower than those of the control group.

The phenomenon of enzyme induction can produce a dramatic tolerance in terms of theeffective dosage of a drug, but it does not necessarily confer the same degree ofprotection against lethal dosage. It fact, the LD-50 can remain virtually the same,while tolerance increases the requirements for an effective dose (the ED-50) untilit may be almost identical to the lethal dose. Let us examine this curiousphenomenon more carefully with a hypothetical extension of the pentobarbitaltolerance shown above.

The upper panel of Figure 9.6 shows the normal course of a barbiturate drug. Afterinjection, the drug is rather quickly absorbed into the plasma compartment. When acertain concentration is reached, sleep ensues while the drug levels continue torise and produce a deeper level of anesthesia. Eventually, the drug will reach itspeak concentration, which is determined by the amount of drug, route ofadministration and other factors discussed in Chapter 3. Meanwhile, the drug isbeing metabolized and the plasma concentration begins to decline. When it reaches acertain level, the animal awakens and the drug metabolism continues until the drughas been eliminated from the system.

After several exposures to the drug, the enzyme that degrades the drug has beeninduced, and the drug is removed from the system more rapidly (Figure 9.6b). Thisshortens the sleeping time by allowing the animal to awaken more quickly. However,the onset of sleep and the peak concentration of the drug in the plasma may showlittle or no change if the absorption of the drug is fast relative to the drugmetabolism.

Now, suppose an attempt is made to duplicate the original drug effect (60 min ofanesthesia) by increasing the drug dosage. The faster rate of drug metabolismrequires a very high dosage to forestall awakening for the full hour. In thishypothetical case (see Figure 9.6c), the peak plasma levels are very near the lethaldosage.

With the margin of safety (the ratio of the LD-50 to ED-50) reduced by tolerance, itmay be advisable to administer multiple doses over time (e.g., a supplemental dosageevery 20 min) to attain the same duration of action (see Figure 9.6d). Theseeffects demonstrate that tolerance can render a drug considerably more dangerous, afinding that has important implications in the clinic, the laboratory, and on thestreet.

Rebound Effects

The various types of tolerance are, in some sense, an extension of the concept ofhomeostasis. The physiology of the organism reacts to a challenge by attempting toreturn the system back to normal. In the case of drugs, this can have importantconsequences not only for the changes in the effectiveness of the drug, but also forthe rebound changes that occur when the drug is no longer present.

The rebound phenomena can be observed readily in the case of nicotine and caffeine. On the surface, it would seem that individuals who use these relatively mild CNSstimulants should be easily identifiable. They should, perhaps, have fasterreflexes, be more vigilant, require less sleep, or be more aware of the environment. Or perhaps they should be more irritable, anxious, or jumpy. None of these effects,positive or negative, is observed. Virtually every attempt to extract anidentifiable difference in physiology or personality between smokers, coffeedrinkers, and nonusers has failed. The differences are revealed when these groupsare compared without drug. The details of the effects are complicated, but nearlyeveryone has seen or been either a coffee drinker before the first cup in themorning or a smoker trying to quit. The major effect of these stimulant drugs isnot to produce an average state of arousal that otherwise could not be attained,rather they come to prevent the rebound effects that would occur without the drug(sleepiness, lack of energy, dysphoria, etc.). The mechanisms of tolerance activelycounterbalance the effects of the drug, and this balance can be unmasked by removingthe drug from the system (see Figure 9.7).

The rebound effects can be considerably more serious than a little early morninggrumpiness. The chronic, heavy use of CNS depressant drugs such as barbiturates oralcohol can set up dangerous counter-effects. When these effects are released bythe abrupt withdrawal from the drug, hyperexcitability occurs, which in severe casescan lead to convulsions and death. With chronic, heavy use of alcohol, this reboundhyperexcitability may be seen as largely irreversible motor tremors, especially ofthe hands (the DT's or delirium tremens). These rebound effects are most pronouncedwhen the drugs are withdrawn abruptly after a period of sustained high dosages, butthis is not a prerequisite. So swift is the body's ability to counter these drugsthat a single dosage can set up rebound effects. An overdose of alcohol orbarbiturate first presents the danger of death through its depressant effects,followed by the susceptibility to seizure activity that may be equally dangerous. It is for this reason that the most superficially obvious treatment of barbiturateoverdose-- the administration of stimulant drugs such as strychnine or picrotoxin--is contraindicated.

Rebound effects are also major factors in the use of amphetamine and related drugs. The actions of amphetamine are complicated and include both direct effects on thepostsynaptic receptors and the indirect release of the neurotransmitter substancefrom the presynaptic vesicles. The behavioral effects include increased arousal,greater physical energy, a heightened sense of well being, and even euphoria. Tolerance to these effects occur readily and probably include all of the mechanisms(transmitter depletion, receptor changes, and enzyme induction) that were discussedabove. A common sequel to the stimulant properties of amphetamine is a profounddepression, the depth of which is related to the amount and duration of the drugadministration. In practice, it is almost impossible to avoid the reboundphenomena. In part because of the indirect actions of the drug, the effects tend tobe self limiting, with the depletion of transmitter rendering the drug ineffectiveuntil a period of time has been allowed to restore the system toward its previousstate.

B. BEHAVIORAL CONTRIBUTIONS

In studying drug actions and drug effects, it is sometimes easy to forget a basicfact about the physiology of the nervous system: It was not designed for thepurpose of responding to drugs invented or harvested by man. The actions of drugscan magnify, interrupt, speed up and delay, but the processes are those that areinherent to normal functions and the maintenance of the brain and behavior. Accordingly, we must not limit the phenomena of tolerance and withdrawal to therealm of drug use, but must search out the relevance to normal functions. Neurotransmitters can be viewed as endogenous drugs and they surely trigger theirown neuromodulatory and rebound effects. We turn now to some situations in whichbehavioral processes impose dramatic limits on the effects of both drugs andenvironmental situations.

