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Nicotine use and dependence is very high in patients with schizophrenia. One possible reason is that altered dopamine or glutamate activity in schizophrenia enhances the reinforcing effectiveness of nicotine. We used animal models to test the hypothesis that a hyperdopaminergic state (induced by repeated intermittent injections of amphetamine) or altered glutamate function (subchronic injection of phencyclidine, PCP) facilitates spontaneous acquisition of nicotine self-administration in rats. In Experiment 1 animals in an amphetamine-induced sensitized state (AISS) did not differ from saline-injected controls in their acquisition and maintenance of nicotine self-administration. This effect was replicated in experiment 2, but it was also found that AISS rats and saline-injected controls showed higher rates of nicotine self-administration compared to uninjected controls. This difference was maintained across several fixed ratio and progressive ratio schedules of reinforcement. In Experiment 3 PCP treated rats and their saline-injected controls did not differ in nicotine self-administration. However, both groups showed consistently increased responding for nicotine on FR and PR schedules compared to an uninjected control group. Injection-stress appeared to influence the outcomes of these experiments in two ways. Firstly, injection stress potentially masked the impact of the AISS and PCP treatment on nicotine self-administration. Secondly, injection stress itself may have been sufficient to induce plastic changes in dopamine and glutamate systems, and these changes enhanced the acquisition and maintenance of nicotine self-administration. Further investigation is needed into the role of stress in the development of nicotine use and dependence, in the aetiology of schizophrenia and in their co-morbidity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The cannabinoid system appears to play a critical facilitative role in mediating the reinforcing effects of nicotine and relapse to nicotine-seeking behaviour in abstinent subjects based on the actions of cannabinoid (CB) receptor antagonists. However, the effects of CB receptor stimulation on nicotine self-administration and reinstatement have not been systematically studied. Here, we studied the effects of WIN 55,212-2, a CB1/2 agonist, on intravenous nicotine self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement in rats. The effects of WIN 55,212-2 on responding for food under similar schedules were also studied. In addition, the effects of WIN 55,212-2 on nicotine- and cue-induced reinstatement of nicotine seeking were also studied, as well as the effects of WIN 55,212-2 on nicotine discrimination. WIN 55,212-2 decreased nicotine self-administration under the FR schedule. However, co-administration of WIN 55,212-2 with nicotine decreased responding for food, which suggests that this effect was non-selective. In contrast, WIN 55,212-2 increased both nicotine self-administration and responding for food under the PR schedule, produced dose-dependent reinstatement of nicotine seeking, and enhanced the reinstatement effects of nicotine-associated cues. Some of these effects were reversed by the CB1 antagonist rimonabant, but not by the CB2 antagonist AM630. In the drug discrimination tests between saline and 0.4 mg/kg nicotine, WIN 55,212-2 produced no nicotine-like discriminative effects but significantly potentiated discriminative stimulus effects of nicotine at the low dose through a CB1-receptor-dependent mechanism. These findings indicate that cannabinoid CB1-receptor stimulation increases the reinforcing effects of nicotine and precipitates relapse to nicotine-seeking behaviour in abstinent subjects. Thus, modulating CB1-receptor signalling might have therapeutic value for treating nicotine dependence., (© 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.)

The dopamine D3 receptor (DRD3) has been suggested to be involved in the mechanisms underlying stimulus-controlled drug-seeking behaviour. Ligands acting as DRD3 antagonists (SB 277011-A) or DRD3 partial agonists (BP 897) have shown some promise for reducing the influence of drug-associated cues on motivational behaviour. Here, effects of SB 277011-A and BP 897 were evaluated on cue-induced reinstatement of nicotine-seeking in rats. The effects of BP 897 on nicotine self-administration under a fixed-ratio 5 (FR5) schedule of reinforcement were also evaluated. SB 277011-A (1-10 mg/kg) was able to block cue-induced reinstatement of nicotine-seeking, indicating that DRD3 selective antagonism may be an effective approach to prevent relapse for nicotine. In contrast, BP 897 did not block the cue-induced reinstatement of nicotine-seeking or nicotine-taking under the FR5 schedule. In a control study, rats did not respond to the light stimuli without nicotine delivery, indicating that the responding for the drug-associated cues was induced by the previous pairing of light stimuli with nicotine's effects. These findings validate the role of DRD3 on reactivity to drug-associated stimuli and suggest that the DRD3 antagonist, but perhaps not the DRD3 partial agonist, could be used to prevent relapse in tobacco smokers.

