Animal knockout studies suggest that trace amine-associated receptor (TAAR) 1 is involved in behavioral effects of psychostimulants such as cocaine. Recently, several highly selective TAAR 1 agonists have been discovered. However, little is known of the impact of TAAR 1 agonists on abuse-related effects of cocaine. Here, we report the effects of a TAAR 1 agonist RO5263397 on several abuse-related behavioral effects of cocaine in rats. RO5263397 was evaluated for its effects on cocaine-induced behavioral sensitization, conditioned place preference (CPP), cue- and cocaine prime-induced reinstatement of cocaine-seeking behavior, and cocaine self-administration using behavioral economic analysis. RO5263397 reduced the expression of cocaine behavioral sensitization, cue- and cocaine prime-induced reinstatement of cocaine seeking, and expression but not development of cocaine CPP. Behavioral economic analysis showed that RO5263397 increased the elasticity of the cocaine demand curve, but did not change cocaine consumption at minimal prices. Taken together, this is the first systematic assessment of a TAAR 1 agonist on a range of behavioral effects of cocaine, showing that RO5263397 was efficacious in reducing cocaine-mediated behaviors. Collectively, these data uncover essential neuromodulatory roles of TAAR 1 on cocaine abuse, and suggest that TAAR 1 may represent a novel drug target for the treatment of cocaine addiction.

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.

Behavioral effects of a nonpeptidic NOP (nociceptin/orphanin FQ Peptide) receptor agonist, Ro 64-6198, have not been studied in primate species. The aim of the study was to verify the receptor mechanism underlying the behavioral effects of Ro 64-6198 and to systematically compare behavioral effects of Ro 64-6198 with those of a m-opioid receptor agonist, alfentanil, in monkeys. Both Ro 64-6198 (0.001-0.06 mg/kg, s.c.) and alfentanil (0.001-0.06 mg/kg, s.c.) produced antinociception against an acute noxious stimulus (501C water) and capsaicin-induced allodynia. An NOP receptor antagonist, J-113397 (0.01-0.1 mg/kg, s.c.), dose-dependently produced rightward shifts of the dose-response curve of Ro 64-6198-induced antinociception. The apparent pA 2 value of J-113397 was 8.0. Antagonist studies using J-113397 and naltrexone revealed that Ro 64-6198 produced NOP receptor-mediated antinociception independent of m-opioid receptors. In addition, alfentanil dose-dependently produced respiratory depression and itch/scratching responses, but antinociceptive doses of Ro 64-6198 did not produce such effects. More important, Ro 64-6198 did not produce reinforcing effects comparable with those of alfentanil, cocaine, or methohexital under self-administration procedures in monkeys. These results provide the first functional evidence that the activation of NOP receptors produces antinociception without reinforcing effects in primates. Non-peptidic NOP receptor agonists may have therapeutic value as novel analgesics without abuse liability in humans.

