title: Electrophysiological evaluation of the time-course of dopamine uptake inhibition induced by intravenous cocaine at a reinforcing dose.
abstract: Cocaine effectively inhibits dopamine (DA) uptake and this action appears to be the primary cause for increased DA transmission following systemic cocaine administration. Although this action had been reliably demonstrated in vivo with cocaine at high doses, data on the extent and the time-course of DA uptake inhibition induced by i.v. cocaine at low, reinforcing doses remain controversial. To clarify this issue, we examined how cocaine affects striatal neuronal responses to repeated iontophoretic DA applications in urethane-anesthetized rats. Because most striatal neurons during anesthesia have low, sporadic activity, DA tests were performed on cells tonically activated by continuous glutamate application. DA phasically decreased the activity of most dorsal and ventral striatal neurons; these responses in control conditions (i.v. saline) were current (dose) -dependent and remained highly stable following repeated DA applications at the same currents. DA also consistently decreased the activity of striatal neurons after i.v. cocaine (1 mg/kg); the magnitude of DA-induced inhibition slowly increased from approximately 5 min, became significantly larger from approximately 9 min, and peaked at 13-15 min after a single i.v. injection. Then, the difference in the DA response slowly decreased toward the pre-cocaine baseline. A similar enhancement of DA induced-inhibition was also seen after i.p. cocaine administration at a high dose (15 mg/kg). In this case, the DA response became significantly stronger at 7-9 min and remained enhanced vs. a pre-drug control up to 24-26 min after the injection. Both regimens of cocaine treatment did not result in evident changes in either onset or offset of the DA-induced inhibitions. Our data confirm that cocaine at low, reinforcing doses inhibits DA uptake, resulting in potentiation of DA-induced neuronal inhibitions, but they suggest that this effect is relatively weak and delayed from the time of i.v. injection. These slow and prolonged effects of i.v. cocaine on DA-induced neuronal responses are consistent with previous binding and our electrochemical evaluations of DA uptake, presumably reflecting the total time necessary for i.v.-delivered cocaine to reach brain microvessels, cross the blood-brain barrier, passively diffuse within brain tissue, interact with the DA transporters, and finally inhibit DA uptake.
authors.affiliation: Behavioral Neuroscience Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, DHHS, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wakazono
authors.forename: E A
authors.initials: EA
authors.lastname: Kiyatkin
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003342:Corpus Striatum / Q000166:cytology; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004594:Electrophysiology; D007262:Infusions, Intravenous / Q000379:methods; D008297:Male; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D020318:Rats, Long-Evans; D013997:Time Factors
chemical_list: D018765:Dopamine Uptake Inhibitors; D003042:Cocaine; D004298:Dopamine