Rationale: The endocannabinoid system has been recently identified as having critical involvement in drug taking and relapse phenomenon for various drugs of abuse and notably nicotine. The endocannabinoid system consists of endocannabinoids (such as anandamide), their target receptors (mostly cannabinoid CB(1) receptors), and the enzymes that degrade those endocannabinoids (fatty-acid-amide-hydrolase (FAAH) for anandamide). It has been recently identified that the utility of rimonabant for smoking cessation may be limited by its psychiatric side effects. Therefore, there is a great need to develop alternative ways of modulating the cannabinoid system that will be better tolerated., Objective: The aim of the study was to explore the effect of inhibiting FAAH enzyme by URB597 on nicotine self-administration under a progressive ratio schedule and reinstatement of nicotine seeking, in comparison with the effect of the CB(1) antagonist rimonabant., Results: Rimonabant, but not URB597, dose-dependently reduced the break point for nicotine self-administration, an effect that was stable over repeated administrations. Rimonabant and URB597 significantly decreased the reinstatement of nicotine seeking induced either by presentation of nicotine-associated stimuli or by nicotine priming., Conclusions: These results indicate that the integrity of the CB(1) receptors is necessary for the incentive motivation of the rats for nicotine and that FAAH inhibition may be as effective as CB(1) receptor blockade to prevent reinstatement of nicotine seeking. Since FAAH inhibition present antidepressant and anxiolytic properties in rodents, targeting the FAAH may represent a novel strategy to prevent relapse for tobacco smoking that may be better tolerated than rimonabant.

Rationale: The use of animal models to study existing medications for smoking cessation can elucidate the mechanism(s) of action of cessation agents and further validate the models for medication development., Objective: The objective of the study was to evaluate the response of nicotine self-administration (NSA) to pharmacological agents related to the smoking cessation medication bupropion and to nicotine dosing mimicking nicotine replacement on fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement., Materials and Methods: NSA was maintained at a nicotine dose of 30 microg/kg/infusion i.v. in rats trained on FR5 and PR40% schedules. Pharmacological manipulations related to bupropion were examined by treating animals with a dopamine reuptake inhibitor [GBR 12909 (GBR)], a norepinephrine reuptake inhibitor [nisoxetine (NIS)], and a nicotinic antagonist [dihydro-beta-erythroidine (DHbetaE)]. The effect of nicotine replacement was examined on the PR schedule by chronic dosing with osmotic minipumps., Results: Significant treatment effects occurred with NIS and combinations of NIS-DHbetaE and with GBR on response rates. Chronic nicotine dosing reduced self-administration. The two schedules yielded different results with some treatments., Conclusions: Noradrenergic-nicotinic cholinergic interactions and enhanced responding consequent to dopamine reuptake inhibition may be part of the complex behavioral pharmacology of bupropion-like compounds. Observation of differential results with the two schedules has implication for the use of self-administration techniques to elaborate the mechanisms of dependence as well as drug discovery.

Rationale: The pedunculopontine tegmental nucleus (PPTg) has been implicated in the self-administration of drugs, particularly nicotine, which acts directly through the PPTg in addition to targeting midbrain dopamine neurons. The direct action of nicotine in PPTg may be through GABAergic mechanisms that have been shown to influence nicotine self-administration preferentially compared to cocaine., Objective: The purpose of these experiments was to examine several pharmacological manipulations that alter neuronal activity in the PPTg for their specificity or generality in nicotine versus cocaine reinforcement., Methods and Results: Rats trained to self-administer nicotine or cocaine intravenously were prepared with brain microcannulae directed to the PPTg. Intra-PPTg microinfusions of the muscarinic agonist carbachol (0.1-1.0 microg), the micro opioid agonist DAMGO (0.005 and 0.05 microg), tetrodotoxin (5 ng) and neostigmine (0.5 nmol) each reduced the self-administration of nicotine and cocaine maintained on an FR5 schedule of reinforcement. The muscarinic antagonist scopolamine (0.1-1.0 microg) and the opioid antagonist CTOP (1 microg) did not affect self-administration, but reversed the effects of the respective agonist when co-administered with it. Carbachol and DAMGO were also tested in self-administration maintained on a progressive-ratio schedule; each agonist again reduced both nicotine and cocaine self-administration., Conclusions: PPTg manipulations are able to alter established self-administration of nicotine, which acts at the level of the ventral tegmental area and the PPTg itself, and cocaine, which acts through the mesolimbic dopamine system. These data suggest that the PPTg is an important substrate in drug dependence.

