Changes in serotonin and norepinephrine uptake sites after chronic cocaine: pre- 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 chronic cocaine on 5-HT and NE transporters have received less attention than its effects on DA transporters. In the present study, quantitative autoradiography was used to map effects of chronic cocaine exposure on the binding of [3H]nisoxetine and [3H]cyanoimipramine to NE and 5-HT transporters, respectively. Female Wistar rats were given increasing concentrations of cocaine in the drinking water for 4 weeks (mean dose during the final two weeks: approximately 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 sacrificed while on cocaine. [3H]cyanoimipramine binding was significantly 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), pedunculopontine n. (+16%, P < 0.05), and vestibular n. (+19%, P < 0.05). These changes were no longer observed when brains were examined either 4 days or 30 days after cessation of cocaine. In animals sacrificed while on cocaine, [3H]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 sacrificed 4 days after cessation of cocaine, these effects were no longer apparent, except for a 16% reduction in the inferior olive (P < 0.05). In this 4-day withdrawal group, a significant increase in [3H]nisoxetine binding was seen in the paraventricular n. of the hypothalamus (PVN, +33%, P < 0.05). This PVN change was still seen in the group sacrificed 30 days after cessation of cocaine (+44%, P < 0.02). Binding of [3H]WIN 35,428 to dopamine transporters was unaltered in this group. Taken together, these observations indicate that chronic cocaine has different effects on brain 5-HT and NE transporters, both while the animals are on cocaine and after withdrawal. They support the notion that increased 5-HT uptake in limbic forebrain may play a role in behavioral/psychiatric effects of chronic cocaine. They are also consistent with previous indications that chronic cocaine does not induce degeneration of nerve terminals in noradrenergic or serotonergic neurons. The persistent increase in [3H]nisoxetine binding in the paraventricular hypothalamus suggests the possibility of neuroendocrine changes after withdrawal from chronic cocaine use.