Testing the abuse liability of anxiolytic and hypnotic drugs in humans.

This paper represents a comprehensive review of laboratory studies investigating the abuse liability of anxiolytic and hypnotic drugs in humans. The subjective effects of these drugs, most of which are either barbiturates or benzodiazepines, have been measured using various self-report questionnaires and their reinforcing effects have been studied using self-administration and choice procedures. Studies using both subjective and reinforcing effects reveal orderly relations between the two main chemical classes of anxiolytic/hypnotics (e.g. barbiturates are associated with higher abuse liability than benzodiazepines), between different doses of the drugs (e.g. higher doses are usually associated with higher abuse liability) and among different compounds within a class. The subjective and reinforcing effects of barbiturates and benzodiazepines depend critically upon the subject populations that are tested and it is argued that individuals with histories of drug abuse provide a more sensitive indicator of abuse liability than healthy volunteers. Several principles of abuse liability testing are discussed, including the selection of an appropriate subject population, the use of blind drug administration procedures, the comparison of a test compound to an appropriate standard, the inclusion of a placebo and a wide range of doses of the test drug and the use of multiple measures of likelihood of abuse.     

PCP and Hallucinogens

In this review phencyclidine and related arylcyclohexylamine and hallucinogens, using LSD as the prototype, are considered as two distinct classes of abused drugs. Within these classes drugs that are found on the street are discussed, and a current epidemiological summary is provided. The abuse liability and dependence potential of these drugs are evaluated by considering four major determinants of their abuse. First, is the ability of a drug to function as a positive reinforcer and increase the probability of operant behavior leading to its delivery. Animal data describing the reinforcing effects of PCP are reviewed with respect to the influence of variable controlling drug-reinforced behavior; however, there are no animal models of hallucinogen-reinforced behavior. Several methods of quantifying reinforcing efficacy are discussed. A second determinant is the subjective effects of the respective drugs. These effects are described and compared across drugs based on clinical reports in humans and drug discrimination studies in animals. A third determinant is the behavioral and physiological toxicity that results from acute and chronic use of these drugs. Clinical reports and results of sensitive tests that have been developed for laboratory animals are reviewed. A fourth determinant is the dependence potential that exists for these drugs, measured by tolerance development and the extent to which behavioral and physiological disturbances occur when drug use is terminated.     

Assessment of abuse liability of stimulant drugs in humans: a methodological survey.

Stimulant drugs have been illicitly consumed for non-medical purposes for centuries. Within the past several decades procedures for assessing the abuse liability of a compound prior to marketing have been developed, which should limit the introduction of new stimulants with high abuse liability to the public. Drugs with high abuse liability are positive reinforcers in that they maintain behavior leading to their consumption. Assessment of abuse liability has traditionally involved a comparison of the profile of effects of a known drug of abuse to that of a drug with unknown abuse liability. With respect to stimulant drugs, amphetamine and cocaine may be considered prototypic stimulants with high abuse liability. Various procedures have been used to study abuse liability including the measuring of (1) subjective effects, (2) drug 'liking', (3) estimates of value, (4) the accuracy of drug identification, (5) the ability of trained subjects to discriminate one drug from another and (6) drug self-administration. In this paper the behavioral effects of a number of stimulant drugs will be compared along these dimensions and the effects along each dimension will be related to each drugs' known abuse liability. Dissociations among the various measures will also be described, and the implications of these dissociations discussed. We conclude that the best single assessment of abuse liability is obtained from drug self-administration studies, but that the most accurate assessment of abuse liability is obtained when the effects of a drug are evaluated along as many of these dimensions as possible.     

Discriminative stimulus, reinforcing, physical dependence, and antinociceptive effects of oxycodone in mice, rats, and rhesus monkeys

Despite oxycodone's (4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one) history of clinical use and the attention it has received as a drug of abuse, few reports have documented its pharmacology's relevance to its abuse or its mechanism of action. The purposes of the present study were to further characterize the analgesic effects of oxycodone, its mechanism of action, and its effects in terms of its relevance to its abuse liability. The results indicate that oxycodone had potent antinociceptive effects in the mouse paraphenylquinone writhing, hot-plate, and tail-flick assays, in which it appeared to be acting as a mu-opioid receptor agonist. It generalized to the heroin discriminative stimulus and served as a positive reinforcer in rats and completely suppressed withdrawal signs in morphine-dependent rhesus monkeys. These results suggest that the analgesic and abuse liability effects of oxycodone are likely mediated through mu-opioid receptors and provide the first laboratory report of its discriminative stimulus, reinforcing, and morphine cross-dependency effects.     

