Bupropion, a dopamine reuptake inhibitor, is an effective therapy for smoking cessation, but the ... more Bupropion, a dopamine reuptake inhibitor, is an effective therapy for smoking cessation, but the behavioral and neurochemical mechanisms mediating its antismoking properties are relatively unknown. To explore the hypothesis that bupropion ameliorates nicotine withdrawal partly by a dopamine-dependent mechanism, we investigated the effects of chronic bupropion on potassium-stimulated dopamine overflow in the nucleus accumbens shell in nicotine-withdrawing rats. We also assessed the effects of chronic bupropion on behavioral aspects of nicotine withdrawal measured by elevations in brain reward thresholds and somatic signs of withdrawal. Rats were treated with nicotine or saline for 7 days and then coadministration of bupropion or saline was initiated. After 14 days of coadministration of bupropion/saline and nicotine/saline, nicotine/saline administration was terminated, whereas bupropion/saline administration continued. These conditions mimic bupropion administration in human smokers. Cessation of nicotine administration in non-bupropion-treated rats elevated reward thresholds reflecting a reward deficit, increased somatic signs and diminished potassium-evoked dopamine overflow in the nucleus accumbens shell. Chronic bupropion lowered reward thresholds and increased potassium-evoked dopamine release regardless of previous nicotine exposure, possibly by inhibition of dopamine reuptake, and thus attenuated the anhedonic and neurochemical effects of nicotine withdrawal. Chronic bupropion blocked withdrawal-associated increased somatic signs. Finally, acute experimenter-administered nicotine enhanced brain reward function equally in all groups, indicating that bupropion does not alter the reward-facilitating effects of experimenter-administered nicotine. In conclusion, the bupropion-induced increase in extracellular dopamine in the nucleus accumbens shell may ameliorate the anhedonia associated with nicotine withdrawal, which in turn may facilitate smoking cessation.
Rationale Nicotine increases glutamate release in the ventral tegmental area and the nucleus accu... more Rationale Nicotine increases glutamate release in the ventral tegmental area and the nucleus accumbens, and thus enhances dopamine neurotransmission in the mesolimbic system that has been implicated in mediating the rewarding effects of drugs. Metabotropic glutamate receptors 5 (mGluR5) are found in the nucleus accumbens and may play a role in modulating the post-synaptic response to both glutamate and dopamine. Objectives The present study investigated the effects of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on intravenous nicotine self-administration in Wistar rats and DBA/2J mice. Methods Rats were allowed to self-administer nicotine (0.01, 0.03 mg/kg per infusion) or respond for food on one of two fixed-ratio 5 schedules of reinforcement. Drug-naive mice were acutely exposed, in pairs, to nicotine (0, 0.016, 0.048, 0.16, 0.48 μg per infusion) self-administration under a fixed ratio 1 schedule of reinforcement, with one subject controlling the delivery of nicotine to both subjects in each pair. Results MPEP (1–9 mg/kg) dose-dependently reduced nicotine self-administration with no effect on food-maintained responding in the rats. Self-administration of nicotine was obtained only at the 0.048 μg per infusion dose by the mice, and administration of MPEP (5–20 mg/kg) decreased nicotine self-administration response rates in the mice. Conclusions 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.
