These results indicate that blockade of mGluR5 decreased nicotine self-administration in both rats and mice, and are consistent with findings showing a role of mGluR5 in cocaine self-administration. It is postulated that mGluR5 plays an essential role in mediating the reinforcing effects of nicotine, possibly but not exclusively, via modulation of mesolimbic dopaminergic neurotransmission.

Escalation in cocaine self-administration is hypothesized to involve increased motivation to consume cocaine. The present study determined the effects of escalated cocaine self-administration in rats on the cocaine dose-response function under a progressive ratio schedule. Two groups of rats were allowed to self-administer cocaine under a fixed ratio schedule, for 1 h (ShA; n = 7) or 6 h (LgA; n = 6) per day. The subjects were then allowed to self-administer five doses of cocaine (0, 0.031, 0.063, 0.125 and 0.25 mg/infusion) under a progressive ratio schedule. The dose-response function was shifted upwards in the LgA compared to the ShA group. In conclusion, the present data suggest that escalation in cocaine self-administration is associated with a significant increase in the incentive motivational value of self-administered cocaine.

The present study characterized nicotine intake, circadian patterns of food and water intake, precipitated somatic signs of withdrawal, and extinction of nicotine-seeking behavior in rats with 23-h access to intravenous self-administration (IVSA). Separate groups of animals were allowed access to nicotine IVSA (0.015, n ϭ 9; 0.03, n ϭ 14; 0.06, n ϭ 16; mg/kg/0.1 ml infusion/s; fixed ratio 1) and trained to nosepoke for food and water 23 h/day for 40 consecutive days. Somatic signs of nicotine withdrawal were examined following saline or mecamylamine administration (1.5 mg/kg i.p.), and extinction of nicotine-seeking behavior was assessed. A dose-dependent decrease in lever responding and an increase in nicotine intake were observed, with the highest nicotine dose producing the lowest amount of lever responding and the highest amount of nicotine intake. Nicotine acutely reduced diurnal and nocturnal food intake, producing smaller and fewer meals, and an increased rate of eating. Differences in rate of nicotine intake between the light and dark phase decreased significantly, especially in rats receiving higher unit nicotine doses (0.03 and 0.06 mg/kg), along with long-term decreases in the circadian profile and amplitude of feeding. Mecamylamine precipitated robust withdrawal signs, the magnitude of which was positively correlated with the total amount of self-administered nicotine. Extinction of nicotine-seeking behavior was observed and was facilitated by removal of nicotine-associated cues. The results demonstrate that rats will self-administer nicotine to the point of producing dependence, as measured by somatic signs, resistance to extinction, and measures of food intake.To more closely model tobacco use in humans, recent studies have examined extended access to nicotine intravenous self-administration (IVSA) in rats. For example, female rats display increased nicotine IVSA during the active phase of the light cycle during 3 weeks of continuous nicotine access (Cox et al., 1984). These rats also display a compensatory increase in nicotine IVSA when the dose is lowered (0.03 to 0.003 mg/kg) and a decrease in nicotine-seeking behavior when nicotine is replaced with saline. Moreover, male rats display nicotine IVSA in extended access models (6 -23 h) using low nicotine doses (0.00375 mg/kg/injection), and the level of nicotine intake approximates that of human smokers (Valentine et al., 1997;Paterson and Markou, 2004;Kenny and Markou, 2006). The 23-h access model of nicotine IVSA seems to be sensitive to genetic differences, since nicotine intake is more quickly acquired and persistently maintained in Lewis versus Holtzman and Fisher strains of male rats (Brower et al., 2002). Furthermore, the 23-h model of nicotine IVSA is sensitive to passive nicotine administration. Nicotine intake decreased following implantation of a minipump that delivers doses of nicotine that are equal to, or higher than, peak levels associated with simulated nicotine intake (LeSage et al., 2002). In addition, nicotine intake in ...

The mGlu5 receptor is implicated in mediating the reinforcing and incentive motivational properties of nicotine, cocaine and food.

