NICOTINIC AGONISTS MODULATE BASAL FOREBRAIN CONTROL OF CORTICAL CEREBRAL BLOOD-FLOW IN ANESTHETIZED RATS

Previous studies have indicated that electrical microstimulation of th e cholinergic (basal forebrain, BF) elicits profound increases in cort ical cerebral blood flow (CBF) that are selectively attenuated by nico tinic receptor antagonists. This study sought to determine whether nic otinic receptor agonists such as (-)-nicotine, and related agents, can enhance the increases in CBF elicited by electrical stimulation of th e BF of urethane-anesthetized rats. The magnitude of cortical CBF resp onses, measured by laser-Doppler flowmetry, increased progressively wi th higher frequencies (range = 6.25-50 Hz) to a maximum of 248% of con trol. (-)-Nicotine and (-)-lobeline each further enhanced the response s to BF stimulation, with (-)-nicotine having the most potent effect ( up to 350%). (+)-Nicotine and (-)-cotinine were without effect, sugges ting stereoselectivity and that the effects were not mediated by the m ajor metabolite of (-)-nicotine. In contrast, (-)-cystisine, another n icotinic receptor agonist, modestly inhibited the BF-elicited increase in CBF suggesting nicotinic receptor subtype selectivity in mediating the response. Arecoline, a potent muscarinic agonist, was without eff ect suggesting that muscarinic mechanisms are not involved in the medi ation of this response. None of the nicotinic agents had overt effects on heart rate or blood pressure in the dose ranges examined. In exper iments targeting the site of action of the nicotinically mediated enha ncement, (-)-nicotine microinjections into the BF elicited profound in creases in cortical CBF, whereas similar injections into the cerebral cortex were without effect suggesting that nicotine receptors mediatin g CBF increases are localized to the BF. These findings suggest that c ortical CBF may be neurogenically regulated by the BF and may be furth er enhanced by some structural classes of nicotinic agonists.