Bupropion is an effective anti-smoking agent in humans, but the behavioral mechanisms mediating t... more Bupropion is an effective anti-smoking agent in humans, but the behavioral mechanisms mediating this effect are unclear. The present studies assessed the effects of chronic bupropion on the reinforcing and reward-enhancing effects of self-administered nicotine, and on the motivational properties of a nicotine-associated conditioned reinforcer. The present studies also assessed the reward-enhancing effects of nicotine self-administration under different levels of access to nicotine, and the effects of enforced abstinence from self-administered nicotine on brain reward function and somatic signs. Rats were prepared with bipolar electrodes in the lateral hypothalamus and trained on a discrete trial intracranial self-stimulation (ICSS) task. After establishing stable ICSS thresholds, rats were prepared with intravenous catheters and allowed to self-administer nicotine at different levels of access. Self-administered nicotine lowered ICSS thresholds, thereby providing a measure of the reward-enhancing effects of nicotine. Abstinence from 6h/d 7d/wk nicotine self-administration was associated with increased somatic signs of nicotine withdrawal and unchanged brain reward thresholds. Chronic bupropion administration via subcutaneous osmotic minipump had no effect on nicotine self-administration, but attenuated nicotine-induced enhancement of brain reward function and enhanced the motivational properties of a previously nicotine-associated conditioned stimulus. Thus, it is unlikely that chronic bupropion exerts anti-smoking effects by attenuating the primary or conditioned reinforcing effects of nicotine. Rather, preclinical investigations suggest that bupropion attenuates nicotine-induced enhancement of brain reward function and reverses the anhedonic, somatic, and neurochemical correlates of nicotine withdrawal.
Rationale Previous work has indicated a potential role for γ-aminobutyric acid-B (GABAB) receptor... more Rationale Previous work has indicated a potential role for γ-aminobutyric acid-B (GABAB) receptor agonists in treating drug addiction in humans. Specifically, GABAB receptor agonists decreased cocaine, heroin and nicotine self-administration in rats. Objectives The purpose of the present studies was to extend previous findings by assessing the effects of additional GABAB receptor agonists on nicotine self-administration and food-maintained responding, under both fixed and progressive ratio schedules in rats. Methods Male Wistar rats were exposed to a progressive ratio schedule where various nicotine doses were made available according to a within-subjects Latin Square design. Additional groups of rats were used to test the effects of the GABAB receptor agonists baclofen and CGP44532 on nicotine self-administration (0.01 and 0.03 mg/kg per infusion) and food-reinforced responding on fixed and progressive ratio (CGP44532 only) schedules. Results Nicotine maintained stable self-administration under a progressive ratio schedule with a linear dose-response function (r=0.61). Both CGP44532 and (−)baclofen dose-dependently reduced nicotine self-administration on the fixed ratio schedule, and also decreased food-maintained responding at higher doses. Further, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive ratio schedule. Conclusion The present data demonstrate that administration of GABAB 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 GABAB receptor agonists as therapeutics for smoking cessation.
Nicotinic acetylcholine receptor (nAChR) antagonists have been shown previously to decrease nicot... more 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.
... that nicotine is self-administered intravenously by non-human primates (eg, Goldberg, Spealma... more ... that nicotine is self-administered intravenously by non-human primates (eg, Goldberg, Spealman, & Goldberg, 1981), dogs (eg, Risner & Goldberg, 1983), rats (eg, Corrigall & Coen, 1989; DeNoble & Mele, 2006; Donny, Caggiula, Knopf, & Brown, 1995; Watkins, Epping-Jordan ...
Previous work indicated a role for GABA and glutamate in the reinforcing effects of drugs of abus... more Previous work indicated a role for GABA and glutamate in the reinforcing effects of drugs of abuse. The present studies assessed the effects of GABAergic and glutamatergic manipulations on the reinforcing effects of nicotine as assessed by intravenous nicotine self-administration. Male Wistar rats were allowed to self-administer either of two nicotine doses under a fixed ratio or a progressive ratio schedule of reinforcement. The effects of a glutamatergic compound on nicotine self-administration in male DBA/2J mice were also explored. Finally, to assess for nonspecific effects of the drug manipulations, the effects of all test compounds on responding maintained by a food reinforcer were investigated. The pharmacological manipulations used were: gamma-vinyl-GABA (vigabatrin or GVG), an irreversible inhibitor of GABA transaminase, the GABAB receptor agonists (-)baclofen and CGP44532, and the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP. GVG, CGP44532, and (-)baclofen dose-dependently decreased nicotine self-administration on the fixed-ratio schedule, but also decreased food-maintained responding. Furthermore, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive-ratio schedule. MPEP dose-dependently decreased nicotine self-administration with no effect on food-maintained responding in rats. MPEP also decreased nicotine self-administration in the mice. These results demonstrate that activation of GABAB receptors or blockade of mGluR5 decreased nicotine self-administration. Although there was some selectivity for the effects of the GABAergic manipulations, there was clear selectivity of the effects of MPEP on nicotine- versus food-maintained responding. Thus, compounds that increase GABAergic neurotransmission and antagonists at mGluR5 have potential as anti-smoking medications for humans.
