Role of alpha-2 adrenergic and kappa opioid receptors in the effects of alcohol gavage-induced dependence on alcohol seeking.

Noradrenaline and alpha-2 receptors are implicated in the neuroadaptive changes in alcohol dependence leading to increased alcohol seeking. Preclinical methods often used to induce dependence, such as alcohol vapor, require long exposure periods. Another method, gavage with alcohol, induces dependence in a shorter time frame (4-6 d), but its effects on relapse are less well understood. We examined the role of alpha-2 receptors in alcohol self-administration (ASA) and relapse in male and female rats made alcohol dependent by gavage. The influence of these variables on the inhibitory effects of the alpha-2 agonist guanfacine on ASA, and on reinstatement induced by the alpha-2 antagonist yohimbine were determined. We also extended this analysis to relapse induced by the kappa opioid receptor agonist U50,488. Male and female Sprague Dawley rats, trained to self-administer alcohol were treated with intragastric vehicle or alcohol (12 g/kg/d for 5 d). In Exp. 1 we examined the effects of alcohol gavage on reinstatement induced by yohimbine (0.625-1.25 mg/kg) and U50,488 (1.25-2.5 mg/kg). In Exp. 2 we determined the effects of a longer period of alcohol gavage on guanfacine (0.25-0.75 mg/kg)-induced reductions in ASA and on yohimbine (0.625-2.5 mg/kg)-induced reinstatement. Our key findings are that alcohol dependence induced by gavage produces sex-specific effects on reinstatement. Non-dependent females had greater reinstatement than males, but dependence reduced reinstatement in females. In males, dependence modestly enhanced yohimbine-induced reinstatement, while U50-induced reinstatement was absent irrespective of dependence condition. Alcohol dependence did not modify the inhibitory effects of guanfacine on ASA in males or females.

Effects of the Alpha-1 Antagonist Prazosin on KOR Agonist-Induced Reinstatement of Alcohol Seeking.

BACKGROUND: Stress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key transmitter in stress responses and in stress-induced drug seeking. The alpha-1 adrenoceptor antagonist prazosin has been investigated as a treatment for alcoholism and for chronic stress disorders that are frequently comorbid with alcoholism. In rats, we previously showed that prazosin blocks reinstatement of alcohol seeking induced by footshock and yohimbine stressors and reduces yohimbine-induced brain activation. The role of alpha-1 adrenoceptors in reinstatement induced by other stressors is not known. Our most recent work is on the role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking and have reported that the selective kappa opioid receptor agonist U50,488 induces reinstatement and neuronal activation in stress- and relapse-related brain regions. Here we determine the involvement of alpha-1 receptors in reinstatement and brain activation induced by U50,488. METHODS: We trained male Long-Evans rats to self-administer alcohol (12% w/v), extinguished alcohol-reinforced responding, and then determined the effects of prazosin (1 mg/kg) on U50,488 (2.5 mg/kg)-induced reinstatement and regional Fos expression. RESULTS: Prazosin blocked U50,488-induced reinstatement and decreased U50,488-induced Fos expression in the orbitofrontal cortex, nucleus accumbens core, ventral bed nucleus of the stria terminalis, central and basolateral amygdalar nuclei and ventral tegmental area. CONCLUSIONS: These findings suggest that prazosin may reduce U50,488-induced relapse by inhibiting activity in 1 or more of these brain areas.

Effect of chronic alcohol vapor exposure on reinstatement of alcohol seeking induced by U50,488.

Alcohol dependence and stress are associated with relapse to alcohol during abstinence, but the underlying mechanisms are poorly understood. Kappa opioid receptors (KOR) are involved in alcohol reward and in the effects of stress. Previously, in non-dependent rats, we showed that KOR in the bed nucleus of the stria terminalis (BNST) mediate reinstatement of alcohol seeking induced by the selective KOR agonist U50,488. Here, we determine the effects of chronic, intermittent exposure to alcohol vapor on U50,488-induced reinstatement of alcohol seeking. We also study brain mechanisms involved using the neuronal activity marker Fos and phosphorylated p38 MAPK (p-p38), an intracellular messenger implicated in the effects of KOR stimulation. We trained male Long-Evans rats to self-administer alcohol (12% w/v) and exposed them to alcohol vapor (14 h vapor/10 h air) daily for 24 d or to the control condition, extinguished alcohol-reinforced responding and determined the dose response for U50,488-induced reinstatement. We then determined the effects of vapor exposure on U50,488-induced Fos and p-p38 expression. Vapor-exposed rats were more sensitive to U50,488-induced reinstatement. U50,488 increased Fos expression in brain areas involved in stress-induced relapse, and Fos activation in the ventral BNST was greater in vapor exposed rats. Vapor exposed rats had increased basal p-p38 expression in the dorsal BNST, LC and NTS. Our findings suggest that changes in the neuronal responses to KOR stimulation in the ventral BNST may be involved in the increased sensitivity to U50,488 accompanying dependence.

