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This report investigates the effect of the negative enantiomer of 1-hydroxy-3-aminopyrrolidone-2 (HA-966) on behavioral and biochemical changes elicited by pharmacological or experimental paradigms which activate mesocorticolimbic dopaminergic neurotransmission. Several paradigms were used, including cocaine sensitization and two stressors: restraint for 30 min and an aversive conditioning model. (S)-(-)-HA-966 (3 and 5 mg/kg i.p.) prevented restraint stress-induced dopamine utilization in both the medial prefrontal cortex and nucleus accumbens, in contrast to the positive enantiomer. Conditioned fear increased dopamine metabolism in both the core and shell subdivisions of the nucleus accumbens, an effect blocked by (S)-(-)-HA-966. The conditioned stress-induced increase in dopamine metabolism in the medial prefrontal cortex was also blocked by (S)-(-)-HA-966. In addition, (S)-(-)-HA-966 suppressed fear-induced behaviors: immobility and defecation. In other studies, (S)-(-)-HA-966 (3 mg/kg i.p.) prevented locomotor sensitization without altering the acute motoric response elicited by cocaine. The highest dose of (S)-(-)-HA-966 (5 mg/kg i.p.) blocked acute cocaine-induced locomotion but resulted in sedation. In addition, the highest dose of (S)-(-)-HA-966 tested suppressed weight gain in control rats, unlike its enantiomer, (R)-(+)-HA-966. Because (S)-(-)-HA-966 has been proposed to act at the gamma-aminobutyric acid (GABA)B receptor, we examined the ability of (S)-(-) and (R)-(+)-HA-966 to displace [3H]-(-)-baclofen from cortical membranes to assess GABAB receptor binding. Neither enantiomer significantly altered [3H]-(-)-baclofen binding at relevant concentrations, indicating the actions of (S)-(-)-HA-966 reported here are the results of a mechanism apparently independent of the baclofen binding site on the GABAB receptor.

Previous work has demonstrated that chronic administration of cocaine induces apparently novel Fos-like transcription factors, termed chronic Fras (Fos-related antigens), in the rat striatum and nucleus accumbens. Induction of these proteins is associated with prolonged increases in AP-1 DNA binding activity that parallel the long half-life of the chronic Fras in brain. The goal of the present study was to characterize pharmacologically the regulation of chronic Fra induction by cocaine. Chronic Fra induction was examined with respect to the cocaine dose, time course and administration intervals used. Cocaine was found to induce the chronic Fras over widely differing treatment regimens in the striatum and nucleus accumbens, although clear differences between the two brain regions were observed. In general, maximal induction occurred with moderate treatment conditions, with more or less intensive treatments resulting in lower levels of chronic Fras. The pharmacological mechanisms underlying cocaine induction of the chronic Fras were also investigated. Pretreatment with a D1 receptor antagonist, which did not affect chronic Fra levels by itself, attenuated cocaine induction of the chronic Fras in striatum and nucleus accumbens. In contrast, treatment with a D2 receptor antagonist alone greatly induced chronic Fra levels, with no further increase seen in response to combined treatment with cocaine. Combined treatment with D1 and D2 receptor agonists, or with amphetamine, led to a strong induction of chronic Fras. Similarly, repeated treatment with a specific dopamine transporter inhibitor increased chronic Fra levels, whereas treatment with a specific serotonin or norepinephrine transporter inhibitor failed to produce this effect. These results support an important role for dopaminergic neurotransmission in the induction of chronic Fras by cocaine. Taken together, the results of the present study provide a more complete understanding of the pharmacological properties underlying cocaine regulation of the chronic Fras, which will assist in identifying the functional role played by these proteins in cocaine action.

Developmental exposure to cocaine is associated with cardiovascular abnormalities as well as neurobehavioral disturbances. Because of the profound influence of cocaine on noradrenergic neurotransmission, we examined its acute effects on norepinephrine release from cardiac nerve terminals in the neonatal rat, as assessed by turnover measurements. Cocaine reduced norepinephrine turnover at all ages studied, but with an apparent transition in the mechanism of action related to the development of central control of sympathetic tone. At 1 day of age, before the establishment of functional connections between the central nervous system and sympathetic neurons, cocaine acted primarily through blockade of norepinephrine reuptake and consequent activation of alpha-2 adrenergic autoreceptors that inhibit transmitter release. Accordingly, its effects were shared by the uptake inhibitor, desmethylimipramine and the alpha-2 agonist, clonidine, but not by drugs whose actions depend upon sympathetic activity or high tonic release of transmitter (yohimbine, pargyline or chlorisondamine). By 21 days, when neuronal activity is under dynamic control by the central nervous system, cocaine was still effective in shutting off norepinephrine release, but the effect was no longer dependent upon blockade of reuptake; desmethylimipramine did not reduce turnover at this age, but clonidine, pargyline and chlorisondamine did. Yohimbine evoked a profound increase in turnover by 21 days.(ABSTRACT TRUNCATED AT 250 WORDS)