Noradrenergic α1 Receptors as a Novel Target for the Treatment of Nicotine Addiction

Nicotine is the main psychoactive ingredient in tobacco and its rewarding effects are considered primarily responsible for persistent tobacco smoking and relapse. Although dopamine has been extensively implicated in the rewarding effects of nicotine, noradrenergic systems may have a larger role than previously suspected. This study evaluated the role of noradrenergic α1 receptors in nicotine and food self-administration and relapse, nicotine discrimination, and nicotine-induced dopamine release in the nucleus accumbens in rats. We found that the noradrenergic α1 receptor antagonist prazosin (0.25–1 mg/kg) dose dependently reduced the self-administration of nicotine (0.03 mg/kg), an effect that was maintained over consecutive daily sessions; but did not reduce food self-administration. Prazosin also decreased reinstatement of extinguished nicotine seeking induced by either a nicotine prime (0.15 mg/kg) or nicotine-associated cues, but not food-induced reinstatement of food-seeking, and decreased nicotine-induced (0.15 mg/kg) dopamine release in the nucleus accumbens shell. However, prazosin did not have nicotine-like discriminative effects and did not alter the dose-response curve for nicotine discrimination. These findings suggest that stimulation of noradrenergic α1 receptors is involved in nicotine self-administration and relapse, possibly via facilitation of nicotine-induced activation of the mesolimbic dopaminergic system. The findings point to α1 adrenoceptor blockade as a potential new approach to the treatment of tobacco dependence in humans

Ventral Striatal Noradrenergic Mechanisms Contribute to Sensorimotor Gating Deficits Induced by Amphetamine

The psychotomimetic drug -amphetamine (AMPH), disrupts prepulse inhibition (PPI) of the startle response, an operational measure of sensorimotor gating that is deficient in schizophrenia patients. Historically, this effect has been attributed to dopaminergic substrates; however, AMPH also increases norepinephrine (NE) levels, and enhancement of central NE transmission has been shown recently to disrupt PPI. This study examined the extent to which NE might participate in AMPH-induced disruptions of PPI and increases in locomotor activity, another classic behavioral effect of AMPH, by determining whether antagonism of postsynaptic NE receptors blocked these effects. Separate groups of male Sprague–Dawley rats received either the α1 receptor antagonist, prazosin (0, 0.3, 1 mg/kg), or the β receptor antagonist timolol (0, 3, 10 mg/kg) before administration of AMPH (0 or 1 mg/kg) before testing for PPI or locomotor activity. As an initial exploration of the anatomical substrates underlying possible α1 receptor-mediated effects on AMPH-induced PPI deficits, the α1 receptor antagonist terazosin (0 or 40 μg/0.5 μl) was microinfused into the nucleus accumbens shell (NAccSh) in conjunction with systemic AMPH administration before startle testing in a separate experiment. Prazosin, but not timolol, blocked AMPH-induced hyperactivity; both drugs reversed AMPH-induced PPI deficits without altering baseline startle responses. Interestingly, AMPH-induced PPI deficits also were partially blocked by terazosin in NAccSh. Thus, behavioral sequelae of AMPH (PPI disruption and hyperactivity) may be mediated in part by NE receptors, with α1 receptors in NAccSh possibly having an important role in the sensorimotor gating deficits induced by this psychotomimetic drug