Angiotensin AT1 and AT2 receptor antagonists modulate nicotine-evoked [H-3]dopamine and [H-3]norepinephrine release

作者：Narayanaswami Vidya; Somkuwar Sucharita S; Horton David B; Cassis Lisa A; Dwoskin Linda P^*

来源：Biochemical Pharmacology, 2013, 86(5): 656-665.

DOI：10.1016/j.bcp.2013.06.025

• Angiotensin II receptors
• Dopamine
• Nicotinic acetylcholine receptors
• Norepinephrine
• Reward
• Smoking

Tobacco smoking is the leading preventable cause of death in the United States. A major negative health consequence of chronic smoking is hypertension. Untoward addictive and cardiovascular sequelae associated with chronic smoking are mediated by nicotine-induced activation of nicotinic receptors (nAChRs) within striatal dopaminergic and hypothalamic noradrenergic systems. Hypertension involves both brain and peripheral angiotensin systems. Activation of angiotensin type-1 receptors (AT1) release dopamine and norepinephrine. The current study determined the role of AT1 and angiotensin type-2 (AT2) receptors in mediating nicotine-evoked dopamine and norepinephrine release from striatal and hypothalamic slices, respectively. The potential involvement of nAChRs in mediating effects of AT1 antagonist losartan and AT2 antagonist, 1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (PD123319) was evaluated by determining their affinities for alpha 4 beta 2* and alpha 7* nAChRs using [H-3]nicotine and [H-3]methyllycaconitine binding assays, respectively. Results show that losartan concentration-dependently inhibited nicotine-evoked [H-3]dopamine and [H-3]norepinephrine release (IC50: 3.9 +/- 1.2 and 2.2 +/- 0.7 mu M; I-max: 82 +/- 3 and 89 +/- 6%, respectively). In contrast, PD123319 did not alter nicotine-evoked norepinephrine release, and potentiated nicotine-evoked dopamine release. These results indicate that AT1 receptors modulate nicotine-evoked striatal dopamine and hypothalamic norepinephrine release. Furthermore, AT1 receptor activation appears to be counteracted by AT2 receptor activation in striatum. Losartan and PD123319 did not inhibit [H-3]nicotine or [H-3]methyllycaconitine binding, indicating that these AT1 and AT2 antagonists do not interact with the agonist recognition sites on alpha 4 beta 2* and alpha 7* nAChRs to mediate these effects of nicotine. Thus, angiotensin receptors contribute to the effects of nicotine on dopamine and norepinephrine release in brain regions involved in nicotine reward and hypertension.

• 出版日期2013-9-1