Rationale: The pedunculopontine tegmental nucleus (PPTg) is part of the neuronal circuit activated by self-administered nicotine. The cholinergic neurons of the PPTg comprise a prominent projection to midbrain dopamine neurons. However, anatomical studies of Fos expression suggest that nicotine targets primarily non-cholinergic neurons in the PPTg, especially GABAergic and glutamatergic neurons., Objective: The objective of these experiments was to examine the role of GABA manipulations in the PPTg on nicotine self-administration., Methods and Results: Rats trained to self-administer nicotine or cocaine intravenously were prepared with brain microcannulae directed to the PPTg. Intra-PPTg microinfusions of the GABA agonists muscimol (10-50 ng) and baclofen (30-60 ng) reduced nicotine self-administration maintained on a fixed-ratio schedule of reinforcement (30 microg/kg per infusion); self-administration of cocaine (0.3 mg/kg per infusion) under an identical schedule was not affected. Muscimol and baclofen were also examined after intra-PPTg microinfusion in animals trained to self-administer nicotine on a progressive-ratio schedule (10 and 30 microg/kg per infusion). Progressive-ratio responding was sensitive to pharmacological manipulations such as a change in the nicotine dose available for self-administration, or intra-PPTg microinfusion of the nicotinic antagonist dihydro-beta-erythroidine (30 microg). However, nicotine self-administration on a progressive-ratio schedule was not altered by intra-PPTg microinfusions of GABA agonists., Conclusions: These data confirm that the PPTg is involved in nicotine self-administration, a conclusion that is independent of the schedule of reinforcement that is used. GABAergic mechanisms in the PPTg play a selective role in nicotine reinforcement compared to cocaine, and that role is restricted to the characteristics of reinforcement measured by fixed-ratio responding.

Rationale: The mesolimbic dopamine system has been implicated in the reinforcing effects of nicotine, a drug which appears to act at least in part through the ventral tegmental area (VTA). Other neuronal elements in the VTA are important in drug reward. In particular, mu opioid receptors in the VTA have been shown to influence cocaine reinforcement., Objective: The aim of this study was to test whether the mu opioid receptors in the VTA also regulate the intake of nicotine., Methods: This research was carried out with animals trained to self-administer nicotine or cocaine, or to respond for food. Mu receptors were targeted with the selective agonist [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO) and gamma-aminobutyric acid (GABA) receptors with the selective agonists baclofen and muscimol; each of these compounds was delivered by microinfusion into the VTA., Results: The mu-selective agonist DAMGO, tested over a dose range of 0.005-0.05 microg, had an effect at the highest dose only, where it produced a reduction in self-administration maintained by doses of either 10 microg/kg or 30 microg/kg per infusion of nicotine. Intra-VTA microinfusions of DAMGO did not reinstate extinguished responding previously established for nicotine, nor did they have prominent effects on operant behavior maintained by food. In contrast to the overall limited effects of DAMGO on nicotine self-administration, the GABA agonists muscimol and baclofen each reduced nicotine self-administration substantially when delivered into the VTA, whereas they were less effective against cocaine self-administration., Conclusions: The lesser effect of DAMGO microinfusions in the VTA on nicotine than cocaine self-administration is associated with the opposite efficacy of GABA agonists. These findings suggest that nicotine and cocaine differentially activate circuitry in which mu receptors are situated, especially GABAergic elements.

The objective of this study was to determine whether the pedunculopontine tegmental nucleus plays a role in the maintenance of nicotine self-administration, and whether the ascending cholinergic projection from this nucleus to midbrain dopamine neurons in the ventral tegmental area might be involved. Studies were done with rats trained to self-administer nicotine intravenously. Self-administration was examined before and after the pedunculopontine tegmental nucleus was lesioned with the ethylcholine mustard aziridinium ion, a selective cholinergic toxin. Lesions were assessed qualitatively and quantitatively in histological sections stained for either nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry to identify cholinergic neurons, or for Nissl. Self-administration was also tested after an acute manipulation in which microinfusions of the nicotinic cholinergic antagonist dihydro-beta-erythroidine were made into the pedunculopontine tegmentum. Infusions of neurotoxin into the pedunculopontine tegmentum reduced nicotine self-administration behaviour when tested weeks later. Toxin treatment reduced the number of cholinergic neurons in the tegmentum, while largely sparing the non-cholinergic population in this area. Lesions were limited to the pedunculopontine area and did not extend to the neighboring laterodorsal tegmental nucleus or to the substantia nigra. Acute manipulation of the pedunculopontine tegmental nucleus with microinfusions of dihydro-beta-erythroidine also produced an attenuation of nicotine self-administration. Collectively these data show that the pedunculopontine tegmental nucleus is part of the neuronal circuitry mediating nicotine self-administration, and that the population of cholinergic neurons is likely a critical element.

