DESENSITIZATION OF CENTRAL NICOTINIC CARDIOVASCULAR EFFECTS BY NICOTINE ISOMERS AND A QUATERNARY ANALOGUE

Abstract Nicotine produces potent cardiovascular and sympathoadrenal effects. Furthermore, repeated administration of nicotine is associated with development of tolerance for many responses. We sought to compare the effects of initial intracerebral administration of nicotine isomers and a quaternary analogue on cardiovascular and sympathoadrenal responses and to compare the desensitizing properties of these nicotinic compounds on subsequent responses to nicotine. Thus we examined the effects of (−)-nicotine, (+)-nicotine, N'-methylnicotinium iodide (N'MN), a quaternary analogue of (-)-nicotine, and saline vehicle, administered into a lateral cerebral ventricle, on heart rate (HR), systolic, diastolic and mean arterial blood pressure (BP), and plasma concentrations of epinephrine and norepinephrine in conscious, freely moving, adult, male rats. (-)-Nicotine (120 nmol, ICV) produced decrease in HR and increases in all other parameters. (+)-Nicotine at this dose produced only small effects on HR, BP and plasma catecholamines. An equimolar dose of N'MN produced similar effects on these parameters, quantitatively intermediate between those of the two nicotine isomers. Thirty min after administration of these nicotinic agonists, all parameters had returned to baseline. At this time, the effects of subsequent ICV administration of (-)-nicotine 120 nmol was studied in all animals. Prior administration of either (-)-nicotine or (+)-nicotine markedly attenuated the bradycardic response to (-)-nicotine, and N'MN was less effective in this regard. In contrast, neither (-)-nicotine nor N'MN inhibited the pressor responses to subsequent (-)-nicotine, whereas (+)-nicotine did produce some attenuation of this pressor response. Similarly, only (+)-nicotine, was found to inhibit the plasma norepinephrine response to subsequent (-)-nicotine when this drug dose and timing of administration were used. The epinephrine response subsequent (-)-nicotine was not affected by this dose (120 nmol) and timing of treatment with any of these ligands. These data support the concept that desensitization of the intracerebral effects of nicotine on cardiovascular and sympathoadrenal function may be mediated at binding sites other than those producing nicotinic responses.