Vol. 283, Issue 2, 712-721, 1997

(S)-()-HA-966, a -Hydroxybutyrate-Like Agent, Prevents Enhanced Mesocorticolimbic Dopamine Metabolism and Behavioral Correlates of Restraint Stress, Conditioned Fear and Cocaine Sensitization¹

Bret A. Morrow, Edward J. K. Lee, Jane R. Taylor, John D. Elsworth, Heather E. Nye and Robert H. Roth

Laboratory of Neuropsychopharmacology, Departments of Pharmacology (E.J.K.L., R.H.R.) and Psychiatry (B.A.M., J.R.T., J.D.E., H.E.N., R.H.R.), Yale University School of Medicine, New Haven, Connecticut 06520-8066

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 -aminobutyric acid (GABA)_B receptor, we examined the ability of (S)-() and (R)-(+)-HA-966 to displace [³H]-()-baclofen from cortical membranes to assess GABA_B 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 GABA_B receptor.