The concepts of behavioral economics have proven to be useful for understanding the environmental control of overall levels of responding for a variety of commodities, including reinforcement by drug self-administration. These general concepts have implications for the assessment of abuse liability and drug abuse intervention and the formulation of public policy on drug abuse. An essential requirement is the ability to compare the demand for different drugs directly in order to assess relative abuse liability, and to compare demand for the same drug under different environmental and biological interventions to assess their ability to reduce demand. Until now, such comparisons were hampered by the confounding effect of varying drug doses and potencies that prevent quantitative comparisons of demand elasticity--sensitivity of consumption and responding to the constraint of price (effort). In this paper we describe a procedure to normalize demand-curve analysis that permits dose- and potency-independent comparisons of demand across drugs. The procedure is shown to be effective for comparing drug demand within and across the drug classes. The technique permits a quantitative ordering of demand that is consistent with the peak levels of responding maintained by the drugs. The same technique is generalized for the comparison of other types of reinforcers under different biological conditions.

MDMA and its stereoisomers serve as reinforcers in rhesus monkeys. We suggest that stimulation of 5-HT(2A) receptors is integral to the reinforcing effects of MDMA.

The role of duration of action on the relative reinforcing effects of three opioid drugs (fentanyl, alfentanil, and remifentanil) was evaluated. Duration and onset of action were determined using measures of respiratory depression and antinociception after i.v. administration. Effects on minute volume of respiration indicated that each of the three opioids had immediate onsets of action after i.v. administration. Fentanyl's duration of suppression of respiration and antinociception was longer than that of alfentanil, which was longer than that of remifentanil. Reinforcing strength was measured in i.v. self-administration studies in which the fixed ratio resulting in drug administration was increased from one session to the next. Comparisons were made of the behavioral economic variables P max and area under the demand curve (O max ). Remifentanil maintained higher rates of responding than did alfentanil, and alfentanil maintained higher rates of responding than did fentanyl. When normalized demand functions were compared, however, the drugs did not differ significantly from each other in terms of P max or O max . These data agree with those of others who have suggested that duration of action is not an important contributor to drugs' reinforcing strength.Relatively little is known about what properties of drugs of abuse contribute to their reinforcing effects. It is generally acknowledged, however, that stimuli function better as reinforcers if there is relatively little delay between the response and reinforcer delivery (Renner, 1964;de Villiers, 1977). There is some evidence to support the notion that drugs that have fast onsets of action are stronger reinforcers than drugs that have slow onsets of action. Balster and Schuster (1973) and Panlilio et al. (1998), for example, reported that lower rates of behavior were maintained by cocaine when it was delivered slowly compared with more rapid administration. We have found that ketamine, an NMDA antagonist with a rapid onset of action, is as strong a reinforcer as phencyclidine, an NMDA antagonist with a somewhat less rapid onset of action, but much stronger as a reinforcer than dizocilpine, an NMDA antagonist with a slow onset of action (Winger et al., 2002).These latter three drugs vary in their durations as well as their onsets of action, and the contribution of duration of action to the relative reinforcing effects of drugs of abuse is not well documented. Panlilio and Schindler (2000) are among the few who have compared behavior maintained by shorter and longer acting drugs. They found that the ultrashort-acting opioid remifentanil served as a reinforcer when delivered intravenously to rats and that it maintained breakpoints under progressive ratio schedules that were not markedly different from those maintained by the longer-acting opioid heroin. They concluded that duration of action was independent of the ability to serve as a reinforcer.Drugs that act at the -opioid receptor are a natural choice for experimental procedures designed to evaluate th...

Behavioral economic concepts have proven useful for an overall understanding of the regulation of behavior by environmental commodities and complements a pharmacological perspective on drug abuse in several ways. First, a quantitative assessment of drug demand, equated in terms of drug potency, allows meaningful comparisons to be made among drug reinforcers within and across pharmacological classes. Second, behavioral economics provides a conceptual framework for understanding key factors, both pharmacological and environmental, that contribute to reductions in consumption of illicit drugs. Finally, behavioral economics provides a basis for generalization from laboratory and clinical studies to the development of novel behavioral and pharmacological therapies.

The effects of self-administered 3,4-methylenedioxymethamphetamine (MDMA) on behavior and neurochemistry have not been previously studied in laboratory primates. We investigated the capacity of MDMA and its enantiomers to maintain contingent responding over an extended duration, whether any decrements in the reinforcing effects of these compounds would be observed over time, whether such decrements would be MDMA-selective, and whether any neurochemical correlates could be identified. Animals were previously trained to self-administer cocaine, then exposed to periodic substitutions of various doses of racemic MDMA and its enantiomers; full dose-effect curves were generated for each MDMA compound repeatedly over the duration of the study. After approximately 18 months of MDMA self-administration, drug exposure was halted and after at least 2 months drug abstinence, animals were scanned using positron emission tomography (PET) with the vesicular monoamine transporter (VMAT) ligand dihydrotetrabenazine (DTBZ). Shortly thereafter, animals were euthanized, brains were dissected, and samples were assayed for brain monoamines and their metabolites using high-performance liquid chromatography (HPLC), and for VMAT using DTBZ binding. The reinforcing effects of racemic and R(À)-MDMA were reduced over a long series (months) of individual self-administration access periods; the reinforcing effects of S( þ )-MDMA were more resistant to this effect, but were attenuated for one animal. The reinforcing effects of cocaine were not altered by chronic MDMA self-administration, nor was the VMAT binding potential as assessed by PET. Further, there were no measurable decrements in serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or VMAT in any brain regions assayed. The reinforcing effects of MDMA are selectively attenuated by chronic MDMA self-administration, although this behavioral change appears to occur in the absence of any frank neurochemical correlates of toxicity.

