Gery Schulteis

Animal models of drug craving

Drug craving, the desire to experience the effect(s) of a previously experienced psychoactive substance, has been hypothesized to contribute significantly to continued drug use and relapse after a period of abstinence in humans. In more theoretical terms, drug craving can be conceptualized within the framework of incentive motivational theories of behavior and be defined as the incentive motivation to self-administer a psychoactive substance. The incentive-motivational value of drugs is hypothesized to be determined by a continuous interaction between the hedonic rewarding properties of drugs (incentive) and the motivational state of the organism (organismic state). In drug-dependent individuals, the incentive-motivational value of drugs (i.e., drug craving) is greater compared to non-drug-dependent individuals due to the motivational state (i.e., withdrawal) developed with repeated drug administration. In this conceptual framework, animal models of drug craving would reflect two aspects of the incentive motivation to self-administer a psychoactive substance. One aspect would be the unconditioned incentive (reinforcing) value of the drug itself. The other aspect would be relatively independent of the direct (unconditioned) incentive value of the drug itself and could be reflected in the ability of previously neutral stimuli to acquire conditioned incentive properties that could elicit drug-seeking and drug-taking behavior. Animal models of drug craving that permit the investigation of the behavioral and neurobiological components of these two aspects of drug craving are reviewed and evaluated. The models reviewed are the progressive ratio, choice, extinction, conditioned reinforcement and second-order schedule paradigms. These animal models are evaluated according to two criteria that are established herein as necessary and sufficient criteria for the evaluation of animal models of human psychopathology: reliability and predictive validity. The development of animal models of drug craving will have heuristic value and allow a systematic investigation of the neurobiological mechanisms of craving.

Ethanol Self-Administration Restores Withdrawal-Associated Deficiencies in Accumbal Dopamine and 5-Hydroxytryptamine Release in Dependent Rats

Basal forebrain dopamine (DA) and 5-HT neurotransmission has been implicated in the mediation of the acute reinforcing actions of ethanol. Neuroadaptation theories predict that compensatory changes in neurochemical systems that are activated by alcohol acutely may underlie symptoms of withdrawal after chronic administration. To test this hypothesis, the release of DA and 5-HT was monitored by microdialysis in the nucleus accumbens of dependent male Wistar rats at the end of a 3–5 week ethanol (8.7% w/v) liquid diet regimen, during 8 hr of withdrawal, and during renewed availability of ethanol involving (1) the opportunity to operantly self-administer ethanol (10% w/v) for 60 min, followed by (2) unlimited access to the ethanol-liquid diet. Results were compared to control groups pair-fed with ethanol-free liquid diet and trained to self-administer either ethanol or water. In nondependent rats, operant ethanol self-administration increased both DA and 5-HT release in the NAC. Withdrawal from the chronic ethanol diet produced a progressive suppression in the release of these transmitters over the 8 hr withdrawal period. Self-administration of ethanol reinstated and maintained DA release at prewithdrawal levels but failed to completely restore 5-HT efflux. 5-HT levels recovered rapidly, however, within 1 hr of reexposure to ethanol liquid diet. These findings suggest that deficits in accumbal monoamine release may contribute to the negative affective consequences ethanol withdrawal and, thereby, motivate ethanol-seeking behavior in dependent subjects.

Suppression of corticotropin-releasing factor in the amygdala attenuates aversive consequences of morphine withdrawal.

The central nucleus of the amygdala is a CRF-containing limbic brain site which mediates both fear-like and avoidance behaviors, and intra-amygdala administration of a CRF antagonist blocks the increase in anxiogenic-like behavior characteristic of ethanol withdrawal. In order to evaluate the role of brain CRF in negative motivational states associated with other classes of abused dings, the present studies examined the effects of suppression of amygdala CRF systems on the characteristic aversive state of precipitated withdrawal in morphine-dependent subjects. In a place conditioning paradigm, administration of a CRF antagonist, α-helical CRF (9–41) (250 ng], bilaterally into the central nucleus of amygdala, reversed the withdrawal-induced conditioned place aversion produced by injection of the opiate antagonist, mothylnaloxonium [500 ug], into the same site. In a conditioned operant suppression paradigm, impairment of CRF neurons by immu-no-targeted toxins administered into the central nucleus of amygdala, one month prior to testing, attenuated the decrease in response rate produced by exposure to distinctive sensory cues associated previously with systemic administration of naloxone [25 μg/kg s.c.] in morphine-dependent subjects. These results indicate that suppression of intra-amygdala CRF systems weakens the aversive stimulus properties of conditioned opiate withdrawal, and suggest a general role for CRF in coordinating behavioral responses to negative motivational effects of drug withdrawal.