The subtype-selective serotonin 5-HT3 antagonists MDL 72222 and ICS 205-930 were tested for their ability to modify nicotine self-administration and locomotor activity in rats. In self-administration experiments, MDL 72222 produced no statistically significant changes over a dose range of 1 to 30 micrograms/kg, nor at the considerably higher dose of 1 mg/kg. MDL 72222 was similarly without effect in nicotine-produced locomotor activity, except at the 1 mg/kg dose, which reduced scores. In an initial test on nicotine self-administration, ICS 205-930 produced a small decrease in drug-taking behavior at 1 and 3 micrograms/kg which just reached statistical significance, but had no effects at higher doses. However, these low-dose effects could not be replicated. In addition, ICS 205-930 was without effect on nicotine locomotor activity, even at the two low doses that had reduced self-administration. We conclude that these 5-HT3 antagonists do not modulate nicotine reinforcement or behavioral arousal.

Microinfusions of the nicotinic antagonist dihydro-beta-erythroidine (DH beta E) were used to examine the role of the mesolimbic dopamine system in nicotine reinforcement in rats. Infusions of DH beta E into the ventral tegmental area (VTA) prior to the start of i.v. nicotine self-administration sessions resulted in a significant decrease in the number of nicotine infusions voluntarily obtained. In contrast, the same doses of DH beta E infused into the nucleus accumbens were without effect on nicotine self-administration. The reductions caused by DH beta E were specific to nicotine reinforcement; neither operant responding maintained by food, cocaine self-administration, or spontaneous locomotor activity were altered by local applications of DH beta E within the VTA. The reduction in nicotine self-administration following treatment in the VTA was also specific to the nicotinic antagonist, and was not duplicated by infusions of the muscarinic antagonist atropine. Partial lesions of the pedunculopontine tegmental nucleus, the likely origin of cholinergic fibers to the VTA, were without effect on nicotine self-administration, suggesting that the effects of DH beta E were not due to disruption of a tonically active cholinergic input to the VTA from this source. These data show that nicotine acts within the VTA region to initiate processes which are critical to the reinforcing properties of the drug.

The ability of D1 and D2 dopamine antagonists to reduce the subjective effects of nicotine was examined in rats trained to discriminate nicotine (0.3 mg/kg, base) from saline. Each of SCH 23390 (a D1 antagonist) and spiperone (a D2 antagonist) reduced responding on the drug-appropriate lever, and produced a reduction in overall response rates. The nicotine cue was also tested for generalization to the dopamine reuptake blocker GBR 12909. Doses of GBR 12909 that produced complete responding on the drug-appropriate lever in cocaine-trained animals led to only minimal selection of the nicotine-appropriate lever in nicotine-trained animals; as with the dopamine antagonists, response rates after GBR 12909 were markedly reduced in nicotine-trained, but not in cocaine-trained, rats. These data suggest that dopaminergic mechanisms play, at best, a small role in the discriminative stimulus properties of nicotine.

Rats were trained to self-administer nicotine on a fixed-ratio schedule of reinforcement. Infusion of the nicotinic antagonist chlorisondamine into the cerebral ventricles produced a sustained reduction in nicotine self-administration compared to vehicle-treated controls. Lesions of the mesolimbic dopamine system were produced by microinfusion of 6-hydroxydopamine into the nucleus accumbens. Following production of the lesions, nicotine self-administration was markedly reduced for the 3-week test period; motor impairment did not appear to be responsible. Post mortem analysis of brain tissue showed that the lesion produced a pronounced decrease in dopamine content of the nucleus accumbens and the olfactory tubercle, and a small depletion in the striatum. These data demonstrate that the reinforcing effects of nicotine occur within the central nervous system, and that the mesolimbic dopamine projection plays an important role in these effects.