The high rates of co-morbidity of drug addiction with depression may be attributable to shared ne... more The high rates of co-morbidity of drug addiction with depression may be attributable to shared neurobiology. Here, we discuss shared neurobiological substrates in drug withdrawal and depression, with an emphasis on changes in brain reward circuitry that may underlie anhedonia, a core symptom of depression and drug withdrawal. We explored experimentally whether clinical antidepressant medications or other treatments would reverse the anhedonia observed in rats undergoing spontaneous nicotine or amphetamine withdrawal, defined operationally as elevated brain reward thresholds. The co-administration of selective serotonin reuptake inhibitors with a serotonin-1A receptor antagonist, or the tricyclic antidepressant desipramine, or the atypical antidepressant bupropion ameliorated nicotine or amphetamine withdrawal in rats. Thus, increases in monoaminergic neurotransmission, or neuroadaptations induced by increased monoaminergic neurotransmission, ameliorated depression-like aspects of drug withdrawal. Further, chronic pretreatment with the atypical antipsychotic clozapine, that has some efficacy in the treatment of the depression-like symptoms of schizophrenia, attenuated nicotine and amphetamine withdrawal. Finally, a metabotropic glutamate 2/3 receptor antagonist reversed threshold elevations associated with nicotine withdrawal. The effects of these pharmacological manipulations are consistent with the altered neurobiology observed in drug withdrawal and depression. Thus, these data support the hypothesis of common substrates mediating the depressive symptoms of drug withdrawal and those seen in psychiatric patients. Accordingly, the anhedonic state associated with drug withdrawal can be used to study the neurobiology of anhedonia, and thus contribute to the identification of novel targets for the treatment of depression-like symptoms seen in various psychiatric and neurological disorders.
Escalation in cocaine self-administration is hypothesized to involve increased motivation to cons... more 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.
Rationale The metabotropic glutamate (mGlu5) receptor subtype 5 antagonist MPEP attenuates self-a... more Rationale The metabotropic glutamate (mGlu5) receptor subtype 5 antagonist MPEP attenuates self-administration of numerous drugs of abuse. Objectives The purpose of the present study was to explore whether MPEP-induced decreases in nicotine and cocaine self-administration reflect attenuation of the reinforcing and incentive motivational effects of nicotine and cocaine. The effects of MPEP on breaking points maintained by nicotine, cocaine or food were assessed using a progressive ratio schedule of reinforcement. Breaking points obtained under such schedules are postulated to reflect both the reinforcing and incentive motivational properties of reinforcers. Methods Rats were allowed to respond for nicotine (0.05 mg/kg per infusion, free base), cocaine (0.18 mg/kg per infusion, salt), or food (45 mg pellets) under a progressive ratio schedule of reinforcement. After establishing stable and equivalent levels of responding for all three reinforcers, rats underwent one test session where no rewards were presented to assess the effects of 1-day extinction, similar to 1-day pharmacological-induced extinction, on performance in this schedule. Subsequently, rats were again allowed to respond for nicotine, cocaine or food until reestablishment of stable levels of responding. Then, MPEP (1–9 mg/kg) was administered intraperitoneally according to a within-subjects Latin square design, 30 min prior to the testing sessions. Results Responding in the absence of a primary reinforcer was significantly decreased compared to responding under baseline conditions. Further, MPEP decreased break points maintained by nicotine, cocaine and food. Conclusions The mGlu5 receptor is implicated in mediating the reinforcing and incentive motivational properties of nicotine, cocaine and food.
