5-HT3 AGONIST-INDUCED DOPAMINE OVERFLOW DURING WITHDRAWAL FROM CONTINUOUS OU INTERMITTENT COCAINE ADMINISTRATION

This experiment examined alterations in the ability of the highly sele ctive 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (mCPBG), to induce dopamine (DA) overflow in caudate brain slices obtained from r ats withdrawn from continuous or intermittent cocaine administration. Rats were pretreated with 40 mg/kg per day cocaine for 14 days by eith er subcutaneous injections or osmotic minipumps, and then withdrawn fr om this regimen for 7 days. Caudate brain slices were obtained, and pe rfused with artificial cerebrospinal fluid. Following an equilibration period, the slices were then perfused with 25, 50, or 100 mu M mCPBG. The samples were assayed for DA content by HPLC with electrochemical detection. The results indicated that the pretreatment with intermitte nt cocaine did not consistently alter the ability of mCPBG to induce D A overflow although there was a reduction in the amount of DA released by the highest concentration of mCPBG. In contrast, pretreatment with continuous cocaine administration consistently and significantly atte nuated the ability of mCPBG to induce DA overflow. The DA overflow ind uced by mCPBG was partially dependent on extracellular Ca2+ in the per fusion medium for the saline control and intermittent administration s ubjects: elimination of Ca2+ from the medium significantly reduced, bu t did not eliminate, DA overflow for these two groups. In contrast, el imination of Ca2+ from the perfusion medium had a significant enhancin g effect on mCPBG-induced DA overflow in the continuous administration rats. These results suggest that distinct temporal patterns of cocain e administration differentially alter the ability of a 5-HT3 agonist t o increase extracellular DA levels, and that this effect may be relate d to an impairment of Ca2+-dependent release. These results further su ggest that 5-HT3 receptor subsensitivity may represent a partial mecha nism for the tolerance following continuous cocaine administration.