EFFECTS OF CHRONIC COCAINE ADMINISTRATION ON DOPAMINE TRANSPORTER MESSENGER-RNA AND PROTEIN IN THE RAT

Male Sprague-Dawley rats were administered cocaine (10, 15 or 25 mg/kg ) or vehicle, i.p., once daily for 8 consecutive days and killed 1 h a fter the last injection. Acute cocaine administration produced dose-de pendent increases in spontaneous locomotor activity. These levels of a ctivity were further enhanced by 8 days of chronic treatment, indicati ng the emergence of behavioral sensitization. Chronic cocaine administ ration resulted in dose-dependent decreases in the density of dopamine transporter (DAT) mRNA in both the substantia nigra pars compacta and ventral tegmental area as shown by in situ hybridization histochemist ry. Changes in DAT binding sites were assessed using [H-3]mazindol qua ntitative autoradiography. In contrast to the levels of mRNA, there we re few changes in the number of [H-3]mazindol binding sites. Although the density of binding sites was unaltered in most regions, [H-3]mazin dol binding was increased in the anterior nucleus accumbens. This stud y extends previous findings by demonstrating the dose-dependent nature of the changes in DAT mRNA that accompanies chronic cocaine administr ation. The levels of DAT binding sites within the dorsal and ventral s triatum, however, were largely unchanged. This mismatch suggests that cocaine may differentially influence the gene expression of DAT in the ventral midbrain as compared to the density of DAT binding sites in t he basal forebrain. (C) 1997 Elsevier Science B.V.