Behavioral Tolerance

The phenomenon of tolerance can be no simpler than the actions of the drug to whichtolerance is developing. One of the fundamental principles of pharmacology is thatno drug has a single action (cf., side effects in Chapter 3). The extendedimplication of this is that no drug can induce a single type of tolerance. If adrug has a major effect and two distinct side effects, then it is very likely thattolerance can develop to each of these independently. In some cases, this can bethe determining factor in the development of a drug for clinical use. For example,if tolerance develops to a troublesome side effect within a few days or weeks, thenthe patient may be able to benefit from the long term use of the drug. On the otherhand, if tolerance develops to the main effect, but not the side effect, then thedrug becomes less and less useful over time.

The development of tolerance to specific aspects of drug action may present somedifficulties, but the picture becomes still more complex when behavior isconsidered. In the previous section, we developed the notion that behavior per secould be likened to a drug, triggering rebound effects comparable to those occurringin response to the administration of drugs. We turn now to a consideration ofbehavioral contributions to drug tolerance and present some of the most intriguingfindings in the pharmacological literature.

The development of tolerance to the effects of a drug poses some of the sameproblems of interpretation that are encountered in the recovery from brain damage. In both instances, the initial effects frequently are more pronounced than the longterm effects. In the case of brain damage, the problems of interpretation areparticularly intractable. Does the recovery of some of the lost function reflectthe "take-over" by a related area of the brain? Is it due to some neuromodulatoryeffect such as denervation supersensitivity? Or, is it the result of learning toaccomplish the same behavioral goal in a different fashion? There is evidence tosupport each of these possibilities, but the conclusions remain tentative because ofthe permanence of brain damage.

As researchers began to look more and more carefully at both tolerance and recovery,some confusing observations began to appear. In some cases, clear recovery offunction following brain damage could be observed on one task but not another. Likewise, drug tolerance could sometimes be observed in one measure but not another. There was something missing in the interpretation of these effects. Fortunately,most drug effects are considerably less permanent than brain damage (although someof the tolerance and rebound effects may be very long lasting) and can beadministered repeatedly. This opens the door for experimental approaches that canbetter answer some of the questions posed above.Pre-Post Design.One of these approaches, known as the pre-post design, can be used to demonstratethe phenomenon known as behavioral tolerance. A series of experiments by Carltonand Wolgin (1971) exemplify this approach. The rats in these experiments received arestricted diet of food pellets and were given a daily period of access to adrinking tube that contained sweetened condensed milk. After several days, theamount of milk that was consumed during this period stabilized and served as abaseline for the drug and drug tolerance effects. If amphetamine was injected a fewminutes before the daily test session, the milk consumption was greatly reduced. However, if rats received amphetamine injections before each daily session, the ratsdrank a little more milk each day until, by the end of the two-week experiment, therats that received amphetamine were drinking as much milk as the control rats thatreceived saline injections. Thus, tolerance had developed (see Figure 9.8).

The most obvious explanation of the increase in milk consumption is that one of thepharmacological tolerance mechanisms described above had taken place to reduce theeffectiveness of the drug. Another possibility, however, is that the drug actionsremained essentially the same, but that the animals made a behavioral compensationthat allowed them to drink the milk despite the drug effects. The pre-post designallowed a test of these alternatives by comparing the milk consumption of thefollowing treatment groups:

Group CON: Saline injections before each session

Group PRE: Amphetamine injections before each session

Group POST: Amphetamine injections after each session

The critical treatment group is the one that received the amphetamine injectionsafter each session. Obviously, the drug cannot be influencing the milk consumptionbefore it is given. (It could influence the consumption during the next session, 23hr later, through residual effects of the drug or through conditioned aversioneffects, but these possibilities were controlled for in the complete design of thestudy.) Even though the measure of milk consumption was taken deliberately in the"wrong" place, one would still expect that pharmacological tolerance would bedeveloping to the amphetamine. Enzyme induction could occur, the number ofreceptors could be changed, the amount of neurotransmitters could be changed, orsome combination of these could occur. But the measure of milk consumption would beblind to these effects because it was taken long after the drug was given (23 hr).

The critical test occurred after these mechanisms of tolerance were given anopportunity to develop. The rats that had been in Group POST now were given a testdosage of amphetamine BEFORE the milk consumption. If tolerance to the amphetaminehad been developing, as it had in the rats in Group PRE, then the milk consumptionshould have remained at the baseline level (see Figure 9.8). Instead, the milkintake was substantially reduced! How could tolerance to amphetamine develop forone group of rats but not the other? The answer (although it does not specify amechanism) is behavioral tolerance: the rats in Group PRE became tolerant to theeffects of amphetamine on milk consumption. Although pharmacological tolerance mayhave developed over the treatment period, this was not sufficient to block itseffects on milk consumption. The necessary component was behavioral experiencewhile the drug was in effect. The rats, in some sense, had learned to consume milkdespite the effects of amphetamine.

A comparable experiment has been done by Campbell and Seiden (1973) usingperformance of a drl task to assess the effects of amphetamine. The performance ofthis task, which requires low rates of responding, is severely impaired by theeffects of amphetamine. However, tolerance develops with repeated injections, andthe behavior returns to the normal baseline that was obtained without drug. Again,the pre-post test design showed that this return of normal behavior could not beattributed to pharmacological tolerance. Rats that had received repeated injectionsof amphetamine, but without the opportunity to perform the drl task while under theinfluence of the drug, still showed serious impairment when the drug was givenbefore the drl test session.

