ar-r-17779 and altinicline-maleate

Repeated administration of nicotine leads to an augmentation of its locomotor activating effects. Although studies have begun to identify the nicotinic receptor subtype(s) mediating the psychostimulant properties of nicotine, none as yet have investigated the subtypes which contribute to the process of sensitisation.. We therefore investigated cross-sensitisation to nicotine using subjects chronically treated with two nicotine subtype-selective agonists in an attempt to identify the relative contribution of each to the sensitisation process.. Rats received ten daily injections of either vehicle, nicotine (0.4 mg/kg), the alpha7-agonist AR-R 17779 (20 mg/kg), or the alpha4beta2-agonist SIB 1765F (3 mg/kg), and their subsequent locomotor response to acute challenge with each of these compounds was assessed.. Chronic administration of both nicotine and SIB 1765F, but not AR-R 17779, resulted in an enhanced locomotor response to acute challenge with either nicotine or SIB 1765F but not AR-R 17779.. These data support a role for the alpha4beta2 receptor in both the initiation and expression of sensitisation to the psychomotor stimulant effects of nicotine.

Topics: Animals; Bridged-Ring Compounds; Male; Motor Activity; Nicotine; Nicotinic Agonists; Pyridines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Spiro Compounds

Neuronal nicotinic receptors are comprised of combinations of alpha(2-9) and beta(2-4) subunits arranged to form a pentameric receptor. Currently, the principal central nervous system (CNS) subtypes are believed to be alpha(4)beta(2) and a homomeric alpha(7) receptor, although other combinations almost certainly exist. The identity of the nicotinic receptor subtype(s) involved in the rewarding effects of nicotine are unknown. In the present study, using some recently described subtype selective nicotinic agonists and antagonists, we investigated the role of the alpha(7) nicotinic receptor in the mediation of nicotine-induced hyperactivity and self-administration in rats. The alpha(7) receptor agonists AR-R 17779 and DMAC failed to stimulate locomotor activity in both nicotine-nontolerant and -sensitized rats. In contrast, nicotine and the putative alpha(4)beta(2) subtype selective agonist SIB1765F increased activity in both experimental conditions. In nicotine-sensitized rats, the high affinity (including the alpha(4)beta(2) subtype) nicotinic antagonist dihydro-beta-erythroidine (DHbetaE), but not the selective alpha(7) antagonist methyllycaconitine (MLA), antagonized a nicotine-induced hyperactivity. Similarly, DHbetaE, but not MLA, pretreatment reduced nicotine self-administration. Electrophysiology experiments using Xenopus oocytes expressing the human alpha(7) receptor confirmed AR-R 17779 and DMAC to be potent agonists at this site, and further studies demonstrated the ability of systemically administered AR-R 17779 to penetrate into the CNS. Taken together, these results indicate a negligible role of alpha(7) receptors in nicotine-induced hyperlocomotion and reward in the rat, and support the view for an involvement of a member from the high-affinity nicotinic receptor subclass, possibly alpha(4)beta(2). Issues such as drug potency, CNS penetration, and desensitization of the alpha(7) receptor are discussed.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Bridged-Ring Compounds; Electrophysiology; Humans; In Vitro Techniques; Ligands; Male; Motor Activity; Nicotine; Nicotinic Agonists; Oocytes; Pyridines; Pyrrolidines; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Receptors, Nicotinic; Reward; Self Administration; Spiro Compounds; Transfection; Xenopus laevis