Chronic Acamprosate Eliminates the Alcohol Deprivation Effect While Having Limited Effects on Baseline Responding for Ethanol in Rats

Acamprosate (calcium-acetyl homotaurinate) is a relatively new compound developed for the treatment of alcoholism and has been shown to be effective in attenuating relapse in human alcoholics. In the current study, the effects of this drug were further examined using an animal model of oral ethanol self-administration in a limited access paradigm. Male Wistar rats were trained to respond for ethanol (10% w/v) or water in a two-lever free-choice operant condition. Acute administration of acamprosate (400 mg/kg) reduced ethanol consumption and increased responding for water. Chronic administration of lower daily doses of acamprosate (100 and 200 mg/kg) blocked the increased ethanol consumption typically observed in rats after an imposed abstinence period. This effect of acamprosate was selective for ethanol, as responding for water was unaffected at any dose tested. These results with rats suggest a model by which to explore the mechanisms for anti-relapse effects of acamprosate.

Brain Penetrance, Receptor Occupancy and Antistress In Vivo Efficacy of a Small Molecule Corticotropin Releasing Factor Type I Receptor Selective Antagonist

The present studies were designed to evaluate the competitive binding properties and functional effects of a novel nonpeptide CRF1 receptor antagonist, R121919. R121919 administered in doses of 0.63 to 20 mg/kg p.o. 60 min pretest in Wistar rats dose dependently attenuated the swim stress-induced anxiogenic-like behavior in the elevated plus-maze model of anxiety. Moreover, receptor autoradiography revealed that R121919 dose-dependently occupied brain CRF1 receptors in subjects tested in the plus-maze experiment. Orally administered doses of up to 20 mg/kg R121919 also blunted basal and swim stress-induced pituitary-adrenocortical activation, produced additional anxiolytic-like behavioral actions in the defensive withdrawal and defensive burying paradigms, and functionally antagonized the locomotor stimulatory properties of exogenously administered CRF. Taken together, these results suggest that the anxiolytic-like efficacy of R121919 in attenuating the stress-, novelty-, shock-, and CRF-induced increases in behavioral arousal is correlated with competitive blockade of central CRF1 receptors.

Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers.

Background:Although the preclinical literature suggests that cannabinoids produce antinociception and antihyperalgesic effects, efficacy in the human pain state remains unclear. Using a human experimental pain model, the authors hypothesized that inhaled cannabis would reduce the pain and hyperalgesia induced by intradermal capsaicin. Methods:In a randomized, double-blinded, placebo-controlled, crossover trial in 15 healthy volunteers, the authors evaluated concentration–response effects of low-, medium-, and high-dose smoked cannabis (respectively 2%, 4%, and 8% 9-&dgr;-tetrahydrocannabinol by weight) on pain and cutaneous hyperalgesia induced by intradermal capsaicin. Capsaicin was injected into opposite forearms 5 and 45 min after drug exposure, and pain, hyperalgesia, tetrahydrocannabinol plasma levels, and side effects were assessed. Results:Five minutes after cannabis exposure, there was no effect on capsaicin-induced pain at any dose. By 45 min after cannabis exposure, however, there was a significant decrease in capsaicin-induced pain with the medium dose and a significant increase in capsaicin-induced pain with the high dose. There was no effect seen with the low dose, nor was there an effect on the area of hyperalgesia at any dose. Significant negative correlations between pain perception and plasma &dgr;-9-tetrahydrocannabinol levels were found after adjusting for the overall dose effects. There was no significant difference in performance on the neuropsychological tests. Conclusions:This study suggests that there is a window of modest analgesia for smoked cannabis, with lower doses decreasing pain and higher doses increasing pain.

Time-dependent quantifiable withdrawal from ethanol in the rat: effect of method of dependence induction.

