title: Dopamine-independent action of cocaine on striatal and accumbal neurons.
abstract: Increasing evidence suggests that dopamine (DA) mechanisms alone cannot fully explain the psychoemotional and behavioural effects of cocaine, including its ability to induce drug-taking behaviour. Although it is known that cocaine, after intravenous administration or smoking, may reach brain levels high enough to inhibit Na+ transport, the role of this action remains unclear. To examine the contribution of local anaesthetic and DA mechanisms to changes in striatal and accumbal neuronal activity induced by cocaine, single-unit recording was combined with iontophoresis in awake, unrestrained rats. Most spontaneously active and glutamate-stimulated neurons were highly sensitive to brief cocaine applications (0-40 nA); cocaine-induced inhibitions occurred at small ejection currents (0-5 nA), were dose-dependent, highly stable during repeated applications and strongly dependent on basal activity rates. These neuronal responses remained almost unchanged after systemic administration of either a selective D1 antagonist (SCH-23390, 0.2 mg/kg) or a combination of SCH-23390 (1 mg/kg) and eticlopride (1 mg/kg), a D2 antagonist. Whereas SCH-23390 alone had a weak attenuating effect, no effect and even a slight enhancement of responses to cocaine occurred in fast-firing glutamate (GLU)-stimulated units after the combined blockade of D1 and D2 receptors. Responses to cocaine were mimicked by iontophoretic procaine (0-40 nA), a short-acting local anaesthetic with minimal effect on DA uptake. Procaine-induced inhibitions occurred at the same low currents, had a similar time-course, and were also strongly dependent on basal discharge rate. Our data support the existence of a DA-independent mechanism for the action of cocaine involving a direct interaction with Na+ channels. Although further studies are required to clarify this mechanism and its interaction with other pharmacological and behavioural variables, a direct interaction with Na+ channels may contribute to changes in neuronal activity induced by self-injected cocaine, thereby playing a role in mediating the psychoemotional and behavioural effects of this drug.
authors.affiliation: Program in Neural Science, Department of Psychology, Indiana University, Bloomington, IN 47405, USA. ekiyatki@intra.nida.nih.gov
authors.forename: E A
authors.initials: EA
authors.lastname: Kiyatkin
authors.forename: G V
authors.initials: GV
authors.lastname: Rebec
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000502:physiology*; D004298:Dopamine / Q000502:physiology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004594:Electrophysiology; D007478:Iontophoresis; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009714:Nucleus Accumbens / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D012044:Regression Analysis; D012457:Salicylamides / Q000494:pharmacology
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D012457:Salicylamides; D003042:Cocaine; C045989:eticlopride; D004298:Dopamine