T. Belej et al., CHANGES IN SEROTONIN AND NOREPINEPHRINE UPTAKE SITES AFTER CHRONIC COCAINE - PRE-WITHDRAWAL VS POST-WITHDRAWAL EFFECTS, Brain research, 736(1-2), 1996, pp. 287-296
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.