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

Vidya Narayanaswami, Sucharita S. Somkuwar, David B. Horton, Lisa A. Cassis, Linda P. Dwoskin

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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-(dipheny- lacetyl)-4,5,6,7- tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (PD123319) was evaluated by determining their affinities for α4β2* and α7* nAChRs using [3H]nicotine and [3H]methyllycaconitine binding assays, respectively. Results show that losartan concentration-dependently inhibited nicotine- evoked [3H]dopamine and [3H]norepinephrine release (IC50: 3.9 ± 1.2 and 2.2 ± 0.7 μM; Imax: 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 [3H]nicotine or [3H]methyllycaconitine binding, indicating that these AT1 and AT2 antagonists do not interact with the agonist recognition sites on α4β2* and α7* 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.

Original languageEnglish
Pages (from-to)656-665
Number of pages10
JournalBiochemical Pharmacology
Issue number5
StatePublished - 2013

Bibliographical note

Funding Information:
The authors acknowledge Dr. Kiran Babu Siripurapu for technical assistance. This research was supported by NIH P50 DA05312 , NIH HL73085 and P20RR021954 , and a Pre-doctoral Fellowship from the American Heart Association , AHA 715489B .


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

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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