Drugs of abuse: behavioural principles, methods and terms.

Current understanding of drug abuse has been greatly influenced by the emphasis on drug-seeking behaviour as the common element. The three main attributes of drugs that maintain, direct and regulate drug-seeking behaviour are their positively reinforcing and discriminative and aversive stimulus properties. Each process may be analysed in terms of underlying behavioural and neural mechanisms that are mutually complementary and interactive. Environmental stimuli conditioned to the effects of the drugs also play a key role in eliciting and maintaining drug-seeking behaviour. Both the behavioural and the neural mechanisms are subject to modulating variables such as social, environmental and genetic factors, including the previous behavioural and pharmacological history of the individual. Thus, the behavioural approach to addiction does not preclude important roles for other factors, but rather seeks to integrate them into a comprehensive theoretical framework strongly linked to empirical data.     

Discriminative and reinforcing stimulus effects of nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys

Concurrent cigarette smoking and cocaine use is well documented. However, the behavioral pharmacology of cocaine and nicotine combinations is poorly understood, and there is a need for animal models to examine this form of polydrug abuse. The purpose of this study was twofold: first to assess the effects of nicotine on the discriminative stimulus effects of cocaine, and second, to study self-administration of nicotine/cocaine combinations in a novel polydrug abuse model. In drug discrimination experiments, nicotine increased the discriminative stimulus effects of low cocaine doses in two of three monkeys, but nicotine did not substitute for cocaine in any monkey. Self-administration of cocaine and nicotine alone, and cocaine + nicotine combinations was studied under a second-order fixed ratio 2, variable ratio 16 (FR2[VR16:S]) schedule of reinforcement. Cocaine and nicotine alone were self-administered in a dose-dependent manner. The combination of marginally reinforcing doses of cocaine and nicotine increased drug self-administration behavior above levels observed with the same dose of either cocaine or nicotine alone. These findings indicate that nicotine may increase cocaine's discriminative stimulus and reinforcing effects in rhesus monkeys, and illustrate the feasibility of combining cocaine and nicotine in a preclinical model of polydrug abuse. Further studies of the behavioral effects of nicotine + cocaine combinations will contribute to our understanding the pharmacology of dual nicotine and cocaine dependence, and will be useful for evaluation of new treatment medications.     

Comparative effects of dextromethorphan and dextrorphan on nicotine discrimination in rats

While the role of dextrorphan and dextromethorphan as N-methyl-d-aspartate (NMDA) receptor antagonists has received considerable research attention, their effects on nicotinic acetylcholine receptors (nAChR) has been less well characterized. Recent in vitro and in vivo research has suggested that these drugs noncompetitively block alpha3beta4*, alpha4beta2, and alpha7 nAChR subtypes and antagonize nicotine's antinociceptive and reinforcing effects. Both drugs were most potent at blocking alpha3beta4* AChR. This study investigated the effects of dextrorphan and dextromethorphan on nicotine's discriminative stimulus effects. Three groups of rats were trained in a two-lever drug discrimination procedure to discriminate 0.4 mg/kg s.c. nicotine from saline. Nicotine dose-dependently substituted for itself in all three groups. In contrast, when dextrorphan (group 1) or dextromethorphan (group 2) were injected i.p., neither substitution for nor antagonism of nicotine was observed for either drug. Since i.p. administration allows substantial metabolism of dextromethorphan to its parent compound dextrorphan, the two drugs were also tested following s.c. administration (group 3). Discrimination results were similar across both routes of administration, in that neither substitution nor antagonism occurred, however, s.c. administration reduced response rates to a much greater extent than did i.p. administration. Previous work suggests that beta2 subunits are crucial for mediation of nicotine's discriminative stimulus effects and may play a role in its reinforcing effects, albeit other research suggests a role for alpha3beta4* nicotinic receptors in the latter. Our results suggest that alpha3beta4* nicotinic receptors do not play a major role in nicotine's discriminative stimulus effects. Further, they suggest that the role of cholinergic mediation of the behavioral effects of dextrorphan and dextromethorphan related to the abuse properties of nicotine may be minimal.     