Human polydrug abusers often take combinations of opioids and stimulants, but it is not clear why. Behavioral economics with demand curve analysis is uniquely able to separate two of the possibilities: that the drug combination increases the reinforcing potency of the component drugs or that the drug combination is a more effective reinforcer than either drug alone. Rhesus monkeys self-administered a range of doses of cocaine, remifentanil, and combinations of the drugs through indwelling intravenous catheters; the number of responses required for each drug infusion increased across drug-availability sessions. Combining small doses of cocaine and remifentanil that by themselves resulted in very low rates of responding yielded rates of responding that were higher than the maximum maintained by any dose of the constituent drugs. Nevertheless, demand curve analysis demonstrated that the drug combination was equally elastic as the component drugs, indicating that it was not more effective as a reinforcer than either cocaine or remifentanil alone. This suggests that enhanced self-administration of this particular drug combination is due primarily to the drug enhancement of the potency of the other drug.The abuse of two or more drugs in temporal proximity is thought to be a prevalent form of psychoactive drug use (Ball and Ross, 1991;Higgins et al., 1994;Schutz et al., 1994). One possible mechanism for this use is that combinations of small doses of the two drugs produce a reinforcing effect that is similar to, but no greater than, larger doses of either drug. A second possibility is that combinations of drugs produce a qualitatively different and quantitatively greater reinforcing effect than would be possible with any dose of either drug by itself.Different procedures have been used in monkeys to evaluate the reinforcing effects of drug combinations. Mello et al. (1995), using a second-order schedule, found that adding heroin to cocaine did not result in an increased number of infusions obtained, suggesting no increase in the reinforcing effectiveness of the drug combination. A similar conclusion was reached by Rowlett and Woolverton (1997) and Rowlett et al. (1998) using progressive ratio schedules. In progressive ratio schedules, the response requirement for drug delivery is systematically increased until responding stops (breakpoint). Cocaine increased the potency of heroin as a reinforcer, and heroin similarly increased the potency of cocaine as a reinforcer, but the breakpoints produced by the combination were no greater than that produced by either drug alone.Progressive ratio schedules have also been used in rats to assess the reinforcing functions of drug combinations. Duvauchelle et al. (1998) reported enhancements in potency with no change in breakpoints of combinations of cocaine and heroin. Ranaldi and Munn (1998) found that adding heroin to cocaine did not alter the potency of cocaine but that it did produce higher breakpoints than that of cocaine alone, suggesting an enhancement of the reinforc...

Neuroscientific approaches to drug addiction traditionally have been based on the premise that addiction is a process that results from brain changes that in turn result from chronic administration of drugs of abuse. An alternative approach views drug addiction as a behavioral disorder in which drugs function as preeminent reinforcers. Although there is a fundamental discrepancy between these two approaches, the emerging neuroscience of reinforcement and choice behavior eventually may shed light on the brain mechanisms involved in excessive drug use. Behavioral scientists could assist in this understanding by devoting more attention to the assessment of differences in the reinforcing strength of drugs and by attempting to develop and validate behavioral models of addiction.

The present study examined whether continued access to methamphetamine or food reinforcement changed economic demand for both. The relationship between demand elasticity and cue-induced reinstatement was also determined. Male Long-Evans rats lever-pressed under increasing fixed-ratio requirements for either food pellets or methamphetamine (20 μg/50 μl infusion). For two groups, demand curves were obtained before and after continued access (12 days, 2-hr sessions) to the reinforcer under a fixed-ratio 3 schedule. A third group was given continued access to methamphetamine between determinations of food demand and a fourth group abstained from methamphetamine between determinations. All groups underwent extinction sessions, followed by a cue-induced reinstatement test. Although food demand was less elastic than methamphetamine demand, continued access to methamphetamine shifted the methamphetamine demand curve upward and the food demand curve downward. In some rats, methamphetamine demand also became less elastic. Continued access to food had no effect on food demand. Reinstatement was higher after continued access to methamphetamine relative to food. For methamphetamine, elasticity and reinstatement measures were correlated. We conclude that continued access to methamphetamine – but not food – alters demand in ways suggestive of methamphetamine accruing reinforcing strength. Demand elasticity and reinstatement measures appear to be related indices of drug-seeking.

By manipulating a signaled upcoming cocaine dose, we investigated how the dose just received and the upcoming dose jointly controlled cocaine self-administration. Three rhesus monkeys self-administered cocaine according to a multiple schedule differing in dose following completion of a fixed-ratio response requirement. The larger dose (0.03 or 0.056 mg/kg) was 10-fold higher than the smaller dose (0.003 or 0.0056 mg/kg). Following each infusion, there was an equal probability that the next dose would be large or small. This resulted in four types of signaled transitions: from a small dose to a small dose, small to large, large to large, and large to small. Across conditions the response requirement was increased. At lower ratios, pauses were brief and run rates were controlled by the upcoming dose. At larger ratios, pauses were pronounced, and run rates suppressed, in transitions from a large to a small dose. The behavioral disruption engendered by this transition occurred with both dose combinations. The results suggest that negative discriminable shifts in drug availability disrupt ongoing responding.

The hypothesis that use of ethanol in combination with sedative and stimulant drugs is due to an ability of ethanol to enhance the reinforcing effects of these drugs is not supported.