Effects of alcohol dependence on discrete choice between alcohol and saccharin.

Dependence on drugs has enduring effects on drug intake and relapse. The role of choice in enhanced susceptibility to drug use in drug dependence has been little studied. Here we determine the effects of alcohol dependence on the choice between alcohol and a non-drug reward, saccharin, using the discrete choice model in food-restricted male rats. We trained rats to self-administer alcohol (12% w/v) and saccharin (0.05, 0.1%), tested their choice of alcohol vs. saccharin, and determined the effects of deprivation and intertrial interval (ITI) duration on choice. We then determined the effects of alcohol dependence, induced by repeated intermittent exposure to alcohol vapor on choice of alcohol vs. saccharin (0.1%) in discrete choice trials as well as on the effects of adulteration of alcohol with quinine on choice. We trained another group of rats to self-administer intravenous (i.v.) nicotine (0.03 mg/kg/infusion) and oral saccharin (0.1%), determined their choice, and examined the roles of ITI duration and concurrent access on choice. Rats chose equivalent amounts of 0.05% saccharin and 12% alcohol, showed a stronger choice for 0.1% saccharin, and alcohol and saccharin choice were modestly decreased and increased, respectively, by deprivation. Alcohol dependence led to profound increases in the choice of alcohol over saccharin while adulteration of alcohol with quinine did not affect choice in non-dependent or dependent rats. Rats showed marked choice for 0.1% saccharin over i.v. nicotine. The strong effect that dependence had on alcohol choice is an important validation of the discrete choice procedure.

Acquisition of nicotine self-administration in amphetamine and phencyclidine models of schizophrenia: A role for stress?

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.

Role of κ-Opioid Receptors in the Bed Nucleus of Stria Terminalis in Reinstatement of Alcohol Seeking.

κ-Opioid receptors (KORs) and their endogenous ligand dynorphin are involved in stress-induced alcohol seeking but the mechanisms involved are largely unknown. We previously showed that systemic injections of the KOR agonist U50,488, which induce stress-like aversive states, reinstate alcohol seeking after extinction of the alcohol-reinforced responding. Here, we used the neuronal activity marker Fos and site-specific injections of the KOR antagonist nor-BNI and U50,488 to study brain mechanisms of U50,488-induced reinstatement of alcohol seeking. We trained male Long-Evans rats to self-administer alcohol (12% w/v) for 23-30 days. After extinction of the alcohol-reinforced responding, we tested the effect of U50,488 (0, 1.25, 2.5, and 5 mg/kg) on reinstatement of alcohol seeking. Next, we correlated regional Fos expression with reinstatement induced by the most effective U50,488 dose (5 mg/kg). Based on the correlational Fos results, we determined the effect of bed nucleus of the stria terminalis (BNST) injections of nor-BNI (4 µg/side) on U50,488-induced reinstatement of alcohol seeking, and reinstatement induced by injections of U50,488 (0, 0.3, 1, and 3 µg/side) into the BNST. U50,488-induced reinstatement of alcohol seeking was associated with increased Fos expression in multiple brain areas, including the BNST, where it was significantly correlated with lever pressing. U50,488-induced reinstatement was blocked by BNST nor-BNI injections, and BNST U50,488 injections partially mimicked the drug's systemic effect on reinstatement. Our data indicate that the BNST is a critical site for U50,488-induced reinstatement of alcohol seeking and suggest that KOR/dynorphin mechanisms in this brain area play a key role in stress-induced alcohol seeking.

Role of Central Amygdala Neuronal Ensembles in Incubation of Nicotine Craving.