Rationale: The study of the effects of repeated amphetamine administration and withdrawal on brai... more Rationale: The study of the effects of repeated amphetamine administration and withdrawal on brain reward function has relevance to both amphetamine dependence and non-drug-induced depressions. Objectives: The purpose of this study was to investigate the effects of continuous amphetamine administration and withdrawal on brain stimulation reward thresholds, and the changes that occur with repeated amphetamine exposures. Methods: Rats were prepared with bipolar electrodes in the lateral hypothalamus and trained in a discrete-trial reward threshold procedure. Then, rats underwent two separate periods of amphetamine administration via subcutaneous osmotic mini-pumps. Results: Continuous amphetamine administration was associated with lowering in brain reward thresholds and decreases in response latencies, while withdrawal was associated with threshold elevations. These effects changed with subsequent amphetamine administration and withdrawal. Conclusions: The results of this study indicated that with the amphetamine administration regime used here, rats developed increased sensitivity to the effects of acute amphetamine administration and tolerance to the effects of amphetamine withdrawal.
Rationale Most nicotine self-administration (NSA) studies in rats are performed under limited-acc... more Rationale Most nicotine self-administration (NSA) studies in rats are performed under limited-access conditions. Few studies have examined the relationship between nicotine dependence and NSA. Objectives To determine how NSA access conditions affect NSA and the duration of nicotine dependence during abstinence, as reflected in somatic signs of withdrawal precipitated by administration of the nicotinic receptor antagonist mecamylamine. Methods The effects of different NSA access conditions (zero, 1 h/5 days, 1 h/7 days and 6 h/7 days per week) and non-contingent nicotine administration on NSA and somatic signs were examined. Results Daily NSA access (30 days) resulted in spontaneous and mecamylamine-induced somatic signs. Both daily access groups (1 h/day and 6 h/day, 7 days/week) exhibited spontaneous somatic signs on day 25 of NSA (17 h post-NSA) and sensitivity to mecamylamine up to 2 and 4 weeks of abstinence, respectively. In contrast, the 1 h/day, 5 days/week access group exhibited mecamylamine-induced somatic signs only up to 1 week of abstinence. NSA behavior was stable in rats with 1 h/day 5 days/week and 1 h/day 7 days/week access, but decreased from initially high rates in the 6 h/day 7 days/week access group, and decreased in rats receiving non-contingent nicotine. In contrast, extended cocaine self-administration access resulted in a gradual escalation in cocaine intake. Conclusion 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.
Rationale Nicotine withdrawal is characterized by depression-like symptomatology that may be medi... more Rationale Nicotine withdrawal is characterized by depression-like symptomatology that may be mediated by dysregulations in norepinephrine transmission. These aversive aspects of nicotine withdrawal and the rewarding effects of nicotine play major roles in maintaining nicotine dependence. Objectives The aim of this work was to evaluate the effects of desipramine (DMI), a preferential norepinephrine reuptake inhibitor and antidepressant, on preclinical models of nicotine dependence in rats. Materials and methods A rate-independent current-intensity discrete-trial threshold intracranial self-stimulation procedure was used to assess brain reward function during nicotine withdrawal induced by cessation of nicotine infusion via subcutaneous osmotic mini pumps (3.16 mg/kg/day, base). Nicotine withdrawal was also measured by somatic signs of withdrawal. DMI was administered acutely (2 or 5 mg/kg, salt) during nicotine/saline withdrawal. In other naïve rats, chronic DMI treatment via mini pump (15 mg/kg/day, salt) began after 7 days of nicotine/saline exposure and continued during administration of nicotine/saline for 14 days and during nicotine/saline withdrawal. Additional rats acquired intravenous nicotine- or food-maintained responding, were prepared with DMI/vehicle-containing mini pumps, and self-administered nicotine or food during 12 days of DMI/vehicle exposure. Results Acute DMI administration had no effect on threshold elevations observed in nicotine-withdrawing rats. Chronic DMI administration prevented the reward threshold elevations and the increased somatic signs of nicotine withdrawal. Although chronic DMI significantly decreased nicotine self-administration, it also decreased food-maintained responding. Conclusions The results suggest that norepinephrine reuptake inhibitors may be effective anti-smoking treatments that reduce the anhedonic depression-like and somatic components of nicotine withdrawal and may alter the rewarding effects of nicotine and food.