Super-additive interaction of the reinforcing effects of cocaine and H1-antihistamines in rhesus monkeys

Histamine H1 receptor antagonists can be sedating and have behavioral effects, including reinforcing and discriminative stimulus effects in non-humans, that predict abuse liability. Previous research has suggested that antihistamines can enhance the effects of some drugs of abuse. We have reported a synergistic interaction between cocaine and diphenhydramine (DPH) in a self-administration assay with monkeys. The present study was designed to extend those findings to other combinations of cocaine and DPH, and to the mixture of cocaine and another H1-antihistamine, pyrilamine. Rhesus monkeys were prepared with chronic i.v. catheters and allowed to self-administer cocaine, DPH or pyrilamine alone or as mixtures under a progressive-ratio schedule of reinforcement. Cocaine, DPH and pyrilamine alone maintained self-administration and cocaine was the stronger reinforcer. When cocaine was combined with DPH or pyrilamine in a 1:1, 1:2 or 2:1 ratio of the ED₅₀s, the combinations were super-additive as reinforcers. Reinforcing strength of the combinations was greater than that of the antihistamines alone but not greater than cocaine. The data support the prediction that the combination of cocaine and histamine H1 receptor antagonists could have enhanced potential for abuse relative to either drug alone. The interaction may involve dopamine systems in the CNS.     

Relation between discriminative and reinforcing effects of midazolam,pentobarbital, chlordiazepoxide,zolpidem, and imidazenil in baboons

Abstract Rationale. If a psychoactive drug shares discriminative effects with one that maintains self-administration, it is often inferred that the test drug is likely to be self-administered and to have abuse liability. This presumed predictive relationship has not been studied directly, however. Objective. To determine at the level of the individual subject (1) whether a novel drug dose that shares discriminative effects with a reinforcing drug dose also will serve as a reinforcer, and (2) whether the results of generalization tests for drugs pharmacologically similar to the training drug predict whether the test drugs will or will not be self-administered. Methods. Baboons were trained to discriminate midazolam (0.32 mg/kg, IV) from saline and also under a schedule of IV drug reinforcement. At the beginning of a period of self-administration, the first self-injection was followed 10 min later by a drug discrimination test session. The baboon then had the opportunity to self-administer the same dose 24 h/day (3-h timeout after each injection). A second drug discrimination test followed the last self-injection of the condition. Results. Zolpidem and imidazenil shared discriminative effects with midazolam. Zolpidem was reinforcing in all baboons, but imidazenil was not. Chlordiazepoxide partially shared discriminative effects with midazolam, and the rate of self-administration was low. Pentobarbital did not share discriminative effects with midazolam, but was reinforcing. For all drugs, some doses did not share discriminative effects with midazolam but were reinforcing. Generalization gradients from tests after the last self-injection were similar to those after the first self-injection. Conclusions. The discriminative effect of a drug in relation to a training drug of the same pharmacological class is not isomorphic with its reinforcing effectiveness. Electronic Publication     

Flupenthixol as a potential pharmacotreatment of alcohol and cocaine abuse/dependence.

Preclinical and clinical studies suggest that the mesolimbic dopamine system plays a major role in mediating the reinforcing effects of drugs of abuse, including alcohol and psychostimulants, and that pharmacological blockade of dopamine D1 and/or D2 receptors may reduce intake of these drugs, as well as relapse rates. The neuroleptic flupenthixol, which has dopamine D1 and D2 receptor antagonist properties and which may be given intramuscularly in order to improve compliance, has been studied as a possible anti-craving drug in substance abuse disorders. Flupenthixol has been shown to attenuate the discriminative stimulus effects of psychostimulants, as well as their intake in animal models of drug abuse. In addition, the compound was found to reduce alcohol intake in a rat model of alcoholism, but the 'anti-alcohol' effect appeared to be only weakly selective and nonspecific. Clinically, the drug has been studied in alcoholics, cocaine addicts and in patients with comorbid psychiatric disorders. Although the data base is still limited and a number of recent trials have not been completely analyzed, these studies suggest that flupenthixol may be useful in decreasing cocaine consumption. Recent studies in alcoholism, however, have shown disappointing results. A number of pilot studies suggest that probably the most promising area may be the treatment of substance abuse/dependence in patients with comorbid psychiatric disorders. Future studies should focus on dosing issues, the differentiation between short- and long-term effects and the identification of subgroups of patients with particular psychopathology.     

