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Amphetamine and naloxone were examined in place conditioning, in order to study possible interactions between endogenous opioids and catecholamines in reinforcement. After initial preferences were determined, animals were conditioned with amphetamine alone (1.0 mg/kg SC), naloxone alone (0.02, 0.2 or 2.0 mg/kg SC) or combinations of amphetamine plus naloxone. A reliable, long-lasting preference for the compartment associated with amphetamine was observed, reflecting the reinforcing properties of this drug. No preference or aversion was observed in animals that received saline in both compartments. Naloxone (0.02, 0.2 and 2.0 mg/kg) produced a dose-dependent place aversion; while the lowest dose had effects similar to saline, the higher doses produced significant place aversions. Naloxone, at all three doses examined, prevented the ability of amphetamine to produce a place preference. Thus, the lowest dose of naloxone, having no effects alone in place conditioning was still able to block the reinforcing effects of amphetamine. These results suggest that the reinforcing effects of amphetamine are dependent on activation of opiate receptors, and provide further evidence that interactions between endogenous opioids and catecholamines may be important in reinforcement.

The present study investigated the response decrement patterns produced by opiate antagonists on intracranial self-stimulation behavior, in order to determine if these drugs affect the reinforcement value of the stimulation or interfere with the ability of the animal to respond. Male rats lever-pressed in 60-min sessions on a continuous reinforcement schedule for self-stimulation of the nucleus accumbens. Naloxone (2.0 and 20 mg/kg) and naltrexone (2.0 and 20 mg/kg) suppressed self-stimulation only after a significant delay, in an extinction-like response decrement pattern, mimicking the effects of reductions in current intensity (75% and 50% of baseline). The increasing behavioral effects characteristic of the extinction pattern were observed despite the fact that testing began after the time point at which maximal suppression of self-stimulation occurs with these drugs, and when brain concentrations of these drugs were declining. Since normal responding was observed for several minutes after the beginning of the session, the results may explain why long sessions are necessary to observe suppression of self-stimulation by opiate antagonists. The extinction-like pattern produced by these drugs suggests that opiate antagonists suppress self-stimulation by reducing the reinforcement value of the stimulation, rather than by interfering with the ability of the animal to respond. These findings are consistent with a role for endogenous opioid peptides in brain stimulation reward.

Naloxone and naltrexone were compared with their quaternary analogues naloxone methobromide and naltrexone methobromide for efficacy in suppressing intracranial self-stimulation behavior. These quaternary analogues effectively block opiate receptors in the periphery, but since they do not readily cross the blood-brain barrier they have little effect on central receptors. Rats with electrodes in the nucleus accumbens were trained to self-stimulate in daily 60-min sessions. Naloxone (0.2, 2.0 and 20 mg/kg) and naltrexone (20 mg/kg) potently suppressed self-stimulation behavior. In contrast, neither naloxone methobromide (0.2 and 20 mg/kg) nor naltrexone methobromide (20mg/kg) had any significant effects on this behavior. These results suggest that blockade of peripheral opiate receptors alone is insufficient to suppress self-stimulation, and therefore support the idea that opiate antagonists suppress self-stimulation by blockade of central receptors that mediate reinforcement.

The action of the opiate antagonist naloxone on relatively easy (nose-poke) and relatively difficult (lever-press) self-stimulation behaviors was compared, in order to determine if opiate antagonists suppress self-stimulation by interfering with the ability of the animal to respond, or by reducing the reinforcement value of the stimulation. Naloxone (0.2, 2.0 and 20 mg/kg) significantly suppressed both nose-poking and lever-pressing self-stimulation rates, and the degree of suppression was virtually identical for both tasks at all doses examined. If naloxone had interfered with the ability of the animal to respond, then lever-pressing--which requires more motor output than nose-poking--should have been more suppressed than nose-poking. The results suggest that opiate antagonists do not interfere with the ability of the animal to respond, and are therefore consistent with the hypothesis that these drugs reduce the reinforcement value of the stimulation.