The results of these experiments suggest some clinical considerations that probablyhave not received the attention they deserve. The amphetamines and relatedcompounds are widely used by dieters in both prescription and over the counterformulations. The long term effectiveness of this therapy is marginal at best. Itseems likely that humans, as well as rats, develop behavioral tolerance and learn toconsume the good things in life (including sweetened condensed milk) despite theeffects of the drug.

One possible explanation of behavioral tolerance is that it somehow blocks out theability to perceive the effects of the drug. This is probably not the case. Buenoand Carlini (1972) showed that the ability of rats to climb a rope was impaired byTHC (the active component of marijuana). After tolerance developed, the rats wereable to climb the rope as well as control animals, but were nonetheless capable ofdiscriminating (in a different task) the presence or absence of THC.

Environment and ritual.One of the most dramatic demonstrations of the power of behavioral tolerance hasbeen demonstrated by
Siegel and coworkers (1982). The repeated administration ofopiate drugs produces a remarkable degree of tolerance. In order to maintain thesame level of analgesia over a period of days, the drug must be administered in everincreasing dosages and can reach levels that may be several times higher than theLD-50 established for naive animals. These investigators administered a schedule ofincreasing dosages of heroin working the rats up to a dose that they could not haveinitially tolerated. Half of the rats had received this series of injections in thecolony room. The other half of the rats were removed from the colony to a test roomthat differed both visually and by the presence of a 60 dB white noise, where theyreceived their injection of heroin. As expected, all of the rats withstood theincreasing dosages of heroin.

After completing this series of increasing dosages, the rats were given a singletest dosage of 15 mg/kg of heroin. This is a very large dosage of the drug, beingclose to the LD-100 (96% mortality) for rats that have had no experience with thedrug. Rats that had received the series of heroin injections showed a substantialincrease in the ability to withstand the drug, with only a 32% mortality rate. However, a large portion of this protective effect was attributable to behavioralrather than pharmacological tolerance. If the rats received the same injection, butsimply in a different room (colony rats in noise room; noise room rats in colony),they were twice as likely to die (64%). The association of a particular environmentwith the administration of a drug adds to the ability to compensate for the effectsof the drug. In this case, the learned aspects of the tolerance can literally meanthe difference between life and death.

Siegel proposes that many of the deaths that occur through drug overdose have abehavioral component. Addicts frequently develop ritualistic behavior associatedwith the administration of a drug (same place, same people, etc.) When this ritualis changed, for example, by purchasing the drugs on the streets of another city, thelikelihood of death through overdose is increased. The common explanation that thedrug obtained was more potent than that usually used may be true in many cases, butthe behavioral component may be a major factor as well.

How is it possible for an animal to behaviorally reduce a drug effect? Some ofSiegel's earlier work provides a possible answer to this question (Siegel, 1975). The work centered on the possibility of the Pavlovian conditioning of drug effects. Suppose, for example that the injection procedure (the room, the handling, theinsertion of the needle) is always conducted in the same manner. This set ofstimuli could serve as a conditioned stimulus (CS) to predict the physiologicalchanges (UR) that would follow as a result of the drug injection (the unconditionedstimulus, or US). What would happen after a number of such pairings if saline weresubstituted for the drug? The CS (injection procedure) would be the same as always,but would a conditioned response (the physiological change) be observed?

The drug under investigation was insulin, which lowers the blood sugar levels. Ifinsulin injections are given in the same manner, is it possible to get a conditionedchange in blood sugar levels that parallels the conditioned salivation that occurswhen a bell has signaled the presentation of food powder? The answer is yes, butthe direction of the effect is opposite that which one might first expect. Insteadof getting a conditioned lowering of blood sugar, Siegel observed a conditionedincrease in blood sugar. This makes perfect sense if the conditioned response isviewed as an attempt to compensate for a predicted change in the environment. Normally, the amount of insulin produced by the animal is controlled within rathernarrow limits to regulate the level of glucose utilization by the cells, prepare fordigestive loads, etc. The injection of an outside source of insulin disturbs thisbalance, and the animal must reduce its own production of insulin in an attempt tocounteract this effect. According to Siegel's results, this compensatory responsecan be learned, and a sham injection procedure causes a reduction in insulin and acorresponding increase in blood sugar. Of course, little or none of this iscognitive learning (try to imagine how you would voluntarily reduce your own insulinlevels), but the mere fact of association is sufficient to trigger these processesaccording to the laws of Pavlovian conditioning.

Once again, the importance of these phenomena in the clinic should not beoverlooked. When drugs that cause pronounced physiological effects are given overlong periods of time, there is a very real possibility that Pavlovian learningprocesses may take place to counteract the effects of the drug.

Opponent Process

TheorySolomon and Corbit's theory of opponent processes is modeled after well establishedevents that occur in the sensory systems. The most familiar of these are thenegative after images that occur in the visual system. If an individual staressteadily at a relatively bright object, say a television screen in a dimly lightedroom, the absence of that stimulus produces a curious illusion. When the vision isshifted to a neutral part of the room, a ghostlike image of the screen is projectedonto the surface and this image is dark rather than light. Hence, the term negativeafter image. The negative after image is also familiar in the case of indoorphotography. The bright flash of light is followed by after images (usuallynegative, but sometimes alternating positive and negative) of small dots that areprojected onto the "real" visual world. These after images even extend into therealm of color vision, with the after images being of the complementary color (redobjects produce a green after image, blue objects produce yellow, and vice versa). Comparable illusions can appear with the motor system, as evidenced by the "light-footed" feeling that occurs when a pair of heavy boots or roller skates is removed. But does it make sense to apply these principles to something as complicated asemotions? Probably yes.

