Yitong Fu

Response of the hypothalamo-pituitary-adrenal axis to nicotine.

Nicotine has been shown to be a potent stimulus for the secretion of the stress-responsive hormones, adrenocorticotropin (ACTH) and prolactin. This paper reviews the findings by our laboratory and others that demonstrate the polysynaptic pathways involved in the neuroendocrine responses to systemic nicotine. It will focus primarily on the hypothalamo-pituitary-adrenal (HPA) axis and the effect of nicotine on ACTH secretion, with supplementary information on prolactin secretion, where relevant. Data are presented demonstrating that nicotine acts via a central mechanism to stimulate indirectly the release of ACTH from the anterior pituitary corticotropes. Nicotine does not appear to act directly at the hypothalamic paraventricular nucleus (PVN), the site of the corticotropin-releasing hormone (CRH) neurons crucial to the regulation of ACTH. However, brainstem catecholaminergic regions projecting to the PVN showed a regionally selective and dose-dependent sensitivity to nicotine, particularly the noradrenergic/adrenergic nucleus tractus solitarius (NTS). A reduction in the modulatory effect of these catecholamines (by neurotoxic lesion, synthetic enzyme inhibitors or adrenergic receptor antagonists) resulted in an inhibition of nicotine-stimulated ACTH secretion. In addition, blockade of nicotinic cholinergic receptors (NAchRs) in the brainstem by the antagonist, mecamylamine, resulted in a dose-dependent reduction in norepinephrine (NE) release from terminals in the PVN, and a concomitant reduction in plasma ACTH. The differential sensitivity of these receptors to the nicotinic agonists, cytisine and nicotine, reflects the heterogeneity of the NAchR subtypes involved. The desensitization characteristics of the neuroendocrine responses to both acute and chronic nicotine exposure are indicative of an alteration in these NAchRs.

Rat strain differences in nicotine self-administration using an unlimited access paradigm

An effective animal model for elucidating the neurobiological basis of human smoking should simulate important aspects of this behavior. Therefore, a 23 h unlimited access nicotine self-administration model was used to compare inbred Lewis rats, which have a propensity to self-administer drugs of abuse, to inbred Fisher 344 rats and to the outbred Holtzman strain. Using this unlimited access model, 88.8% of Lewis vs. 57.1% of Holtzman rats achieved maintenance self-administration at a fixed ratio 1 (FR 1) at 0.03 mg/kg IV nicotine (P<0.05). In contrast, Fisher rats did not acquire self-administration under these conditions. Of the Lewis and Holtzman rats that achieved maintenance self-administration on an FR 1 schedule, a greater percentage of Lewis rats acquired nicotine self-administration at FR 2 (P<0.05) and progressed to FR 4 (P<0.05). Using naïve cohorts in a progressive dose reduction study, 83.3% of Lewis rats achieved maintenance at 0.0075 mg/kg nicotine as compared to 31.8% of Holtzman rats (P<0.05). Furthermore, only Lewis rats showed differences in active vs. inactive bar presses during maintenance at sequential dose reductions (P<0.001). Thus, in this unlimited access model, inbred Lewis rats will more reliably acquire nicotine self-administration than outbred Holtzman rats. Moreover, Lewis rats showed a significantly higher likelihood of continuing to self-administer nicotine in face of both increasing work requirements and decreasing drug reinforcement. Therefore, it is likely that Lewis rats would be genetically susceptible to nicotine addiction.

Chronic nicotine self-administration augments hypothalamic-pituitary-adrenal responses to mild acute stress.

We investigated the effect of chronic nicotine self-administration (SA) on hypothalamic–pituitary–adrenal (HPA) hormonal responses to acute stressors. Adult male Sprague–Dawley rats were given access to nicotine (0.03 mg/kg) for 23 h per day for 20 days. On day 1 of acquisition of nicotine SA, plasma levels of both adrenocorticotropin and corticosterone were significantly increased 15–30 min after the first dose of nicotine. These hormonal changes were no longer significant on day 3, when adrenocorticotropin levels were <60 pg/ml and corticosterone levels were <110 ng/ml during the hour after the first dose of nicotine. Chronic nicotine SA (20 days) significantly augmented (2–3-fold) both hormonal responses to mild foot shock stress (0.6 mA, 0.5 s per shock, 5 shocks per 5 min), but did not affect hormonal responses to moderate shock (1.2 mA, 0.5 s per shock, 5 shocks per 5 min), lipopolysaccharide or immobilization. Similar data were obtained in Lewis rats. These results provide further support for the concept that chronic nicotine SA is a stressor. In alignment with the effects of other stressors, nicotine activated the HPA axis on the first day of SA, but desensitization occurred with repeated exposure. Furthermore, chronic nicotine SA selectively cross-sensitized the HPA response to a novel stressor. These observations suggest that nicotine may selectively increase the HPA response to stressors in human smokers.