Bupropion, a dopamine reuptake inhibitor, is an effective therapy for smoking cessation, but the ... more Bupropion, a dopamine reuptake inhibitor, is an effective therapy for smoking cessation, but the behavioral and neurochemical mechanisms mediating its antismoking properties are relatively unknown. To explore the hypothesis that bupropion ameliorates nicotine withdrawal partly by a dopamine-dependent mechanism, we investigated the effects of chronic bupropion on potassium-stimulated dopamine overflow in the nucleus accumbens shell in nicotine-withdrawing rats. We also assessed the effects of chronic bupropion on behavioral aspects of nicotine withdrawal measured by elevations in brain reward thresholds and somatic signs of withdrawal. Rats were treated with nicotine or saline for 7 days and then coadministration of bupropion or saline was initiated. After 14 days of coadministration of bupropion/saline and nicotine/saline, nicotine/saline administration was terminated, whereas bupropion/saline administration continued. These conditions mimic bupropion administration in human smokers. Cessation of nicotine administration in non-bupropion-treated rats elevated reward thresholds reflecting a reward deficit, increased somatic signs and diminished potassium-evoked dopamine overflow in the nucleus accumbens shell. Chronic bupropion lowered reward thresholds and increased potassium-evoked dopamine release regardless of previous nicotine exposure, possibly by inhibition of dopamine reuptake, and thus attenuated the anhedonic and neurochemical effects of nicotine withdrawal. Chronic bupropion blocked withdrawal-associated increased somatic signs. Finally, acute experimenter-administered nicotine enhanced brain reward function equally in all groups, indicating that bupropion does not alter the reward-facilitating effects of experimenter-administered nicotine. In conclusion, the bupropion-induced increase in extracellular dopamine in the nucleus accumbens shell may ameliorate the anhedonia associated with nicotine withdrawal, which in turn may facilitate smoking cessation.
Rationale Nicotine increases glutamate release in the ventral tegmental area and the nucleus accu... more Rationale Nicotine increases glutamate release in the ventral tegmental area and the nucleus accumbens, and thus enhances dopamine neurotransmission in the mesolimbic system that has been implicated in mediating the rewarding effects of drugs. Metabotropic glutamate receptors 5 (mGluR5) are found in the nucleus accumbens and may play a role in modulating the post-synaptic response to both glutamate and dopamine. Objectives The present study investigated the effects of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on intravenous nicotine self-administration in Wistar rats and DBA/2J mice. Methods Rats were allowed to self-administer nicotine (0.01, 0.03 mg/kg per infusion) or respond for food on one of two fixed-ratio 5 schedules of reinforcement. Drug-naive mice were acutely exposed, in pairs, to nicotine (0, 0.016, 0.048, 0.16, 0.48 μg per infusion) self-administration under a fixed ratio 1 schedule of reinforcement, with one subject controlling the delivery of nicotine to both subjects in each pair. Results MPEP (1–9 mg/kg) dose-dependently reduced nicotine self-administration with no effect on food-maintained responding in the rats. Self-administration of nicotine was obtained only at the 0.048 μg per infusion dose by the mice, and administration of MPEP (5–20 mg/kg) decreased nicotine self-administration response rates in the mice. Conclusions 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.