There are three major components to the opponent process theory:

Affective contrast is the most fundamental of these, and closely parallels theresponse of the visual system to light. The presentation of a bright light producesa peak response followed by rapid adaptation to a stable level (the A-response inFigure 9.9). When the light is turned off, a negative after image occurs andgradually dissipates with time. The magnitude of these effects is related to theintensity of the stimulus. Several observations can be cited to relate this toemotions. An infant may be lying quietly in its crib, exhibiting no particularemotion. If a nipple containing a sugar solution is offered, a positive response isobtained (the A-response). Withdrawal of the nipple results in vigorous crying (theB-response), an effect which would not have been observed if the positive stimulushad not been presented. Comparable effects can be observed in the case of initiallynegative stimuli. Electric shock administered to dogs can produce an increase inheart rate. When the shock is terminated, there is a dramatic decline in heart rateand the dogs may show behavioral excitement. This is very likely the laboratoryequivalent of the frenzied play activity that sometimes follows the administrationof a bath to a dog (or a child, for that matter!). A more familiar example tostudents may be the excited chatter that frequently fills the hallways after a majorexamination.

The story gets more complicated with affective habituation. If a bright light ispresented for a long period of time, habituation occurs and the perceived brightnessis greatly diminished (the A'-response in Figure 9.9). But when the light isterminated, the negative after image is both stronger and more enduring than it wasfollowing a brief, initial exposure (the B'-response). In the laboratory, this canbe observed with repeated presentation of shock to dogs. After a time, the shock nolonger produces a change in the heart rate, but the "after-image" (the decrease inheart rate) becomes very pronounced. Again, the same pattern emerges in the case ofhuman emotions: The heart throbbing, adrenergic effects of a new amour might wellbecome a health hazard if they continued; but in the words of the songwriter, "...after 16 years of marriage, the fires don't burn so hot!" (Harry Chapin). Returning to the theory, the A'-response takes over, but the stage is set for atremendous B'-response if the stimulus should be terminated, e.g, the grief responsethat follows the loss of a loved one.

The third aspect of the theory, affective withdrawal, is really just a sharpening ofthe concepts described by the first two. We will describe two of the numerousexamples put forth by the theorists. One of these involves the sport (?) ofskydiving. For the naive jumper, the period before the jump is filled with anxiety. This anxiety is galvanized into terror with the actual jump, and relief follows asafe landing. Should the individual continue this pastime, the emotions that colorthe experience undergo the pattern of affective habituation and contrast describedabove. Anxiety is replaced by eagerness, the terror is downgraded to a thrill, andrelief is transformed into intense exhilaration--the raison d'etre for what wouldotherwise be a silly thing to do. A similar pattern can be applied to the abuse ofa drug, for example, heroin. The initial presentation is preceded by a state ofrest, the drug's actions produce a "rush", and the aftereffect is one of craving. With veteran users, there is a shift in the emotions, and the drug's actions producea state of contentment (rather than a rush). This contentment (the A'-response) isfollowed by abstinence agony (the B'-response), which turns into an intense cravingfor the drug, and the drug now has only the capacity to relieve the craving ratherthan reproducing the initial rush-- and the circle continues (see Figure 9.10).

The opponent process model is also relevant to many of the paradoxical effects thataccompany goal attainment. Reinforcement in an operant schedule does notnecessarily spur the pigeon into immediate further action, but rather may befollowed by a post-reinforcement pause. The attainment of a long-sought goal suchas a college degree is frequently followed by a bout of depression, and thepostpartum blues are almost unavoidable. Solomon and Corbit emphasize the view thatall of these effects are noncognitive in nature. That is, they are not the resultof a logical, cognitive analysis of the present environment, but rather are theresult of a previous environment that no longer applies.

These changes may well be noncognitive, but they cannot-- if we continue ourattempts to view the brain and behavior in a lawful relationship-- be nonphysical. Powerful stimuli produce powerful changes in the neurotransmitter systems, and thesein turn trigger the processes of neuromodulation, changes in receptor sensitivity,and even transmitter depletion. These reactions, like tolerance to a drug, alterthe responses to standard stimuli and set the stage for withdrawal reactions.

Although the opponent process theory has not gained universal acceptance, we shallrisk pushing it one step further in terms of the noncognitive aspects of emotions. There will not be many students of this book who will recall the Mary Tyler Mooreshow, but one of the episodes provided a poignant example of opponent processes inaction. A dear friend of Mary's, Chuckles the Clown, died. Of course, she wasstricken with grief, and she decried all references to the lighter side of his lifeand career. At the funeral, however, she was overcome by an uncontrollable urge tolaugh; not hysterical, unfeeling laughter, but true, euphoric, high spiritedlaughter. Why? The grief reaction is understandable in the framework presentedabove. However, the grief itself is a powerful stimulus that can set up its ownopponent processes, and as grief subsides, periods of unexplainable high spirits maypenetrate the prevailing negative mood (bringing with it a certain burden of guilt).