Norepinephrine release in amygdala of rats during chronic nicotine self-administration: an in vivo microdialysis study.

The essential role of the amygdala in learning and memory, including cue-associated learning, is influenced by local release of norepinephrine (NE). The current study investigated changes in amygdaloid NE secretion in rats learning to self-administer nicotine in an unlimited access model (23 h/day). In vivo microdialysis of NE was performed for 9 h intervals during three phases of nicotine self-administration: acquisition (day 1); early maintenance, when self-administration rates first stabilized (day 8.4+/-0.7); and later, during fully stable maintenance (day 17.6+/-1.0). On day 1, a greater number of self-administration episodes (SAEs) were associated with elevated NE levels in rats bar-pressing for nicotine (88% vs. 39% with saline). By early maintenance, such episodes increased threefold and overall NE levels were greater. During later maintenance, however, bar-pressing behavior was similar and NE was elevated by the first SAE of the day, but total daily NE levels were no longer elevated. In all the three phases, the enhanced NE release during the first daily SAE did not occur in the last SAE 9 h later. Thus, in an animal model of unlimited nicotine self-administration that approximates the human pattern of nicotine consumption via smoking, the amygdaloid NE response to nicotine diminishes over each day and with the stabilization of self-administration. The decline of amygdaloid NE secretion after long-term nicotine self-administration likely reflects desensitization to the pharmacological effects of nicotine. In addition, amygdaloid NE release, which enhances the consolidation of amygdala-dependent memory, may no longer be necessary once self-administration behavior has been established.

Inhibition of nicotine-induced hippocampal norepinephrine release in rats by alpha-conotoxins MII and AuIB microinjected into the locus coeruleus

Hippocampal norepinephrine (NE) is secreted by neurons projecting from the locus coeruleus (LC) to the hippocampus; LC nicotinic receptors (NAchRs) are involved in the effects of systemic nicotine on this pathway. To clarify the NAchR subtypes, NAchR antagonists, termed alpha-conotoxins, were microinjected into the LC before nicotine; MII and AuIB were used to assess the potential involvement of alpha3beta2 and alpha3beta4 subunit-containing NAchRs, respectively. Nicotine dose-dependently stimulated hippocampal NE release (P < 0.01). MII (>0.25 pmol) reduced the NE response to nicotine (67% decrease; P < 0.05), as did AuIB (44% reduction by 25 pmol; P < 0.05). Administered together, however, MII and AuIB were no more effective than MII. Thus, MII and AuIB are capable of interacting with NAchR subtypes other than those previously defined as alpha3beta2 and alpha3beta4, respectively. NAchRs containing both beta2 and beta4-subunits may be involved.

Desensitization and resensitization of norepinephrine release in the rat hippocampus with repeated nicotine administration

Desensitization of norepinephrine release was investigated with repeated intravenous (i.v.) infusions of nicotine and in vivo microdialysis of the hippocampus. At 100 min intervals, rats received three infusions of one of the following doses of nicotine: 0.045, 0.09 or 0.135 mg/kg. Doses of 0.09 mg/kg or higher increased norepinephrine release (F= 2.41, P < 0.05). However, the norepinephrine response to the second or third infusion was significantly reduced, compared to the first. The extent of desensitization and rate of resensitization was investigated further by administering consecutive infusions of nicotine (0.135 mg/kg) 40, 60, 100 or 200 min apart. Less norepinephrine was released after a second nicotine infusion given 40 to 100 min later, but this was not reduced further by a third infusion. Norepinephrine release was unchanged with a 200 min inter-infusion interval. Therefore, in the hippocampus, maximal desensitization of nicotine-stimulated norepinephrine release occurs as early as 40 min and persists for at least 100 min; thereafter, resensitization becomes the dominant process.