Bupropion is an effective anti-smoking agent in humans, but the behavioral mechanisms mediating t... more Bupropion is an effective anti-smoking agent in humans, but the behavioral mechanisms mediating this effect are unclear. The present studies assessed the effects of chronic bupropion on the reinforcing and reward-enhancing effects of self-administered nicotine, and on the motivational properties of a nicotine-associated conditioned reinforcer. The present studies also assessed the reward-enhancing effects of nicotine self-administration under different levels of access to nicotine, and the effects of enforced abstinence from self-administered nicotine on brain reward function and somatic signs. Rats were prepared with bipolar electrodes in the lateral hypothalamus and trained on a discrete trial intracranial self-stimulation (ICSS) task. After establishing stable ICSS thresholds, rats were prepared with intravenous catheters and allowed to self-administer nicotine at different levels of access. Self-administered nicotine lowered ICSS thresholds, thereby providing a measure of the reward-enhancing effects of nicotine. Abstinence from 6h/d 7d/wk nicotine self-administration was associated with increased somatic signs of nicotine withdrawal and unchanged brain reward thresholds. Chronic bupropion administration via subcutaneous osmotic minipump had no effect on nicotine self-administration, but attenuated nicotine-induced enhancement of brain reward function and enhanced the motivational properties of a previously nicotine-associated conditioned stimulus. Thus, it is unlikely that chronic bupropion exerts anti-smoking effects by attenuating the primary or conditioned reinforcing effects of nicotine. Rather, preclinical investigations suggest that bupropion attenuates nicotine-induced enhancement of brain reward function and reverses the anhedonic, somatic, and neurochemical correlates of nicotine withdrawal.
Rationale Previous work has indicated a potential role for γ-aminobutyric acid-B (GABAB) receptor... more Rationale Previous work has indicated a potential role for γ-aminobutyric acid-B (GABAB) receptor agonists in treating drug addiction in humans. Specifically, GABAB receptor agonists decreased cocaine, heroin and nicotine self-administration in rats. Objectives The purpose of the present studies was to extend previous findings by assessing the effects of additional GABAB receptor agonists on nicotine self-administration and food-maintained responding, under both fixed and progressive ratio schedules in rats. Methods Male Wistar rats were exposed to a progressive ratio schedule where various nicotine doses were made available according to a within-subjects Latin Square design. Additional groups of rats were used to test the effects of the GABAB receptor agonists baclofen and CGP44532 on nicotine self-administration (0.01 and 0.03 mg/kg per infusion) and food-reinforced responding on fixed and progressive ratio (CGP44532 only) schedules. Results Nicotine maintained stable self-administration under a progressive ratio schedule with a linear dose-response function (r=0.61). Both CGP44532 and (−)baclofen dose-dependently reduced nicotine self-administration on the fixed ratio schedule, and also decreased food-maintained responding at higher doses. Further, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive ratio schedule. Conclusion The present data demonstrate that administration of GABAB 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 GABAB receptor agonists as therapeutics for smoking cessation.
Nicotinic acetylcholine receptor (nAChR) antagonists have been shown previously to decrease nicot... more 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.
... that nicotine is self-administered intravenously by non-human primates (eg, Goldberg, Spealma... more ... that nicotine is self-administered intravenously by non-human primates (eg, Goldberg, Spealman, & Goldberg, 1981), dogs (eg, Risner & Goldberg, 1983), rats (eg, Corrigall & Coen, 1989; DeNoble & Mele, 2006; Donny, Caggiula, Knopf, & Brown, 1995; Watkins, Epping-Jordan ...
Previous work indicated a role for GABA and glutamate in the reinforcing effects of drugs of abus... more Previous work indicated a role for GABA and glutamate in the reinforcing effects of drugs of abuse. The present studies assessed the effects of GABAergic and glutamatergic manipulations on the reinforcing effects of nicotine as assessed by intravenous nicotine self-administration. Male Wistar rats were allowed to self-administer either of two nicotine doses under a fixed ratio or a progressive ratio schedule of reinforcement. The effects of a glutamatergic compound on nicotine self-administration in male DBA/2J mice were also explored. Finally, to assess for nonspecific effects of the drug manipulations, the effects of all test compounds on responding maintained by a food reinforcer were investigated. The pharmacological manipulations used were: gamma-vinyl-GABA (vigabatrin or GVG), an irreversible inhibitor of GABA transaminase, the GABAB receptor agonists (-)baclofen and CGP44532, and the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP. GVG, CGP44532, and (-)baclofen dose-dependently decreased nicotine self-administration on the fixed-ratio schedule, but also decreased food-maintained responding. Furthermore, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive-ratio schedule. MPEP dose-dependently decreased nicotine self-administration with no effect on food-maintained responding in rats. MPEP also decreased nicotine self-administration in the mice. These results demonstrate that activation of GABAB receptors or blockade of mGluR5 decreased nicotine self-administration. Although there was some selectivity for the effects of the GABAergic manipulations, there was clear selectivity of the effects of MPEP on nicotine- versus food-maintained responding. Thus, compounds that increase GABAergic neurotransmission and antagonists at mGluR5 have potential as anti-smoking medications for humans.