The point of all this is that the brain is a dynamic system that can respond quicklyin terms of neuronal action potentials, but more slowly in terms of the chemicaladjustment of the overall tonus of a transmitter system. These changes occur indirect response to the changes in the environment, but the properties of inertia andmomentum do not always allow the changes to reflect, in a veridical manner, what ishappening at a particular moment. An appreciation of these facts can make theemotional responses to a loss (or for that matter, a gain) a lot moreunderstandable. Clinicians now expect a recurring cycle of mood changes following aloss such as a serious knee injury in an athlete. The first phase is one of denialthat the injury is serious or that the loss will have a major impact on theindividual's loss. This is followed by anger. The anger is followed by depression. The depression, in turn, may be followed by denial that may even take on a flavor ofa high spirited, can-do attitude about coping with the injury. Most of thesechanges can be characterized as noncognitive in that they bear little relationshipto the current changes in the outside environment. They are, almost literally, drugeffects.

C. FOUNDATIONS OF ABUSE

Terminology
The terms drug addiction and drug abuse once seemed like eminently reasonabledescriptive terms. The use of certain drugs produced a physical dependence,creating a situation in which the body required the presence of the drug to maintainnormal physiological functions. This
physical dependence on the drug was the basisfor the individual's profound need for the drug, the addiction. These definitionsworked fairly well for certain classes of drugs and drug users, but there was agrowing list of instances in which the definitions seemed inappropriate. Tobaccouse, for example, certainly involves craving, but the degree of actual dependence(i.e., physiological need) is much less dramatic than in the case of morphine orbarbiturates. There is virtually no danger of death or severe symptoms ofwithdrawal even with complete abstinence. A distinction has sometimes been madebetween a drug habit and a drug addiction to reflect, in a rather rough manner, thediffering physiological bases that control the use of the drug. These distinctionsblur, however, with differing patterns of use, and the three-pack-a-day smoker maywell have a greater physiological need than the individual who manages to limit theuse of morphine. The distinction is equally blurry when one tries to draw the linesbetween moderate drinking, heavy drinking, and alcohol addiction.

As it became apparent that the physiological measures of dependence or the amount ofdrug used could not clearly define addiction, new terminology began to arise. Theterm addiction began to give way to the term drug abuse, which suggests a greaterbehavioral contribution. If an individual's use of a drug is extensive enough tointerfere with work, family, or lifestyle, then the drug is being abused. There arestill fuzzy edges in this definition, but the term is somewhat more realistic thanthe term addiction, because it reflects the pattern of use as well as the amount ofdrug used.

There also can be some argument concerning the term drug. Almost everyone willagree that morphine is a drug, but some will balk at considering coffee as a drug,and consensus becomes even more difficult in the case of chocolate bars, nutmeg orpeanut butter. This dilemma was met with yet another evolution of the terminology,and researchers now speak of substance abuse. This too shall pass: There is agrowing recognition (especially with the burgeoning business of state lotteries)that behavior itself can be the object of abuse. There is a commonality among theheroin junkies, smokers, coffee drinkers, beer drinkers, gamblers, overeaters,workaholics, and maybe even runners. They are neither inherently evil nornecessarily burdens on society, but they are all caught, to some degree, in abehavioral and pharmacological trap. We turn now to an examination of this trap.

Self Administration

Although physiological dependence may not be essential for addiction or abuse (cf.,Bozarth & Wise, 1984), it certainly can be an important contributor. This is mosteasily seen in laboratory models of addiction in which animals are given theopportunity to self administer drugs. In some cases, the animals may simply begiven access to a solution that contains the drug and allowed to freely ingest thesubstance. More commonly, the drug is used as a reinforcer in an operantconditioning situation as shown in Figure 9.11. A catheter may be permanentlyimplanted into a blood vessel (e.g., the jugular vein or carotid artery), withprovision made to connect the catheter to an outside source via a small tube. Whenthe animal has fulfilled the requirements of the schedule of reinforcement, a smallamount of drug is injected as a reinforcer.

In general, there is a fairly close correspondence between the list of drugs thatare abused by humans and the list of drugs that animals will self administer in thelaboratory. Among these are the opiates, the barbiturates, amphetamines, and somehallucinogens. The drugs that can be used as reinforcers appear to have threecharacteristics in common:

Reinforcement restructured.The behavior of a rat in a self administration experiment shows many parallels todrug use in humans. In the case of morphine, for example, the initial rate ofpressing the lever to obtain the drug may be very low. Gradually, over a period ofdays and weeks, tolerance to the morphine begins to develop (this can bedemonstrated by independent testing of pain thresholds) and the lever pressing showscorrespondingly greater rates in order to inject the greater amount of drug that isrequired to produce the "desired" effects. If the rat is given a dosage of morphinevia a standard injection procedure, the amount of lever pressing is greatlydecreased for the duration of the drug effect. If the rat is removed from theapparatus and withdrawn from the morphine for a period of time, physical withdrawalsymptoms will be seen, and if the rat is returned to the apparatus, very high ratesof lever pressing may be observed as the animal restores the morphine levels.

The administration of morphine under laboratory settings not only parallels some ofthe features of human drug use, but also parallels some of the aspects ofconventional drives and reinforcers. As in the case of food and water, the drug canserve as a reinforcer for operant behavior. If the reinforcer is given outside ofthe operant setting, there will be a corresponding decrease in lever pressing, whilewithdrawal from the reinforcer will result in higher rates of responding when thesubject is returned to the operant chamber. But there is an important difference. The drug not only acts as a reinforcer, but sets the stage for the development ofthe motivation to obtain the drug. Presumably, the rat has not had a lifelongyearning to obtain morphine, nor can we attribute the initial lever pressing to peerpressure or the ills of society. The first dosage of morphine appears to have someimmediate reinforcing value, but more importantly, it initiates a chain ofphysiological events that now result in a deprivation state that was not therebefore: The absence of morphine is aversive. Eventually, the positive rewardingeffects of morphine may pale in comparison to the aversive effects of not having thedrug, and the resulting behavior may be more akin to avoidance behavior thanresponding for reward.

