CHANGES IN SEROTONIN AND NOREPINEPHRINE UPTAKE SITES AFTER CHRONIC COCAINE - PRE-WITHDRAWAL VS POST-WITHDRAWAL EFFECTS

Although acute cocaine is a strong reuptake inhibitor at dopamine (DA) , norepinephrine (NE) and serotonin (5-HT) synapses, the effects of ch ronic cocaine on 5-HT and NE transporters have received less attention than its effects on DA transporters. In the present study, quantitati ve autoradiography was used to map effects of chronic cocaine exposure on the binding of [H-3]nisoxetine and [H-3]cyanoimipramine to NE and 5-HT transporters, respectively. Female Wistar rats were given increas ing concentrations of cocaine in the drinking water for 4 weeks (mean dose during the final two weeks: similar to 25 mg/kg body weight) and sacrificed either on the 30th day of cocaine administration or at one of two time points after withdrawal (4 days or 30 days). In animals sa crificed while on cocaine, [H-3]cyanoimipramine binding was significan tly elevated in the infralimbic cortex (+13%, P < 0.05), n. accumbens (+16%, P < 0.05, P < 0.05), lateral septal n. (+21%, P < 0.05), pedunc ulopontine n. (+16%, P < 0.05), and vestibular n. (+19%, P < 0.05). Th ese changes were no longer observed when brains were examined either 4 days or 30 days after cessation of cocaine. In animals sacrificed whi le on cocaine. [H-3]nisoxetine binding was decreased in the bed n. of the stria terminalis (-18%, P < 0.05), the lateral parabrachial area ( -35%, P < 0.05) and the inferior olive (-26%, P < 0.05). In animals sa crificed 4 days after cessation of cocaine, these effects were no long er apparent, except for a 16% reduction in the inferior olive (P < 0.0 5). In this 4-day withdrawal group, a significant increase in [H-3]nis oxetine binding was seen in the paraventricular n. of the hypothalamus (PVN, +33%, P < 0.05). This PVN change was still seen in the group sa crificed 30 days after cessation of cocaine (+44%, P < 0.02). Binding of [H-3]WIN 35,428 to dopamine transporters was unaltered in this grou p. Taken together, these observations indicate that chronic cocaine ha s different effects on brain 5-HT and NE transporters, both while the animals are on cocaine and after withdrawal. They support the notion t hat increased 5-HT uptake in limbic forebrain may play a role in behav ioral/psychiatric effects of chronic cocaine. They are also consistent with previous indications that chronic cocaine does not induce degene ration of nerve terminals in noradrenergic or serotonergic neurons. Th e persistent increase in [H-3]nisoxetine binding in the paraventricula r hypothalamus suggests the possibility of neuroendocrine changes afte r withdrawal from chronic cocaine use.