UNLABELLED: The craving response to smoking-associated cues in humans or to intravenous nicotine-associated cues in adult rats progressively increases or incubates after withdrawal. Here, we further characterized incubation of nicotine craving in the rat model by determining whether this incubation is observed after adolescent-onset nicotine self-administration. We also used the neuronal activity marker Fos and the Daun02 chemogenetic inactivation procedure to identify cue-activated neuronal ensembles that mediate incubation of nicotine craving. We trained adolescent and adult male rats to self-administer nicotine (2 h/d for 12 d) and assessed cue-induced nicotine seeking in extinction tests (1 h) after 1, 7, 14, or 28 withdrawal days. In both adult and adolescent rats, nicotine seeking in the relapse tests followed an inverted U-shaped curve, with maximal responding on withdrawal day 14. Independent of the withdrawal day, nicotine seeking in the relapse tests was higher in adult than in adolescent rats. Analysis of Fos expression in different brain areas of adolescent and adult rats on withdrawal days 1 and 14 showed time-dependent increases in the number of Fos-positive neurons in central and basolateral amygdala, orbitofrontal cortex, ventral and dorsal medial prefrontal cortex, and nucleus accumbens core and shell. In adult Fos-lacZ transgenic rats, selective inactivation of nicotine-cue-activated Fos neurons in central amygdala, but not orbitofrontal cortex, decreased "incubated" nicotine seeking on withdrawal day 14. Our results demonstrate that incubation of nicotine craving occurs after adolescent-onset nicotine self-administration and that neuronal ensembles in central amygdala play a critical role in this incubation. SIGNIFICANCE STATEMENT: The craving response to smoking-associated cues in humans or to intravenous nicotine-associated cues in adult rats progressively increases or incubates after withdrawal. It is currently unknown whether incubation of craving also occurs after adolescent-onset nicotine self-administration. The brain areas that mediate such incubation are also unknown. Here, we used a rat model of incubation of drug craving, the neuronal activity marker Fos, and the Daun02 chemogenetic inactivation method to demonstrate that incubation of nicotine craving is also observed after adolescent-onset nicotine self-administration and that neuronal ensembles in the central nucleus of the amygdala play a critical role in this incubation in adult rats.

The role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking in rats.

INTRODUCTION: Stress is related to heavy alcohol use and relapse in alcoholics. Using the reinstatement model, we have shown that corticotropin-releasing factor (CRF) underlies stress-induced relapse to alcohol seeking in laboratory rodents. Little is known about how other neurotransmitters interact with CRF in these effects. Dynorphin and its receptor (kappa opioid receptor, KOR) are involved in stress responses and in alcohol seeking. KOR and CRF receptors (CRF R) may interact in the production of stress-related behaviors but it is not known whether this interaction is involved in reinstatement of alcohol seeking. METHODS: Male Long Evans rats were trained to self-administer alcohol (12% w/v). After extinction of responding, we determined the effects of the KOR agonist, U50,488 (2.5, 5 mg/kg) on reinstatement of alcohol seeking, and their sensitivity to the selective KOR antagonist nor-binaltorphimine dihydrochloride (nor-BNI) (10 mg/kg) administered at different times before U50,488. We then examined the effects of nor-BNI on reinstatement induced by the stressor yohimbine (1.25 mg/kg) and on reinstatement induced by exposure to alcohol-associated cues. Finally, we determined whether CRF R1 blockade with antalarmin (10, 20 mg/kg) attenuates alcohol seeking induced by U50,488. RESULTS: U50,488 reinstated alcohol seeking. Prior treatment with nor-BNI 2, but not 24 h before administration of U50,488 or yohimbine blocked reinstatement induced by these drugs. Cue-induced reinstatement was blocked by nor-BNI administered 2 h prior to testing. Finally, U50,488-induced reinstatement was blocked by antalarmin. CONCLUSIONS: These data further support a role for KOR in reinstatement of alcohol seeking under nonstress and stressful conditions and that KOR and CRF R interact in these effects.

Operant self-administration of alcohol and nicotine in a preclinical model of co-abuse.

RATIONALE AND OBJECTIVES: Alcohol and nicotine are often taken together. In humans, intake of nicotine, via smoked tobacco, increases alcohol drinking, and alcohol increases smoking. Chronic nicotine treatment increases alcohol self-administration (SA) in laboratory animals; the reverse relationship is less clear. Most animal work modeling this has used passive administration, which lacks relevance to human co-abuse. Here, we describe a model based on sequential operant SA of alcohol and nicotine. METHODS: Animals are first trained on alcohol SA (0.19 ml of 12 % alcohol (w/v)/delivery) and then receive separate alcohol (8 %, w/v) and nicotine (15 µg/kg/infusion) SA sessions on the same day ("daily dual access"). Animals then receive access to alcohol and then to nicotine (or in the reverse order) in alternating 5-min periods in 2-h sessions ("alternating access"). We then determine if alternating access modifies the effects of naltrexone on responding for alcohol and nicotine. RESULTS: We found that with daily dual access, nicotine significantly increased alcohol SA when alcohol access occurred prior to nicotine access and that nicotine SA significantly decreased when the alcohol SA session preceded it. During alternating access, nicotine also significantly increased alcohol intake. Naltrexone (0.3 or 1 mg/kg) significantly reduced alcohol SA during these alternating access sessions in animals that also received nicotine SA, but had minimal effects on animals receiving alcohol SA alone. Naltrexone did not affect nicotine SA under any condition. CONCLUSIONS: This sequential access procedure effectively models the effects of nicotine on alcohol intake noted in humans.

Sex differences in yohimbine-induced increases in the reinforcing efficacy of nicotine in adolescent rats.

