NICOTINIC AGONISTS ADMINISTERED INTO THE 4TH VENTRICLE STIMULATE NOREPINEPHRINE SECRETION IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS - AN IN-VIVO MICRODIALYSIS STUDY

Nicotinic cholinergic agonists stimulate ACTH secretion by a central m echanism involving brainstem catecholamines. In vivo microdialysis stu dies were conducted to measure the release of norepinephrine (NE) in t he hypothalamic paraventricular nucleus (PVN) in response to the admin istration of nicotine (Nic) or another nicotinic cholinergic (NAch) ag onist, cytisine (Cyt), directly into the IVth ventricle. Alert, freely mobile rats, equipped 24 h previously with a chronic guide cannula in the IVth ventricle and microdialysis probe in the PVN, were injected with artificial cerebrospinal fluid (CSF, 500 nl/60 s), Nic (1-5 mu g) , or Cyt (1-25 mu g) after three 20-min baseline samples had been take n. Analysis of the dialysates by HPLC with electrochemical detection d emonstrated the dose-dependent secretion of PVN NE to Nic or Cyt with ED(50)s of approximately 1 or 6 mu g, respectively; these were complet ely blocked by prior IVth ventricular injection of the NAch antagonist , mecamylamine (4 mu g). In contrast, alpha-bungarotoxin, which antago nizes the action of NAch agonists by acting through the alpha(7) bunga rotoxin-type NAchR, failed to reduce the NE response to Nic. Partial, but significant desensitization of NE secretion in response to a secon d injection of Nic (2.5 or 5 mu g) 100 min after the first was seen, w hereas NE responses to the second injection of Cyt (5 or 25 mu g) were completely desensitized. However, cross-desensitization of each agoni st to the other did not occur. This may reflect heterogeneity of the N Ach receptor subtypes involved. The results of this study establish a correlation between the action of nicotine on brainstem norepinephrine rgic regions and the resultant release of NE in the PVN, which would l ead to the release of ACTH secretagogues.