Norepinephrine secretion in the hypothalamic paraventricular nucleus of rats during unlimited access to self-administered nicotine: An in vivo microdialysis study

Norepinephrine (NE) secretion within the hypothalamic paraventricular nucle us (PVN) is pivotal to endocrine and behavioral responses. Activation of NE afferents to PVN also is necessary for the hypothalamo-pituitary-adrenal a xis response to passively administered nicotine. The mode of drug delivery is a critical determinant of the dynamics of neurotransmitter secretion, ye t the PVN NE response to nicotine self-administration (SA) is unknown. Here in, rats housed in operant chambers had unlimited 23 hr access to self-admi nistered nicotine. In vivo microdialysis of PVN NE was performed, collectin g consecutive 7 min samples over 9 hr sessions during three phases of nicot ine SA: acquisition (day 1); early maintenance, once stable rates of SA wer e achieved (day 9.2 +/- 0.6); later maintenance (day 18.6 +/- 0.8). On d1, nicotine animals had an increased percentage of SA episodes (SAEs) in which NE levels were elevated (80 vs 30% with saline; p < 0.01). By early mainte nance, a fourfold increase in such episodes was observed in nicotine animal s (p < 0.01), and the overall NE level was greater (1.30 +/- 0.24 vs 0.63 /- 0.07 pg/10 mul in saline; p < 0.05); NE increased during the first, but not the last, SAE. The pattern was similar during later maintenance, althou gh NE responsiveness declined (overall NE level, 0.96 +/- 0.19 in nicotine vs 0.52 +/- 0.08 pg/10 <mu>l in saline; p < 0.05). Therefore, nicotine SAEs were associated with sustained increases in NE secretion during all three phases of SA. However, the reduced NE responsiveness observed both within t he dialysis session in each phase and by later versus early maintenance is consistent with progression of partial daily desensitization of PVN NE secr etion to nicotine SA. Therefore, in rats chronically self-administering nic otine, the drug stimulates sustained PVN NE secretion that may alter neuroe ndocrine and behavioral responses mediated by the PVN. Compared with studie s of chronic human smokers, our nicotine SA model may reflect the CNS norad renergic responses that occur during human cigarette smoking.