The importance of temporal factors on the presence and severity of ethanol withdrawal signs in the rat was quantified using rating scale, tremor, and acoustic startle paradigms. Ethanol dependence was induced in naive male Wistar rats by liquid diet administration (n = 21) or vapor inhalation (n = 13). Subjects were analyzed for intensity and duration of physiological ethanol dependence in repeated-measures trials conducted over 72 h post-ethanol withdrawal. Indices of dependence included CNS hyperexcitability manifested as observable withdrawal signs increased acoustic startle reactivity, and tremor activity. Data analysis revealed that withdrawal signs, observed and elicited, generally reached peak intensities between 12 and 24 h postwithdrawal and were more readily observed following vapor inhalation than liquid diet administration, probably because of the higher BALs attained with the inhalation procedure. Results suggest a difference in time course observed with the different behavioral paradigms. In particular, a possible sensitization to startle stimuli was exhibited independent of both startle intensity and dependence induction method. The neural substrates governing these behavioral time course differences remain to be determined.

Reinforcement processes in opiate addiction: A homeostatic model

The development of tolerance and dependence has traditionally been considered an integral aspect of the drug addiction process, and opiate dependence has been studied extensively as a model system in this regard. However, recent emphasis on the positive reinforcing properties of drugs has led to the suggestion that tolerance, dependence, and withdrawal may be of secondary or even negligible importance in motivating compulsive drug use. The current article argues for an integrated view of addiction in the form of a homeostatic neuroadaptation model which emphasizes the motivational significance of both the positive affective state produced by opiates and the negative affective state characteristic of drug withdrawal. The model is supported by evidence at both the behavioral and neural systems levels of analysis. Understanding the important distinction between somatic and affective components of opiate withdrawal is key to recognizing the factors which contribute to the motivational significance of opiate dependence and withdrawal. In addition, the critical role of conditioning processes in the maintenance of compulsive drug use and relapse after periods of abstention is discussed. Finally, it is argued that both the positive reinforcement produced by acute administration of a drug and the negative affective state produced by withdrawal are common to multiple classes of abused drugs, suggesting that an understanding of homeostatic neuroadaptation within motivational systems provides a key to the etiology, treatment and prevention of drug addiction.

Opponent process and drug dependence: Neurobiological mechanisms

The development of tolerance and dependence has long been considered an integral part of drug addiction, but has lost its impact in drug dependence theory due to new emphasis on the neurobiological substrates for the positive reinforcing properties of drugs. The present article reemphasizes opponent process theory as a model for the motivational effets of drug dependence. Further, it explores the neurobiology of the adaptations of brain motivational systems postulated to underlie some aspects of drug dependence. The same neural substrates hypothesized to be involved in the acute reinforcing properties of drugs (located within the basal forebrain regions of nucleus accumbens and amygdala) are hypothesized to be altered during chronic drug treatment to produce the negative motivational states characterizing drug withdrawal. Within these brain regions, both the neurochemical system (s) on which the drug has its primary actions, and other neurochemical systems may undergo adaptations to chronic presence of the drug. An understanding of such motivational adaptations leads to predictions about the etiology, treatment and prevention of drug addiction.

Anxiogenic-like effects of spontaneous and naloxone-precipitated opiate withdrawal in the elevated plus-maze.

Withdrawal from opiates and other drugs of abuse in human addicts is associated with a state of anxiety that may be of motivational relevance for the maintenance of drug addiction. Previous attempts with rats to model the anxiogenic-like effects of opiate withdrawal using the elevated plus-maze have met with mixed success. The current study sought to determine whether spontaneous and naloxone-precipitated opiate withdrawal could be observed reliably in rats made dependent on morphine through implantation of two morphine pellets (75 mg morphine base each). Seventy-two hours after implantation of either morphine or placebo pellets, rats were tested in the elevated plus-maze. In Experiment 1, pellets were removed 8 or 12 h prior to test; results indicated an anxiogenic-like effect (reduction in time spent in the open arms) of opiate withdrawal at 8 but not 12 h postpellet removal. In Experiment 2, pellets were not removed, but withdrawal was precipitated with naloxone (0.003-0.03 mg/kg s.c.). Naloxone dose dependently precipitated a reduction in exploration of the open arms of the plus-maze. The results suggest that both spontaneous and precipitated withdrawal from continuous morphine administration via pellet implantation result in demonstrable anxiogenic-like effects in the plus-maze.