Regulation of Drug Taking by Sensitization and Habituation

Brain Research, 2004

Rats provided limited daily access to cocaine (1 h) maintain stable levels of drug self-administration over time while those switched to longer access (6 h or more) exhibit escalating patterns of drug intake. These results are reminiscent of human recreational and compulsive drug-taking behavior, respectively. We found that the brains of cocaine-self-administering rats were also qualitatively different in subjects having experienced 6-h (Coc6h) daily access compared to 1-h (Coc1h) access. Fourteen days after an eight-day protocol of cocaine selfadministration, all subjects received one infusion of cocaine. Coc1h animals showed enhanced c-Fos reactivity in dopaminergic mesocorticolimbic brain regions and a sensitized locomotor response to IV cocaine. In contrast, both the neural and behavioral sensitization to cocaine was diminished in Coc6h animals. These data suggest that the transition to escalating patterns of drug use is associated with neuroadaptive changes that counteract those initially associated with controlled stable patterns of drug use. D

1981

Like other reinforcing stimuli, drug effects may vary with the reinforcement history of an individual. Data are presented which demonstrate that histories contribute to individual differences in response to reinforcement contingencies and modification of maladaptive behavioral persistence. Possible relevance of these findings to an understanding of drug effects in humans is discussed.

1967

2 has existed for at least 3000 years (Terry, C. E., and Pellens, M. , 1928) , oowever the relation between drug dependence and basic learning phen:mena has been a relatively recent discovery. Evidence of such a relation was first suggested by clinical observations (Kolb, L., 1939) and anina.l experiments (Spfigg, S. D. S., 1940; Massennan, J. H., and Yum, K. S., 1946), indicating that drugs can have effects similar to t:h:>se of known reinforcing events in openmt conditioning. It was not until the mid-1950's, however, that experinental evidence definitely relating operant conditioning to drug dependence was presented. In general, operant behavior is controlled by its consequences. The specific consequence which strengthens the preceding behavior is called a reinforcer. In 1955 uorphine Was sh::>wn to serve as a reinforcer for physically deperrlent rats (Headlee, C. P., Coppock, H. toJ., and Nichols, J. R., 1955), much as food is a re:inforcer for a hungry aninaJ.. The fact that drugs can serve as re:inforcers for operant responses has been widely confirmed. Procedures which provide an:i:rrals with the opportunity to inject themselves with drug solutions (such as figure ) (Iavis,

2014

This Research Topic in Addictive Disorders and Behavioral Dyscontrol, a section of the journal Frontiers in Psychiatry, focuses on motivational mechanisms underlying substance use, abuse, and dependence. This is an important topic in addiction research, since most psychobiological models of drug addiction consider the motivational or reinforcing aspects of drugs to be the central drive for drug use [for an extensive overview of craving and motivationbased addiction models, see a review by Skinner and Aubin (1)]. However, motivational models alone do not seem to fully cover the complexity of addictive behaviors observed in humans, especially in relation to the more chronic, highly relapsing patterns of addiction. In recent years, habit formation theory has become more prominent for explaining the persistent pattern of addiction despite decreasing reinforcing properties of the drug and increasing negative consequences of continued drug use. According to this model, there is a shift from motivated goaldirected behavior toward more automatic and habitual behavior over the course of long-term drug abuse, which is extensively described by . Within this framework, which is derived primarily from animal studies, habits and goal-directed behaviors (the latter being behavior motivated by the desirability of the goal) are opposing ends of the spectrum. However, human behavior is more complex than observed in laboratory animal settings, as is confirmed by clinical observations, and translation from animal to human behavior remains a challenge. Moreover, motivations and habits could be more intertwined than previously assumed. Therefore, some questions rise considering the construct of habits: is habitual behavior completely devoid of motivational underpinnings (i.e., goal-directedness) or is it possible that motivation still plays a role in habitual behavior? Moreover, is habit a unitary construct or are there different types of habituation? In this article, we present considerations in the context of human addiction and motivation in order to open the discussion toward a more careful consideration of the concept of habit and its role in drug addiction.

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2007

In animal models considerable evidence suggests that increased motivation to seek and ingest drugs of abuse are related to conditioned and sensitized activations of the mesolimbic dopamine (DA) system. Direct evidence for these phenomena in humans, though, is sparse. However, recent studies support the following. First, the acute administration of drugs of abuse across pharmacological classes increases extracellular DA levels within the human ventral striatum. Second, individual differences in the magnitude of this response correlate with rewarding effects of the drugs and the personality trait of novelty seeking. Third, transiently diminishing DA transmission in humans decreases drug craving, the propensity to preferentially respond to reward-paired stimuli, and the ability to sustain responding for future drug reward. Finally, very recent studies suggest that repeated exposure to stimulant drugs, either on the street or in the laboratory, can lead to conditioned and sensitized behavioral responses and DA release. In contrast to these findings, though, in individuals with a long history of substance abuse, drug-induced DA release is decreased. This diminished DA release could reflect two different phenomena. First, it is possible that drug withdrawal related decrements in DA cell function persist longer than previously suspected. Second, drug-paired stimuli may gain marked conditioned control over the release of DA and the expression of sensitization leading to reduced DA release when drug-related cues are absent. Based on these observations a two-factor hypothesis of the role of DA in drug abuse is proposed. In the presence of drug cues, conditioned and sensitized DA release would occur leading to focused drug-seeking behavior. In comparison, in the absence of drug-related stimuli DA function would be reduced, diminishing the ability of individuals to sustain goal-directed behavior and long-term objectives. This conditioned control of the expression of sensitized DA release could aggravate susceptibility to relapse, narrow the range of interests and perturb decision-making, accounting for a wide range of addiction related phenomena.

