Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid.

The preclinical pharmacology of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to alpha4beta2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a partial agonist with 45% of nicotine's maximal efficacy at alpha4beta2 nAChRs. In neurochemical models varenicline has significantly lower (40-60%) efficacy than nicotine in stimulating [(3)H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by partially activating alpha4beta2 nAChRs, while preventing full activation of these receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.

CP-135,807, a selective 5-HT1D agonist: effects in drug discrimination and punishment procedures in the pigeon.

CP-135,807 [3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2- yl)amino-1H-indole] binds with high affinity to central 5-HT1D receptors, and in functional studies produces dose-dependent decreases in extracellular serotonin. These and other findings have suggested that CP-135,807 may act as a terminal 5-HT autoreceptor agonist. In an attempt to characterize the behavioral activity of selective 5-HT1D ligands, adult male Carneau pigeons were trained to discriminate IM injections of 0.1 mg/kg CP-135,807 from saline under a two-key, fixed ratio schedule of food-reinforced key pecking. CP-135,807 and the structurally unrelated 5-HT1D agonist CP-286,601 fully and dose-dependently substituted for the training dose. In contrast, little substitution was observed following administration of 8-OH-DPAT, a potent 5-HT1A agonist, the 5-HT1B agonist CP-94,253, or the serotonin reuptake inhibitor sertraline. In addition, the discriminative stimulus produced by CP-135,807 was not blocked by WAY 100,635, a selective 5-HT1A antagonist, but was completely and dose-dependently antagonized by the selective 5-HT1D antagonist, GR 127935. In subjects trained under a multiple schedule of punished and unpunished responding, 8-OH-DPAT produced large increases in punished responding while having little effect on unpunished responding. In contrast, CP-135,807 and CP-94,253 produced no antipunishment effects, while GR 127935 produced modest increases in punished responding. Collectively, these results suggest that CP-135,807 produces centrally mediated psychoactive effects that differ distinctly from those of 5-HT1A agonists.

Effects of the competitive nicotinic antagonist erysodine on behavior occasioned or maintained by nicotine: comparison with mecamylamine.

RATIONALE: The cellular effects of nicotine underlying its addictive liability are thought to be mediated by neuronal nicotinic receptors (nACHRs) in the central nervous system. It is believed that densely expressed beta32-containing nACHRs in the central nervous system are responsible for these actions, but few data are available that can directly assess subtype mediation of nicotine's acute subjective and reinforcing effects. OBJECTIVE: The present study compared the effects of the competitive nACHR antagonist erysodine and the noncompetitive antagonist mecamylamine in rats trained to discriminate or self-administer nicotine. METHODS: Adult male rats were trained to discriminate 0.4-mg/kg injections of nicotine from vehicle in a two-lever procedure of food-maintained behavior, or to self-administer 0.03-mg/kg injections of nicotine under fixed-ratio 5 or progressive-ratio schedules of reinforcement. Additional rats were trained under a food-maintained procedure of lever pressing. RESULTS: Erysodine (0.3-10 mg/kg) and mecamylamine (0.1-1.0 mg/kg) blocked nicotine discrimination, although only erysodine produced the rightward shift that would be predicted of a competitive antagonist. Erysodine (0.32-32 mg/kg) and mecamylamine (0.32-3.2 mg/kg) also selectively reduced nicotine self-administration on a fixed-ratio schedule and lowered break points on a progressive-ratio schedule. CONCLUSIONS: Based on the known affinity of erysodine for alpha4beta2 nACHRs and its selectivity relative to alpha7 and alpha1beta1gammadelta receptors, the present data support a critical role of beta2-containing nACHR constructs in the discriminative and reinforcing actions of nicotine.

Effects of the cannabinoid CB1 receptor antagonist SR141716A on the behavior of pigeons and rats.

SR141716A (Sanofi Recherche), a pyrazole derivative with high affinity for rat and human CB1 cannabinoid receptors, has recently been reported to reverse biochemical, physiological and behavioral effects induced by cannabinoid agonists. The present experiments characterized the activity of SR141716A (SR) in behavioral procedures designed to assess its antagonistic and intrinsic effects on unconditioned behavior and on complex learned behaviors. Six adult male pigeons were trained to discriminate injections of 0.56 mg/kg delta 9-tetrahydrocannabinol (delta 9-THC) from vehicle under a two-key, fixed-ratio schedule of food reinforcement. SR (IM) produced a nearly complete blockade of THC-appropriate responding occasioned by the training dose without inducing significant changes in session response rates, but also produced partial substitution for delta 9-THC when administered alone. In another group of pigeons trained under a multiple schedule of signaled and unsignaled fixed consecutive number (FCN) responding, SR had little effect on accuracy, but delta 9-THC produced dose-related decreases in accuracy under both schedule components. SR was also evaluated in acoustic startle procedures in rats. SR produced little effect either on startle amplitude or prepulse inhibition of acoustic startle. In contrast, the potent cannabinomimetic CP-55, 940 produced large decreases in startle responses elicited by 120 dB [A] broad-band noise. These decreases were completely reversed by SR (10 mg/kg, IP). In concurrent measures, SR blocked the hypothermic effect CP-55,940. These results suggest that SR is an effective antagonist of the psychoactive effects of cannabinoids.

The role of monoamine neurotransmitter systems in the nicotine discriminative stimulus.

Nicotine serves as a reinforcer and induces a robust discriminative stimulus which is primarily mediated by neuronal nicotinic receptors. As a secondary effect of nicotinic stimulation, nicotine elicits an enhanced release of the biogenic amine neurotransmitters dopamine, norepinephrine and serotonin. In particular, compounds with dopaminergic activity have been reported to modify both the reinforcing and discriminative stimulus properties of nicotine. The present study examined a number of dopaminergic, noradrenergic and serotonergic compounds for their effectiveness in reproducing or modifying the stimulus properties of nicotine in rats. The non-selective dopamine agonists amphetamine, cocaine and apomorphine produced partial substitution for nicotine, while the selective D2/D3 agonists bromocriptine and 7-OH-DPAT and the dopamine autoreceptor antagonist (+)-AJ-76 had little effect. The substitution of amphetamine for nicotine was not blocked by haloperidol, suggesting a minimal role for D2 receptors in the nicotine-like discriminative effects of stimulants. The selective D1 agonist SKF 81,297 produced partial substitution for nicotine (45% maximum), but further experiments with the D1 antagonist SCH 23,390 and with rats trained in a three-way discrimination procedure failed to support a primary role for this receptor in the substitution of dopaminergic drugs for nicotine. Finally, tests of compounds with effects on noradrenergic or serotonergic neurotransmission did not yield strong evidence for the involvement of these systems. Taken together, these data support earlier suggestions that activation of dopamine receptor subtypes plays a role in the nicotine-like stimulus properties of abused stimulants, but do not clearly identify a single subtype that is uniquely responsible.