High concentrations of cocaethylene (EC), the ethyl ester of benzoylecgonine, were measured in the blood of individuals who had concurrently used cocaine and ethanol. Since the powerful reinforcing effects of cocaine appear to be dependent on inhibition of dopamine reuptake in brain, we compared the effects of EC on the dopamine uptake system and its behavioral effects with those of cocaine. EC was equipotent to cocaine with respect to inhibition of binding of [3H]GBR 12935 to the dopamine reuptake complex, inhibition of [3H]dopamine uptake into synaptosomes and in its ability to increase extracellular dopamine concentration in the nucleus accumbens following its systemic administration to rats. Moreover, in rats, EC and cocaine each increased locomotor activity and rearing to the same extent following i.p. administration. In self-administration studies in primates, EC was approximately equipotent to cocaine in maintaining responding. The in vivo formation of this active, transesterified ethyl homolog of cocaine may contribute to the effects and consequences of combined cocaine and ethanol abuse.

Cocaine addiction and overdose have long defied specific treatment. To provide a new approach, the high-activity catalytic antibody mAb 15A10 was elicited using a transition-state analog for the hydrolysis of cocaine to nontoxic, nonaddictive products. In a model of cocaine overdose, mAb 15A10 protected rats from cocaine-induced seizures and sudden death in a dose-dependent fashion; a noncatalytic anticocaine antibody did not reduce toxicity. Consistent with accelerated catalysis, the hydrolysis product ecgonine methyl ester was increased >10-fold in plasma of rats receiving mAb 15A10 and lethal amounts of cocaine. In a model of cocaine addiction, mAb 15A10 blocked completely the reinforcing effect of cocaine in rats. mAb 15A10 blocked cocaine specifically and did not affect behavior maintained by milk or by the dopamine reuptake inhibitor bupropion. This artificial cocaine esterase is a rationally designed cocaine antagonist and a catalytic antibody with potential for medicinal use.Cocaine is presently abused in the United States by Ϸ2 million hardcore addicts and Ͼ4 million regular users (1). The acute toxicity of cocaine overdose frequently complicates abuse and the potential medical consequences of this syndrome include convulsions and death (1). Despite decades of effort, however, no useful antagonists of cocaine's reinforcing or toxic effects have been identified. This failure is due, in part, to the drug's mechanism of action as a competitive blocker of neurotransmitter reuptake (2). Cocaine's blockade of a dopamine reuptake transporter in the central nervous system is hypothesized to be the basis of its reinforcing effect (3), and the difficulties inherent in blocking a blocker appear to have hindered the development of antagonists for addiction. Further, dopamine appears to play such a general role in many types of behavior that dopamine receptor agonists and antagonists that might be expected to modify cocaine's actions do not act selectively (4). For cocaine overdose, this problem is compounded by the binding of cocaine at high concentrations to multiple receptors in the central nervous system and the cardiovascular system. For example, blockade of serotonin reuptake transporters contributes to cocaine-induced convulsions (5); dopamine reuptake blockade (5, 6), and dopamine D 1 receptor binding (6) contribute to lethality; and blockade of norepinephrine-reuptake transporters, as well as blockade of cardiac myocyte Na ϩ channels and other ion transporters, contribute to arrhythmias and sudden death (7). Thus, cocaine abuse and toxicity may well pose insurmountable problems for the classical receptor-antagonist approach.These difficulties in developing antagonists for cocaine led us to embark on an alternative approach-to intercept cocaine with a circulating agent, thereby rendering it unavailable for receptor binding. An antibody is a natural choice for a circulating interceptor, and, in 1974, antiheroin antibodies were shown to block heroin-induced reinforcement in a rhesus monkey (8). However...

This article deals with some of the recent evidence bearing on the issues of the liability of benzodiazepines to lead to abuse, dependence, and adverse behavioral effects. Reviews of epidemiological, clinical and experimental literature indicated that the previous conclusion about abuse of these drugs still holds: the vast majority of the use of benzodiazepines is appropriate. Problems of nonmedical use arise nearly exclusively among people who abuse other drugs. Nevertheless, there are reasons for concern about patients who take benzodiazepines regularly for long periods of time. These drugs can produce physiological dependence when taken chronically, and although this does not appear to result in dose escalation or other evidence of "psychological dependence," physiological dependence can result in patient discomfort if drug use is abruptly discontinued. Also, physicians are currently prescribing shorter-acting benzodiazepines in preference to longer-acting benzodiazepines. The shorter-acting drugs can produce a more intense withdrawal syndrome following chronic administration. Furthermore, rates of use of benzodiazepines increase with age, and elderly patients are more likely than younger ones to take the drug chronically. The clearest adverse effect of benzodiazepines is impairment of memory. This, too, may be particular concern in older patients whose recall in the absence of drug is typically impaired relative to younger individuals, and who are more compromised following drug administration.