Drug and Alcohol Dependence, 1993

Problems in the application of exposure techniques to the management of long term dishabituation in addicts are discussed in the light of human and animal evidence. Extinction and habituation of responses to drug cues or drug aftereffects are unstable and strongly dependent on context, thus limiting the effectiveness of cue exposure treatments in the prevention of relapse. Several strategies are suggested to improve the stability of extinction and habituation in order to enduringly prevent relapse in addictions. (i) Warning patients about the episodic resurgence of unexpected urges or cravings precipitated by conditioned contexts and exposing them to such contexts. (ii) To obtain a maximum protection against relapse, extinction should 'recreate' all the original learning contexts (i.e. all possible drug cues). (iii) The behavioral chains involved in self administering drugs ought to be incorporated into cue exposure treatments (without permitting consummatory responses) in order to decrease their signal value as cues for drugs.

Pharmacology, 2007

3) reward allostasis, (4) an increase in the incentive salience of drug-associated stimuli, (5) an increase in the reinforcing strength of the drug reinforcer relative to alternative reinforcers, or (6) habit formation. From the pharmacological perspective, models 1-3 allow predictions about the change in the shape of drug dose-effect curves that are based on mathematically defined models governing receptor-ligand interaction and signal transduction. These predictions are tested in the present review, which also describes the other currently championed models for drug use escalation and other components of apparent 'reinforcement' (in its original meaning, like 'tolerance' or 'sensitization', a purely descriptive term). It evaluates the animal experimental approaches employed to support or prove the existence of each of the models and reinforcement components, and recapitulates the clinical evidence, which strongly suggests that escalation of drug use is predominantly based on an increase in the frequency of intoxication events rather than an increase in the dose taken at each intoxication event. Two apparent discrepancies in animal experiments are that (a) sensitization to overall reinforcement has been found more Abstract Escalation of drug use, a hallmark of drug dependence, has traditionally been interpreted as reflecting the development of tolerance to the drug's effects. However, on the basis of animal behavioral data, several groups have recently proposed alternative explanations, i.e. that such an escalation of drug use might not be based on (1) tolerance, but rather be indicative of (2) sensitization to the drug's reinforcing effect, Zernig et al. Pharmacology 2007;80:65-119 66 often for psychostimulants than for opioids, and that (b) tolerance to the reinforcing and other effects has been observed more often for opioids than for cocaine. These discrepancies are resolved by the finding that cocaine levels seem to be more tightly regulated at submaximum reinforcing levels than opioid levels are. Consequently, animals selfadministering opioids are more likely to expose themselves to higher above-threshold doses than animals self-administering psychostimulants, rendering the development of tolerance to opioids more likely than tolerance to psychostimulants. The review concludes by making suggestions on how to improve the current behavioral experimental approaches.

Journal of Neuropsychiatry, 2008

Persons recovering from addiction must refrain from drug use even when the opportunity to use exists. Understanding how behavioral response to drug reward opportunities is modified is key to treating addiction. Most effective behavioral therapies encourage patients to increase reinforcement opportunities by engaging unidentified sources of nondrug reward. The authors integrate transdisciplinary research on the brain and behavioral effects of increasing reward availability to demonstrate one neurobiological mechanism by which behavioral therapies help patients abstain. Explicating neurobiological processes underlying psychotherapy provides predictions about the interaction between dopaminergic medications and therapy and the impact of individual differences in dopamine receptor expression on addiction vulnerability.

Psychopharmacology, 1992

Repeated administration of opioid drugs results in tolerance, a lessening of the drug's effect. There is pre-clinical evidence suggesting a conditioning component to drug tolerance. In the present study, six former opiate dependent subjects received i.v. opiate either by un-signalled infusion or by signalled self-injection and the effects were compared with those of saline under double-blind conditions. The subjects' pre-injection rituals constitute a signal which reliably predict the appearance of the opiate. These rituals produced drug-opposite physiological responses which resulted in an attenuation of the effects of the drug. Thus, tolerance was observed when the subjects injected the opiate, but not when the same dose was received by un-signaled intravenous infusion. These results are consistent with a conditioning explanation for the observed drug tolerance.

Addiction, 2000

The question of addiction speci cally concerns (1), the process by which drug-taking behavior, in certain individuals, evolves into compulsive patterns of drug-seeking and drug-taking behavior that take place at the expense of most other activities and (2), the inability to cease drug-taking; the problem of relapse. In this paper current biopsychological views of addiction are critically evaluated in light of the "incentivesensitization theory of addiction", which we rst proposed in 1993, and new developments in research are incorporated. We argue that traditional negative reinforcement, positive reinforcement, and hedonic accounts of addiction are neither necessary nor suf cient to account for compulsive patterns of drug-seeking and drug-taking behavior. Four major tenets of the incentive-sensitization view are discussed. These are: