COCAINE ADMINISTERED IN-VITRO TO BRAIN-SLICES FROM RATS TREATED WITH COCAINE CHRONICALLY IN-VIVO RESULTS IN A GAMMA-AMINOBUTYRIC-ACID RECEPTOR-MEDIATED HYPERPOLARIZATION RECORDED FROM THE DORSOLATERAL SEPTUM

Previous reports of membrane hyperpolarizations, associated with acute application of cocaine, have been recorded from brain slice preparati ons containing aminergic nuclei and have always been attributed to coc aine's ability to elevate levels of local biogenic amines followed by activation of their receptors. The majority of these studies were cond ucted with brain slices obtained from rats that had not received prior chronic in vivo treatment with cocaine. We observed that cocaine alon e, at 3 mu M, could induce a membrane hyperpolarization (COC-HYP) in 1 00% of rat dorsalateral septal nucleus (DLSN) neurons from brain slice s of rats treated chronically with cocaine for either 14 or 28 days in vivo. The DLSN is a nucleus absent of biogenic amine cell bodies, but does contain biogenic amine terminals with GABAergic cell bodies and terminals. Cocaine applied to brain slices from rats not previously ad ministered cocaine or administered cocaine for up to seven days in viv o yielded a maximum incidence of COC-HYPs at only 50%. COC-HYPs record ed from DLSN neurons were not blocked by previous treatment with amine receptor antagonists or by a mt and zero calcium medium. Based on the se results, the ability of DLSN neurons to respond to a cocaine challe nge with a COC-HYP did not involve inhibition of amine reuptake/uptake or action potential release of neuroactive substances. Rather, the CO C-HYP, with an apparent reversal potential of -80 mV, was reduced by t he GABA receptor antagonists-bicuculline and CGP-55845A. Lowering extr acellular Na+ or Cl-, lowering of temperature, or previous superfusion with the GABA uptake blocker NO-711 could block the COC-HYP. In summa ry, our data suggest that COC-HYPs, after application of a cocaine cha llenge to brain slices from rats treated chronically (14 - 28 days, bu t not acutely, 7 days) with cocaine are due to cocaine-induced changes in GABA release and/or transporter function. The latter changes in tr ansporter function may involve the reversal of the GABA transporter wi th release of GABA and subsequent activation of postsynaptic GABA(A) a nd GABA(B) receptors.