Not all drugs that have abuse potential show such close parallels between humanusage and laboratory models. Researchers have found that it is almostembarrassingly difficult to get laboratory animals to consume alcohol. The taste issufficiently aversive to the naive palate to prevent consumption in amounts thatlead to tolerance, rebound effects, etc. It is usually necessary to coerce theanimals to consume the alcohol by making it a part of their required food or watersupply. However, once the alcohol consumption has been established, the animalswill readily and voluntarily maintain the "habit". But why should it be sodifficult to establish alcohol abuse in the rat while it is so difficult to preventit in man? There is no simple answer to this question, but a more careful analysisof the drug administration procedures may provide some important clues.

Environmental bridges.
Goldberg and associates (1981) performed an experiment in which monkeys were giventhe opportunity to press a lever to obtain a small intravenous injection ofnicotine. Although the monkeys pressed the lever enough to receive a few injections(thereby having the opportunity to experience the drug effects), the rate ofpressing did not increase, but rather remained at the low level that was shown by acontrol group that received saline injections. Again, the failure to demonstrateself administration was curious in view of the ability of nicotine to reinforcebehavior in humans. These investigators made a clever extension of their results ina second experiment: Whenever the rats earned a reinforcement, it resulted in boththe drug injection and the change of a green light into amber as the subjectsentered a 3-min period of darkness during which time the drug effect developed. This additional stimulus had no effect on animals that were receiving salineinjections, but greatly enhanced the self administration of nicotine.

Why should the addition of an external stimulus aid the establishment of a nicotinehabit? And even if it works, does it not belittle the results somewhat to have toresort to this sort of a crutch to demonstrate the drug administration? The answerto both questions may be found in a series of experiments performed by Snowden(1969). There was some controversy about whether the regulation of the amount offood eaten is controlled by the acts of chewing, tasting and swallowing, or bymonitoring the caloric feedback from the food in the stomach. One way of testingthese alternatives was to place the rat in a situation in which all nutrients wereobtained by pressing a lever to inject liquid diet directly into the stomach. Thisprocedure is directly comparable to that used for the self administration of drugs,and most experiments demonstrate that the rats are remarkably accurate incontrolling the overall calories that are ingested in this manner. But Snowdenshowed that the results were not as clear-cut as they seemed. The liquid diet isprone to spoilage in these long term experiments, but the problem can easily beavoided by keeping the reservoir in an ice bath. This prevents the spoilage, butwhen the rat earns a reinforcement, it receives not only a small amount of diet inthe stomach, but also experiences a cool tactile sensation as the liquid passesthrough the tube under the skin of the head and neck en route to the stomach. WhenSnowden warmed the liquid to body temperature before it reached the skin, theability of the liquid diet injections to serve as a reward was greatly diminished. Why should this happen?

In both cases, the reinforcing value of a substance was enhanced by the addition ofsome external stimulus. The most likely explanation of these results is that theexternal stimulus helps to bridge the gap in time between the physical delivery ofthe reinforcer and the actual physiological change that results. In the real worldand most laboratory situations the presence of these external mediators are the rulerather than the exception. The sight, smell, taste, and texture of food are allpowerful reinforcers that signal the ultimate physiological reward, caloric energy. In terms of the immediate ability to control behavior, these harbingers ofphysiological change are more important than the real change. When the situation isso tightly controlled that only the physiological change can be experienced, thereinforcing value is greatly diminished. The situation becomes, in a sense, aPavlovian delayed conditioning procedure which is successful only after many trials,if at all.

The picture that emerges is that environmental cues and behavior are an inextricablepart of drug effects and of drug abuse. These behaviors become an important part ofthe overall pattern of abuse, even when the drug action is so fast that an externalstimulus is not essential to bridge the gap. Consider, for example, theadministration of nicotine by cigarette smoking. How does a drug that requires anenvironmental bridge in the laboratory gain such control over so many people in thenatural environment? One reason is that the route of administration is ideal interms of the speed of the effect. The inhalation of nicotine in tobacco smokeproduces very rapid effects, reaching the brain within 8 seconds (Jaffe, 1980). This is even faster than an intravenous injection into the arm, and is fast enoughthat each puff of the cigarette can produce a discrete, detectable drug effect! This rapid delivery of distinct reinforcements serves not only to maintain thebehavior, but also provides an excellent environment for the development ofsecondary reinforcers of associated behaviors such as manipulation of thecigarettes, oral contact, the smell of the smoke, and specific times and places(e.g., after meals, while driving, while reading the paper, etc.)

Environmental and behavioral cues are not only important contributors to therewarding effects of drugs, but also to the motivational states that direct theorganism toward specific drug effects. Certainly, a major aspect of thesemotivational states can be attributed directly to the physiological actions of thedrug. The effects of enzyme induction, neuromodulation and rebound phenomena allcontribute to an internal environment that can be "corrected" by an additionaldosage of the drug. But certain aspects of these physiological changes can beinfluenced by learning, as we have already seen in the cases of insulin or morphineinjections. Stressful environments may be especially potent in this regard becauseof previous situations in which engaging in the rewarded behavior (e.g., smoking acigarette) has led to a rapid, rewarding effect. The rewarding effects may be evenmore pronounced with a drug such as alcohol, which has some inherent properties ofanxiety reduction.