Stress is an important factor in the initiation and maintenance of smoking in adolescents. Women are more vulnerable to the development of addiction to smoking and have more difficulty quitting than men. Women also showe enhanced responses to stress. Despite these differences, no work has been done examining the effects of stress on the reinforcing efficacy of self-administered nicotine in adolescent rats, or if there are sex differences. Male and female adolescent Long Evans rats were trained to self-administer one of three different intravenous doses of nicotine (7.5, 15, 30 µg/kg/infusion) first on fixed ratio, and then on a progressive ratio (PR) schedule beginning on postnatal day 33. The effect of the pharmacological stressor yohimbine (0.3, 0.6 mg/kg, i.p.) on the reinforcing efficacy of nicotine was then determined using the PR schedule. Yohimbine stimulated nicotine intake and increased PR breakpoints and numbers of infusions received in both male and female adolescent rats. The infusion dose of nicotine was positively associated with yohimbine-induced increases in responding. Female rats showed significantly increased breakpoints at yohimbine doses and nicotine infusion doses at which males did not. The effects of the pharmacological stressor, yohimbine on the reinforcing efficacy of nicotine are therefore linked to sex and nicotine infusion dose. Female rats are more sensitive to stress-induced potentiation of nicotine self-administration.

Role of corticotropin-releasing factor in the median raphe nucleus in yohimbine-induced reinstatement of alcohol seeking in rats.

The pharmacological stressor yohimbine increases ongoing alcohol self-administration and reinstates alcohol seeking in rats. This effect is attenuated by systemic injections of a corticotropin-releasing factor (CRF) antagonist. The brain sites involved in CRF's role in yohimbine-induced alcohol taking and seeking are unknown. We report that injections of the CRF receptor antagonist d-Phe CRF into the median raphe nucleus (MRN) attenuated yohimbine-induced reinstatement of alcohol seeking but had no effect on yohimbine-induced increases in alcohol intake during ongoing self-administration. Results indicate an important role of MRN CRF receptors in yohimbine-induced reinstatement of alcohol seeking but not yohimbine-induced increases in alcohol intake.

Cannabinoid receptor stimulation increases motivation for nicotine and nicotine seeking.

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.

Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats.

RATIONALE AND OBJECTIVES: Relapse to alcohol use during abstinence or maladaptive eating habits during dieting is often provoked by stress. The anxiogenic drug yohimbine, which causes stress-like responses in humans and non-humans, reliably reinstates alcohol and food seeking in a rat relapse model. Yohimibine is a prototypical alpha-2 adrenoceptor antagonist, but results from studies on noradrenaline's role in yohimbine-induced reinstatement of drug and food seeking are inconclusive. Here, we further addressed this issue by studying the effect of the alpha-1 adrenoceptor antagonist prazosin and the alpha-2 adrenoceptor agonist guanfacine on yohimbine-induced reinstatement. METHODS: In exp. 1, we trained rats to self-administer alcohol (12% w/v, 1 h/day), and after extinction of alcohol-reinforced lever pressing, we tested prazosin's (0.5, 1.0, and 2.0 mg/kg, i.p.) or guanfacine's (0.125, 0.25, and 0.5 mg/kg, i.p.) effect on yohimbine (1.25 mg/kg, i.p.)-induced reinstatement; we also examined prazosin's effect on intermittent-footshock-stress-induced reinstatement. In exp. 2, we trained food-restricted rats to self-administer 45 mg food pellets and first examined prazosin's or guanfacine's effects on food-reinforced responding, and then, after extinction of lever presses, on yohimbine-induced reinstatement. RESULTS: Prazosin (0.5-2.0 mg/kg) blocked yohimbine-induced reinstatement of food and alcohol seeking, as well as footshock-induced reinstatement of alcohol seeking. Guanfacine attenuated yohimbine-induced reinstatement of alcohol seeking at the highest dose (0.5 mg/kg), but its effect on yohimbine-induced reinstatement of food seeking was not significant. Neither prazosin nor guanfacine affected high-rate food-reinforced responding. CONCLUSIONS: Results demonstrate an important role of postsynaptic alpha-1 adrenoceptors in stress-induced reinstatement of alcohol and food seeking.

The selective dopamine D3 receptor antagonist SB 277011-A, but not the partial agonist BP 897, blocks cue-induced reinstatement of nicotine-seeking.

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.

Inhibition of fatty acid amide hydrolase reduces reinstatement of nicotine seeking but not break point for nicotine self-administration--comparison with CB(1) receptor blockade.

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.

Medication-related pharmacological manipulations of nicotine self-administration in the rat maintained on fixed- and progressive-ratio schedules of reinforcement.

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.

Pharmacological manipulations of the pedunculopontine tegmental nucleus in the rat reduce self-administration of both nicotine and cocaine.

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.