Effects of food deprivation and satiation on sensitivity to the discriminative-stimulus effects of pentobarbital in pigeons and morphine in rats

Food deprivation can produce a substantial increase in the self-administration of drugs of abuse, suggesting that food deprivation increases their reinforcing properties. This finding has been replicated with a wide variety of reinforcing drugs. The present experiments examined the effects of food deprivation and satiation on the discriminative stimulus properties of drugs, to determine whether food deprivation affects the discriminative-stimulus effects of drugs in a similar manner. Using pigeons that were trained to discriminate 5mg/kg i.m. pentobarbital from saline, dose-effect curves were determined under both food-deprivation conditions (80% free-feeding body weight) and partial food-satiation conditions (25% and 50% of the amount of full satiation). It was found that generalization curves for both pentobarbital and saline were similar at all levels of food deprivation. In a second set of experiments, rats were trained to discriminate 10mg/kg i.p. morphine from saline, and the discriminative properties of morphine were then tested when the animals were either food-deprived or after a 15min supplemental feeding. The ED(50) value for the food-deprived condition was comparable to that the food-satiated condition (3.6 vs. 4.8mg/kg, respectively). Thus, in both pigeons and rats, there was little evidence that food deprivation increased sensitivity to the discriminative stimulus properties of drugs. Thus, food deprivation must increase drug self-administration by a mechanism other than by increasing the discriminative stimulus properties of self-administered drugs.     

Application and prospect of drug discrimination in field of drug abuse北大核心CSCD

药物辨别技术是一种研究药物主观刺激效应的行为药理学技术。目前,药物辨别技术已广泛应用于中枢神经系统药物临床前药物研发中,其中最为广泛的是用于药物的精神依赖性评价。该文简要介绍了药物辨别技术的基本原理,初步阐述了药物辨别的主观效应、时程效应、立体特异性和个体差异,以及受体机制等相关特点和应用,并对其在新型精神活性物质致幻剂和大麻类药物方面的应用进行展望。     

Abuse liability studies of opioid agonist-antagonists in humans

Prediction of the abuse liability of a drug before it reaches the market is complicated by the fact that there are many factors that influence the actual abuse of a drug. Laboratory methods used in humans to assess the abuse liability of the opioids are reviewed and illustrative studies of morphine and the agonist-antagonist opioids, pentazocine, butorphanol, nalbuphine and buprenorphine, are presented. Three assessment methods, subjective effect measurement, self-administration and drug discrimination, provide information relevant to measuring reinforcing efficacy, a major determinant of the degree to which a drug is sought and self-administered by abusers. Physical dependence capacity, which can contribute to sustained drug use, is evaluated in direct addiction and substitution/suppression studies. Withdrawal precipitation studies measure antagonist activity which might limit abuse. The results of testing the agonist-antagonist opioids are generally consistent across these various methods and consistent with historical experience with these drugs, suggesting that these methods are useful in predicting abuse liability of novel opioids.     

Interaction of lobeline and nicotinic receptor ligands with the discriminative stimulus properties of cocaine and amphetamine

Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular and plasmalemmal monoamine transporters. Moreover, lobeline has been shown to alter the neurochemical and behavioral effects of psychostimulants. The present study determined the effect of lobeline and drugs selective for nicotinic receptors on the discriminative stimulus properties of low doses of cocaine (1.6 or 5.0 mg/kg) or d-amphetamine (0.3 mg/kg) in rats, using a standard two-lever drug discrimination procedure with food reinforcement. Nicotine substituted for both amphetamine and cocaine. The nicotinic receptor antagonists mecamylamine and hexamethonium did not substitute for or block the cocaine or amphetamine stimulus. In contrast, lobeline substituted for cocaine, but did not substitute for amphetamine. In antagonism tests, lobeline doses that did not substitute for cocaine decreased responding on the cocaine-paired levers. Surprisingly, lobeline did not alter the discriminative stimulus properties of amphetamine. This research further supports the supposition that nicotine, cocaine and amphetamine produce similar, but distinct subjective states. Furthermore, the present findings suggest that lobeline has a complex mechanism of action to disrupt the behavioral effects of drugs of abuse.     