It is even possible to go a step further in the analysis of environmental cues and show that these are important not only in helping to mediate the motivational stateand the rewarding effects, but also in contributing to the behavioral outcome of thedrug use. A particularly intriguing example of this has been shown in a cleverexperimental design that was developed by John Carpenter (cf., Marlatt & Rohsenow,1981). This design unveiled the phenomenon that has come to be known as theThink-Drink effect. The critical feature of the design was the development of acocktail that tasted the same with or without alcohol. The recipe was four partstonic water, one part vodka, and one part lime juice. The nonalcoholic version ofthis was simply five parts tonic water and one part lime juice. Preliminary testsshowed that the identification of these two recipes was at chance levels, theprotestations of the seasoned drinkers' palates notwithstanding. The design of theexperiment, shown in Figure 9.12, was a 2 X 2 design in which the subject eitherreceived alcohol or not and were told that they were receiving alcohol or not. Thus, some of the subjects expected the effects of alcohol when it was not present,while other were not expecting the effects of alcohol when it was present. Thebehavioral measures (including social aggressiveness, talkativeness, motorcoordination, and others) showed that the behavior was more closely related to whatthe participants thought they were drinking than to what they actually weredrinking! Obviously, alcohol is a real drug, and with large dosages there is no wayto think one's way to normalcy. However, the results of these experiments suggestthat much of the stereotyped behavior associated with alcohol use may occur beforethe physiological effects are present or at doses which would not be sufficient toproduce the behavior directly, and there is also evidence for behavioral tolerancewhen specific behaviors are practiced under the influence of the drug (e.g., Wengeret al, 1981).

The environmental factors become especially important when a distinction is madebetween use and abuse of drugs. Alcoholism is certainly one of the most costly ofsociety's ills. The obvious solutions of voluntary abstinence or legal prohibitionseem not to work. Accordingly, many researchers have turned their attention to thecauses of alcoholism. One of the most interesting set of findings is that there aresome subcultures that use a fairly large amount of alcohol, but have very lowincidences of abuse (e.g., Aronow, 1980). Several features of alcohol use seem tobe common among these groups. Children are exposed to alcohol and use alcohol at anearly age, usually in the form of wine or beer as part of the meal. The parents donot become inebriated and there are strong sanctions against those who do. Inebriation is never viewed as something humorous or daring. The use of alcohol inmoderation is simply taken for granted, with neither positive nor negativeattributes attached. A glass of wine can be accepted or refused with the sameimpunity as one accepts or refuses a slice of bread. This contrasts sharply withthe more traditional Middle America pattern that prohibits the use of alcohol in theyoung, while viewing inebriation as a source of humor ("Did you hear the one aboutthe drunk who...") and the ability to drink as a sign of adulthood, authority andpower. As children approach adulthood (or as they want to approach adulthood), theysurreptitiously obtain and consume alcohol, usually in excess and almost alwaysunder conditions of stress--the perfect conditions for establishing the use of thedrug for the purposes of aggrandizement and stress reduction.

Breaking the CycleOne of the greatest ironies of humanity is that almost everyone assumes free willand control over behavior while, at the same time, ruing the fact that they cannotstop smoking, overeating, drinking coffee, gambling, drinking alcohol, takingtranquilizers, or biting fingernails. Breaking these so-called habits is one of themost difficult areas of behavior. There are those who claim it is simply a matterof will power and that they could stop at any time they really wanted to. Indeed,some do, but the rate of recidivism is high. One of the main reasons for the highrate of returning to the habit is that it has been linked to stressful situations. Abstinence is itself a stressful event, and only serves to increase the likelihoodof the behavior, especially during the early stages. Schachter has claimed (on thebasis of informal surveys;
1982) that the statistics are unnecessarily pessimisticbecause they are based upon individuals who seek professional help. Hisobservations suggest that there are many individuals who lose weight or give upsmoking without professional help and with considerably lower chances for returningto the original patterns of behavior. Whether or not these observations will holdup under more rigorous scrutiny, it is clear that there are many cases in which thebehavior is especially intractable. There is no clear formulation that canguarantee success in the attempt to break drug abuse patterns, but severalsuggestions can be made, based upon the way in which the abuse pattern has beenestablished and maintained.

1. Change the US effects of the drug

If drug use is viewed as a straightforward example of conditioning, then therewarding drug effects can be considered as the unconditioned stimulus or US. Oneof the more obvious ways to interfere with this chain of events is to change theeffects of the drug. Perhaps the best known example of this is the drug known asAntabuse, which interferes with the metabolism of alcohol. The ingestion of alcoholcauses severe gastrointestinal illness when this drug is present, and it isnecessary to refrain from taking Antabuse for about three days before alcohol can beconsumed without experiencing these ill effects. This drug has been used with somesuccess in clinical settings, but one of the obvious drawbacks is that theindividual must take the Antabuse on a regular basis.

Another example of interference with the US effect is the substitution of methadonefor heroine abuse. The methadone is not without its own potential for abuse, butthe cravings for the drug and the withdrawal effects appear to be somewhat lesssevere and (perhaps most importantly) it is usually prescribed under carefulconditions in known quantities and purity.

A third example is somewhat akin to fighting fire with fire. One of the ways inwhich smokers have been aided in breaking the cycle of smoking cigarettes is toproduce the drug effects via a different route. Chewing gum that contains nicotinecan produce the drug effects without engaging in the sequence of behaviors that hasbeen established by smoking. Others may turn to what is by most standards (baseballplayers excepted) the even less socially accepted habit of taking snuff or chewingtobacco (Will restaurants adopt spitting and non-spitting sections?) Social customsaside, these are valid methods of interrupting the cycle, because it provides forthe first time, a separation between the behavioral patterns and the drug effect. If it is properly guided (and there is always the danger of substituting one habitfor another, or even adding one habit to the other), the individual can eliminatemany of the behavior patterns without suffering the physical symptoms that mightaccompany abstinence.

