Prenatal cocaine exposure increases serotonergic inhibition of electrically evoked acetylcholine release from rat striatal slices at adulthood

Abstract

This study tests the hypothesis that prenatal cocaine (pCOC) exposure (20 mg/kg, bidaily from embryonic days 15-21) modifies 5-HT(3) receptor regulation of electrically-evoked [(3)H]acetylcholine (ACh) overflow from adult male and female (proestrus, diestrus) rat striatal slices. Also, the influence of endogenous dopamine (DA) on serotonin (5-HT) regulation of ACh overflow was determined by assessing the effects alpha-methyl-para-tyrosine (AMPT) pretreatment or sulpiride. Phenylbiguanide (PBG, 5-HT(3) agonist) superfusion dose-dependently inhibited ACh overflow in all groups except the diestrus pCOC group in which there was an enhanced sensitivity to PBG. PBG (10, 30, and 60 microM) produced greater effects in the pCOC male than in the prenatal saline (pSAL) group. The pCOC male group also exhibited greater sensitivity to PBG (30 and 60 microM) than the pCOC proestrus group. PBG inhibition of ACh overflow was comparable in the pSAL male and female (proestrus) groups. PBG inhibition of ACh overflow was greater in the pCOC diestrus group than in the pCOC proestrus (10, 30, and 60 microM), the pSAL diestrus (10 and 30 microM), and the pCOC male (10 microM) conditions. In slices from untreated rats superfused with 30 microM PBG, AMPT pretreatment (68% DA loss) reduced inhibition of ACh overflow, and 1 microM sulpiride increased ACh overflow. ICS205-930 (5-HT(3) antagonist) reduced effectiveness of PBG indicating 5-HT(3) receptor specificity for PBG. In summary, pCOC exposure enhances modulatory effects of 5-HT (via 5-HT(3) receptors) on striatal ACh release in male and females rats and the inhibitory actions of 5-HT(3) receptors are mediated by DA.