(S)-(-)-HA-966, A GAMMA-HYDROXYBUTYRATE-LIKE AGENT, PREVENTS ENHANCEDMESOCORTICOLIMBIC DOPAMINE METABOLISM AND BEHAVIORAL-CORRELATES OF RESTRAINT STRESS, CONDITIONED FEAR AND COCAINE SENSITIZATION

This report investigates the effect of the negative enantiomer of 1-hy droxy-3-aminopyrrolidone-2 (HA-966) on behavioral and biochemical chan ges elicited by pharmacological or experimental paradigms which activa te mesocorticolimbic dopaminergic neurotransmission. Several paradigms were used, including cocaine sensitization and two stressors: restrai nt for 30 min and an aversive conditioning model. (S)-(-)-HA-966 (3 an d 5 mg/kg i.p.) prevented restraint stress-induced dopamine utilizatio n in both the medial prefrontal cortex and nucleus accumbens, in contr ast to the positive enantiomer. Conditioned fear increased dopamine me tabolism in both the core and shell subdivisions of the nucleus accumb ens, an effect blocked by (S)-(-)-HA-966. The conditioned stress-induc ed increase in dopamine metabolism in the medial prefrontal cortex was also blocked by (S)-(-)-HA-966. In addition, (S)-(-)-HA-966 suppresse d fear-induced behaviors: immobility and defecation. In other studies, (S)-(-)-HA-966 (3 mg/kg i.p.) prevented locomotor sensitization witho ut altering the acute motoric response elicited by cocaine. The highes t 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 i ts enantiomer, (R)-(+)-HA-966. Because (S)-(-)-HA-966 has been propose d to act at the gamma-aminobutyric acid (GABA)(B) receptor, we examine d the ability of (S)-(-) and (R)-(+)-HA-966 to displace [H-3]-(-)-bacl ofen from cortical membranes to assess GABA(B) receptor binding. Neith er enantiomer significantly altered [H-3]-(-)-baclofen binding at rele vant concentrations, indicating the actions of (S)-(-)-HA-966 reported here are the results of a mechanism apparently independent of the bac lofen binding site on the GABA(B) receptor.