Relative abuse liability of different benzodiazepines in drug abusers

There is a convergence of data from various sources suggesting that there are meaningful differences among the benzodiazepines with respect to their attractiveness as drugs of abuse for drug abusers. Laboratory studies of subjective and reinforcing effects in drug abusers, interviews with drug abusers, clinical judgment of medical professionals, and epidemiological studies all indicate that diazepam, in particular, has a greater abuse liability than many of the other benzodiazepines. Some of the available data also suggest that lorazepam and alprazolam are more diazepam-like in having relatively high abuse liability, while oxazepam, halazepam, and possibly chlordiazepoxide, are relatively low in this regard. These differences in abuse liability among benzodiazepines are analogous to the widely recognized differences in abuse liability within the barbiturate class that have proved to be important in helping guide clinicians' drug prescribing practices.     

Drug discrimination studies

Opioid agonists and agonist/antagonists comprise a heterogeneous body of compounds that can be partitioned into at least three groups on the basis of their discriminative stimulus properties in several animal species: (1) stimulus effects similar to those of morphine or fentanyl and blocked completely by low doses of antagonists, such as naloxone and naltrexone; (2) stimulus effects similar to those of ethylketocyclazocine or nalorphine and blocked by higher doses of antagonists; (3) stimulus effects similar to those N-allylnormetazocine or phencyclidine and not blocked by antagonists. This diversity of stimulus properties is consistent with other evidence that multiple populations of receptors mediate the actions of opioids. In man, drugs in group 1 produce subjective effects that are entirely morphine-like and highly reinforcing whereas drugs in groups 2 and 3 produce dysphoric and psychotomimetic subjective effects. Thus, discriminative stimulus properties of opioids appear to reflect drug actions at the neuronal level that are directly relevant to potential for abuse in man.     

Assessing the abuse potential of methylphenidate in nonhuman and human subjects: a review

Methylphenidate (MPH) is widely used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children, adolescents, and adults. Methylphenidate is clearly effective for the treatment of ADHD, but there is controversy as to whether it has significant abuse potential like other psychostimulants (e.g., D-amphetamine and cocaine). In general, the drug is believed to be abused at rates much lower than those for other stimulants. The present review examines studies that investigated the behavioral pharmacological profile of methylphenidate and discusses how results from these studies address its abuse liability. Using MEDLINE search terms methylphenidate, drug discrimination, reinforcement, self-administration, subjective effects, subject-rated effects, abuse potential, and abuse liability, along with a review of the references from identified articles, 60 studies were located in which the reinforcing, discriminative-stimulus, or subjective effects of methylphenidate were directly assessed in nonhumans or humans. Forty-eight (80.0%) of the studies reviewed indicate that methylphenidate either functions in a manner similar to D-amphetamine or cocaine (e.g., functions as a reinforcer, substitutes fully in drug discrimination experiments), or produces a pattern of subjective effects suggestive of abuse potential. The results are discussed as they pertain to factors that may account for the apparent discrepancy in abuse rates between methylphenidate and other stimulants, including characterization of actual abuse rates, defining abuse and misuse, pharmacokinetic factors, and validity of abuse liability assays.     

Serotonergic receptor subtypes and hallucinogen-induced stimulus control.

More than a quarter century has passed since the demonstration that indoleamine and phenethylamine hallucinogens can function as discriminative stimuli in the rat, and that serotonergic systems are critically involved. During that period our knowledge of the physiology, pharmacology, biochemistry, and molecular biology of serotonergic receptors has increased exponentially; with each advance it has been necessary to reexamine our assumptions regarding hallucinogen-induced stimulus control. Of particular interest is the hypothesis that a drug may act, at a molecular level, upon multiple receptors to produce, at a behavioral level, a compound discriminative stimulus. The salience of the individual elements of such compound stimuli may be influenced by a variety of experimental factors including training dose, pretreatment time, the state of sensitization of the systems being acted upon, and the nature of the drugs chosen for tests of generalization. This article provides examples of experimental approaches to these complexities using selective agonists and antagonists, depletion-induced sensitization, and antagonist correlation analysis.