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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 primary purpose of this study was to examine the regulation of prodynorphin peptides by dopaminergic agents in the central nervous system. The indirectly acting catecholamine agonist D-amphetamine sulfate (AMPH) and the dopamine receptor antagonist haloperidol (HAL) were administered to rats across a variety of treatment schedules and drug doses. The striatum, substantia nigra and hippocampus were dissected and examined by radioimmunoassay for 5 different prodynorphin peptides, covering all 3 opioid domains in the prodynorphin precursor: dynorphin A(1-8) and dynorphin A(1-17) of the dynorphin A domain, dynorphin B(1-13) of the dynorphin B domain, and alpha-neo-endorphin and beta-neo-endorphin of the neo-endorphin domain. In addition, the proenkephalin peptide Met-enkephalin-arg6-gly7-leu8 (MERGL) was examined in the striatum. AMPH administered one hour prior to sacrifice caused a dose-dependent depletion of prodynorphin peptides in both the striatum and substantia nigra. In animals treated with AMPH once each day for 7 days and sacrificed 24 h later, a dramatic dose-dependent increase in prodynorphin peptides was observed in these brain regions. Animals treated with AMPH once each day for 7 days and sacrificed one hour after the final injection showed no changes in prodynorphin peptides. In addition to changes in individual prodynorphin peptides, AMPH treatment caused alterations in the relationships between intermediate peptides (dynorphin A(1-17) and alpha-neo-endorphin) and their immediate products (dynorphin A(1-8) and beta-neo-endorphin). AMPH caused no consistent changes in prodynorphin peptides in the hippocampus, or in MERGL in the striatum. Taken together these data suggest that acute dopaminergic activation causes depletion of dynorphins from striatonigral prodynorphin neurons, presumably due to dopamine-dependent release of these peptides; repeated activation causes repeated release, with a rebound increase in biosynthesis. HAL, in contrast to AMPH caused relatively subtle changes in striatonigral prodynorphin peptides. Although no significant changes in individual prodynorphin peptides were observed, HAL treatment caused a change in the relationship between dynorphin A(1-17) and dynorphin A(1-8), a change opposite in direction to that observed with AMPH treatment. As has been previously reported, repeated HAL administration caused a dose-dependent increase in the proenkephalin peptide MERGL. The relatively subtle effects of HAL on prodynorphin peptides suggests that tonic dopamine activity is not important in the regulation of striatonigral prodynorphin neurons. The potential functional and behavioral significance of the present results are discussed.

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.