Detection by in vivo microdialysis of nicotine-induced norepinephrine secretion from the hypothalamic paraventricular nucleus of freely moving rats: dose-dependency and desensitization.
The ACTH response to many stimuli depends on the secretion of norepinephrine, which activates neurons in the hypothalamic paraventricular nucleus (PVN). Studies with adrenergic antagonists and inhibitors of catecholamine synthesis indicate that norepinephrine is a mediator of nicotine-induced ACTH secretion. To directly assess the effect of nicotine on PVN norepinephrine secretion, in vivo microdialysis was performed. Nicotine (0.5 mg/kg BW, ip) induced peak norepinephrine levels within 20 min (approximately 2 x basal). The central nicotinic receptor antagonist, mecamylamine, abolished this response, whereas hexamethonium, a peripheral antagonist, was ineffective. The norepinephrine response was dose dependent (ED50, approximately 0.25 mg/kg), and nicotine (0.5 mg/kg BW) induced maximal secretion. Rapid desensitization occurred, as evidenced by a significant reduction (approximately 50%) in the response to a second injection of nicotine (0.5 mg/kg BW). Animals also received four injections of nicotine to determine whether repetitive dosing leads to progressive reduction of the norepinephrine response. The responses to the third and fourth nicotine injections were similar. Thus, desensitization occurred after a single exposure to nicotine and was not progressive. In contrast, nicotine pretreatment did not affect the release of norepinephrine due to yohimbine. These results indicate that basal and nicotine-stimulated levels of norepinephrine can be detected in microdialysates from the PVN; rapid desensitization of the norepinephrine response to nicotine and inhibition by mecamylamine, but not hexamethonium, parallel the findings previously reported for ACTH.
Endocrine-Neuroscience Research Laboratory, Minneapolis Medical Research Foundation, Minnesota 55404.
B M
BM
Sharp
S G
SG
Matta
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003956:Dialysis; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D009627:Nomifensine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D015016:Yohimbine / Q000494:pharmacology
D009627:Nomifensine; D015016:Yohimbine; D009538:Nicotine; D000324:Adrenocorticotropic Hormone; D009638:Norepinephrine