Effects of chronic cocaine administration on dopamine transporter mRNA 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 after the last injection. Acute cocaine administration produced dose-dependent increases in spontaneous locomotor activity. These levels of activity were further enhanced by 8 days of chronic treatment, indicating the emergence of behavioral sensitization. Chronic cocaine administration 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 histochemistry. Changes in DAT binding sites were assessed using [3H]mazindol quantitative autoradiography. In contrast to the levels of mRNA, there were few changes in the number of [3H]mazindol binding sites. Although the density of binding sites was unaltered in most regions, [3H]mazindol binding was increased in the anterior nucleus accumbens. This study extends previous findings by demonstrating the dose-dependent nature of the changes in DAT mRNA that accompanies chronic cocaine administration. The levels of DAT binding sites within the dorsal and ventral striatum, 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 the basal forebrain.
Letchworth
S R
SR
Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Winston-Salem, NC 27157, USA. sletchwo@bgsm.edu
Daunais
J B
JB
Hedgecock
A A
AA
Porrino
L J
LJ
D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D002352:Carrier Proteins / Q000096:biosynthesis*; D003042:Cocaine / Q000494:pharmacology*; D015342:DNA Probes; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D017403:In Situ Hybridization; D008297:Male; D008454:Mazindol / Q000378:metabolism; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009043:Motor Activity / Q000187:drug effects*; D009419:Nerve Tissue Proteins; D009928:Organ Specificity; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects*; D014316:Tritium
D002352:Carrier Proteins; D015342:DNA Probes; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C493216:Slc6a3 protein, rat; D014316:Tritium; D008454:Mazindol; D003042:Cocaine