2. Change the reward structure

To some extent, this category overlaps with the previous one, but there are ways inwhich the reward structure can be changed to aid in reducing some of the behavioralcomponents of the pattern. One way which has been moderately successful (althoughcare must be taken to avoid nicotine poisoning) is forced smoking. The individualis forced to rapidly smoke one cigarette after another, rather than leisurelypuffing away in the normal manner. This has two consequences: It usually causessome degree of discomfort due to the rapid effects of the high dosage (therebyassociating aversive consequences with the behavior of smoking), and it again allowsa way in which the drug effects can be obtained under unusual circumstances.

This general type of technique has also been used in the case of food abuse(overeating) by attempting to limit eating strictly to mealtimes under rigidconditions.

3. Change the environmental cues

One of the hallmarks of substance abuse (it is unfortunate that the phrase abusivebehavior has the wrong connotation) is that it involves a high degree ofritualization-- the cigarette after breakfast, the drink or two after work, thepretzels while watching TV. An important part of any program to eliminate habitualbehaviors is to change these environmental cues whenever possible. This may involvea new schedule, such as skipping breakfast or eating breakfast at a later hour,avoiding certain locations, moving the TV to a different room, changing a workschedule, etc. Usually, this is not easy. There are too many restrictions in mostlifestyles to allow very major changes. One of the major advantages of a formalclinical setting is also one of the major disadvantages: On the one hand, the new,controlled environment is a tremendous aid in helping to interrupt the patterns ofbehavior that have maintained the pattern of abuse. On the other hand, once thebehavior has been changed and the patient leaves, it is very likely that the returnto the previous environment will re-trigger all sorts of cues that have supportedthe habit in the past. Clinical psychology (and medical practice, for that matter)would be much simpler if the patients did not have to return to the causes of theirdisorders when they left the couch.

4. Avoid using the drug

This is an obvious truism, but it is mentioned here because of some recentcontroversy concerning alcohol consumption. Several different support groups, mostnotably Alcoholics Anonymous, have long advocated complete abstinence once thedrinking behavior had been disrupted. Their view is that there is never a cure, andthat any drinking will reestablish all of the behavioral patterns of abuse. It hasbeen suggested that this requirement may be a bit too Spartan, and that controlleddrinking might be allowable (cf., Sobell & Sobell, 1978). This seems not to be thecase: In a follow-up study of 20 alcoholics who participated in the controlleddrinking experiment (Pendery et al, 1982), the following dismal results were found: 1 was successful, 8 continued to have drinking problems, 6 returned to abstinencevoluntarily, 4 died, and 1 was missing.

The presence of the drug in the body not only serves to reactivate some of themetabolic systems that were changed through previous exposure, but also recreatesinternal conditions that have been strongly associated with the relevant behaviorpatterns that supported the pattern of abuse. Apparently, truisms prevail.

D. SUMMARY

PRINCIPLES

1. The effect of a drug can be decreased or increased by changing the access of thedrug molecules to the receptors, or by setting up a physiological opposition to thedrug.

2. The mechanisms of tolerance (or sensitization) can change nearly any feature ofthe drug's actions.

3. Indirect acting drugs may lose their effectiveness rapidly through depletion ofthe transmitter stores.

4. As neuromodulatory processes take place, the changes in receptor number orsensitivity is reflected by a gradual change in response to the drug.

5. The presence of a drug may induce the formation of enzymes that will inactivatethe drug more quickly when it is administered in the future.

6. If a drug that has been present for some time is abruptly withdrawn from thesystem, it unmasks compensatory reactions and opposite, rebound effects may beobserved.

7. The opponent process theory applies many features of tolerance to emotionalresponses and to some of the phenomena of addictive behaviors.

8. In some cases, the development of tolerance requires that specific behaviorsoccur while the drug is in effect, a phenomenon known as behavioral tolerance.

9. The pre-post design has been used to separate the effects of pharmacologicaltolerance from behavioral tolerance.

10. Some aspects of behavioral tolerance may be the result of the Pavlovianconditioning of compensatory responses.

11. Drug addiction, drug abuse, and substance abuse are all terms that apply tobehavior that is maintained by acquired motives.

12. Self administration procedures are used as animal models of drug abuse inhumans.

13. Environmental stimuli associated with drug use may serve as important bridgesfor the development and maintenance of habitual drug use.

14. The effectiveness of a drug may be significantly changed by the user'sexpectations, as in the think-drink effect.

15. The development of substance abuse may interact with normally occurring states,especially those involving stress.

16. The drug abuse cycle may be interrupted at several points that are specified bythe laws of learning.

TERMS

Acetylcholinesterase

Acquired motivation

Affective habituation

Affective contrast

Affective withdrawal

Barbiturates

Behavioral tolerance

Carbachol

Compensatory response

Delirium tremens

Denervation supersensitivity

Drug effect

Drug action

Enzyme induction

Ephedrine

Half-life

Indirect action

LD-50

Negative after image

Neuromodulation

Opponent process

Pavlovian conditioning

Pharmacological tolerance

Physical dependence

Pre-post design

Rebound effects

Ritualistic behaviors

Secondary reinforcer

Self administration

Sensitization

Substance abuse

Tachyphylaxis

Think-drink effect

Tolerance

Withdrawal effects

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