Rats were trained to self-administer cocaine in 1-h sessions on a fixed ratio 5 (FR5) schedule of reinforcement. Acquisition was carried out at a unit dose of 0.3 mg/kg and responding was then stabilized at cocaine doses of 0.1, 0.3, and 1.0 mg/kg/infusion. Pretreatments with naltrexone (0.1-10 mg/kg, SC) 20 min prior to the start of self-administration sessions resulted in decreases in cocaine self-administration at doses of 0.1 and 0.3 mg/kg/infusion, but not at 1.0 mg/kg/infusion. Decreases depended on the dose of naltrexone used, with greater decreases in self-administration occurring at higher antagonist doses. In addition, treatment with the opiate antagonist naloxone also reduced cocaine self-administration at a unit dose of 0.3 mg/kg. A group of rats trained to self-administer nicotine at a dose of 0.03 mg/kg/infusion on the same schedule of reinforcement was unaffected by naltrexone treatment. These results may indicate that an endogenous opiate system plays a role in cocaine reinforcement.

The effects of selective D1 (SCH23390) and D2 (spiperone) dopamine antagonists, as well as of haloperidol, were examined on nicotine self-administration, food-maintained responding, and locomotor activity in rats. Antagonists reduced both operant responding and locomotor activity. Response patterns indicated that motor impairment was not the cause of the decreases, since responding was attenuated only in the latter half of operant sessions. Locomotor activity scores were significantly reduced by SCH23390, but not by spiperone. The effects of dopamine antagonists on nicotine self-administration are different from the effects of these antagonists on cocaine self-administration. Results are discussed in terms of the role of dopamine in drug reinforcement versus its role in sensorimotor integration.

Rats that had been trained to respond for food on a fixed-interval 3-minute schedule were treated once daily with nicotine (2 mg/kg) for 50 days. Animals developed marked tolerance to the depressant effect of nicotine as measured by the decreased effect of the treatment dose on response rates over days. Substitution of saline for nicotine during chronic treatment resulted in response rates which were significantly less than pretreatment values. In addition, following cessation of chronic treatment, response rates were initially suppressed below pretreatment rates; by the third day of withdrawal, response rates had returned to baseline levels. It is proposed that the response deficit observed during nicotine absence represents one behavioral component of a nicotine withdrawal syndrome.

Intravenous nicotine maintained substantial responding on the drug-reinforced lever with a limited-access, fixed-ratio 5 schedule of self-administration. Responding demonstrated the expected pharmacological sensitivity; it was dose-dependently reduced by pre-session treatment with either nicotine or mecamylamine but not with hexamethonium. In addition, responding was dependent on the size of the unit dose, with maximum values occurring at 0.01 and 0.03 mg/kg/infusion. Self-administration behavior decreased at doses both above and below these, and extinction followed the substitution of saline for nicotine. Total session drug intake increased with unit dose up to a maximal value of approximately 0.5 mg/kg at 0.03 mg/kg/infusion, but did not increase further at the 0.06 mg/kg/infusion dose. A decrease in the time-out duration at the dose of 0.03 mg/kg/infusion also did not change the total session intake of nicotine. It is suggested that nicotine intake is controlled both by the total amount of drug obtained and by the magnitude of the unit dose. These results demonstrate that intravenous nicotine can maintain substantial self-administration behavior in rodents.

The effects of nicotine, heroin, mecamylamine, and naltrexone were studied in rats trained to respond under a fixed-interval 3-min schedule of food presentation. Nicotine (0.1-3.0 mg/kg) first increased, then decreased response rates; heroin (0.03-0.6 mg/kg) produced only dose-related response rate decreases. Mecamylamine (0.1-3.0 mg/kg) and naltrexone (0.3-10.0 mg/kg), administered alone, each had little effect on response rates. However, when administered in combination with increasing doses of nicotine, mecamylamine (1.0 mg/kg) blocked the increases in response rate caused by 0.3 and 1.0 mg/kg nicotine and partially reversed the decreases in rate caused by 3.0 mg/kg nicotine. In contrast, the combination of naltrexone and nicotine, at doses of each that alone either had no effect or increased response rates, markedly decreased responding. This phenomenon was not evident during the first pairing of naltrexone and nicotine, but appeared in the second and subsequent pairings. After drug combinations had been tested, the nicotine dose-response curve was unchanged from its previous values, and naltrexone alone produced no tendency to decrease response rate. These observations may be related to previous results that have suggested a role for endogenous opioids in mediating certain of the behavioral effects of nicotine.