Nicotinic acetylcholine receptor (nAChR) antagonists have been shown previously to decrease nicotine self-administration and precipitate elevations in brain reward thresholds and somatic signs of withdrawal in animals chronically exposed to nicotine. Both the positive-reinforcing effects of acute nicotine and the negative effects of nicotine withdrawal have been hypothesized to contribute to the development and maintenance of nicotine dependence. The aim of the present study was to use methyllycaconitine (MLA), an alpha 7 nAChR antagonist, to investigate the role of alpha 7 receptors in the reinforcing effects of nicotine and nicotine withdrawal. MLA was administered to animals allowed to self-administer nicotine intravenously, and also to animals that had been prepared with nicotine-containing osmotic mini-pumps and trained on a brain stimulation reward procedure. The results indicated that pretreatment with the highest doses of MLA used (3.9 and 7.8 mg/kg) significantly reduced nicotine self-administration at two doses of self-administered nicotine (0.03 and 0.06 mg/kg/infusion). Nevertheless, MLA administration, at all doses tested, had no effect on brain reward thresholds or the number of somatic signs of withdrawal observed in rats chronically exposed to either nicotine or saline. In conclusion, the alpha 7 nAChR subtype appears to play a significant role in the reinforcing effects of acute nicotine administered intravenously, but not in nicotine dependence, as reflected in the lack of precipitation of the nicotine withdrawal syndrome in nicotine-treated animals.

The present data demonstrate that administration of GABA(B) receptor agonists decreased intravenous nicotine self-administration under both fixed and progressive ratio schedules of reinforcement, possibly reflecting reduced rewarding effects of nicotine. Both baclofen and CGP44532 exhibited specificity for nicotine- versus food-maintained responding on the fixed ratio schedules but not on the progressive ratio schedule (CGP44532 tested only), indicating the potential usefulness of GABA(B) receptor agonists as therapeutics for smoking cessation.

There was no escalation in nicotine intake with extended access conditions, unlike cocaine self-administration. Nevertheless, daily nicotine self-administration seven days per week, for either 1 or 6 h per day, was sufficient to induce long-lasting adaptations in nicotinic acetylcholine receptor activity reflected in spontaneous and antagonist-precipitated somatic signs of withdrawal, possibly reflecting aspects of nicotine dependence.

Acute administration of ␥-aminobutyric acid (GABA)-B receptor agonists decreases nicotine, cocaine, ethanol, and heroin selfadministration and also decreases food-maintained responding and suppresses locomotor activity at high doses. GABA B receptor-positive modulators may represent potentially improved therapeutic compounds because of their fewer side effects than receptor agonists. The present study investigated the effects of administration of the GABA B receptor-positive modulators 2,6-di- tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) and coadministration of the GABA B receptor-positive modulator N,NЈ-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) with the GABA B receptor agonist (3-amino-2[S]-hydroxypropyl)-methylphosphinic acid (CGP44532) on nicotineand food-maintained responding under fixed ratio (FR) 5 and progressive ratio schedules of reinforcement. Furthermore, the effects of BHF177 and CGP44532 on nicotine-induced enhancement of brain reward function were evaluated. The results indicated that administration of CGP7930 decreased nicotine selfadministration under an FR5 schedule. Administration of either GS39783 or CGP44532 selectively decreased nicotine selfadministration, whereas coadministration of these compounds had additive effects. BHF177 administration selectively decreased nicotine-but not food-maintained responding under FR5 and progressive ratio schedules. The nicotine-induced enhancement of brain reward function was blocked by BHF177 or CGP44532, although the highest doses of both compounds, particularly CGP44532, decreased brain reward function when administered alone, suggesting an additive, rather than interactive, effect. Overall, the present results indicate that GABA B receptor-positive modulators, similarly to GABA B receptor agonists, attenuated the reinforcing and reward-enhancing effects of nicotine, perhaps with higher selectivity than GABA B receptor agonists. Thus, GABA B receptor-positive modulators may be useful antismoking medications.