The high rates of co-morbidity of drug addiction with depression may be attributable to shared ne... more The high rates of co-morbidity of drug addiction with depression may be attributable to shared neurobiology. Here, we discuss shared neurobiological substrates in drug withdrawal and depression, with an emphasis on changes in brain reward circuitry that may underlie anhedonia, a core symptom of depression and drug withdrawal. We explored experimentally whether clinical antidepressant medications or other treatments would reverse the anhedonia observed in rats undergoing spontaneous nicotine or amphetamine withdrawal, defined operationally as elevated brain reward thresholds. The co-administration of selective serotonin reuptake inhibitors with a serotonin-1A receptor antagonist, or the tricyclic antidepressant desipramine, or the atypical antidepressant bupropion ameliorated nicotine or amphetamine withdrawal in rats. Thus, increases in monoaminergic neurotransmission, or neuroadaptations induced by increased monoaminergic neurotransmission, ameliorated depression-like aspects of drug withdrawal. Further, chronic pretreatment with the atypical antipsychotic clozapine, that has some efficacy in the treatment of the depression-like symptoms of schizophrenia, attenuated nicotine and amphetamine withdrawal. Finally, a metabotropic glutamate 2/3 receptor antagonist reversed threshold elevations associated with nicotine withdrawal. The effects of these pharmacological manipulations are consistent with the altered neurobiology observed in drug withdrawal and depression. Thus, these data support the hypothesis of common substrates mediating the depressive symptoms of drug withdrawal and those seen in psychiatric patients. Accordingly, the anhedonic state associated with drug withdrawal can be used to study the neurobiology of anhedonia, and thus contribute to the identification of novel targets for the treatment of depression-like symptoms seen in various psychiatric and neurological disorders.
Escalation in cocaine self-administration is hypothesized to involve increased motivation to cons... more 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.
Rationale The metabotropic glutamate (mGlu5) receptor subtype 5 antagonist MPEP attenuates self-a... more Rationale The metabotropic glutamate (mGlu5) receptor subtype 5 antagonist MPEP attenuates self-administration of numerous drugs of abuse. Objectives The purpose of the present study was to explore whether MPEP-induced decreases in nicotine and cocaine self-administration reflect attenuation of the reinforcing and incentive motivational effects of nicotine and cocaine. The effects of MPEP on breaking points maintained by nicotine, cocaine or food were assessed using a progressive ratio schedule of reinforcement. Breaking points obtained under such schedules are postulated to reflect both the reinforcing and incentive motivational properties of reinforcers. Methods Rats were allowed to respond for nicotine (0.05 mg/kg per infusion, free base), cocaine (0.18 mg/kg per infusion, salt), or food (45 mg pellets) under a progressive ratio schedule of reinforcement. After establishing stable and equivalent levels of responding for all three reinforcers, rats underwent one test session where no rewards were presented to assess the effects of 1-day extinction, similar to 1-day pharmacological-induced extinction, on performance in this schedule. Subsequently, rats were again allowed to respond for nicotine, cocaine or food until reestablishment of stable levels of responding. Then, MPEP (1–9 mg/kg) was administered intraperitoneally according to a within-subjects Latin square design, 30 min prior to the testing sessions. Results Responding in the absence of a primary reinforcer was significantly decreased compared to responding under baseline conditions. Further, MPEP decreased break points maintained by nicotine, cocaine and food. Conclusions The mGlu5 receptor is implicated in mediating the reinforcing and incentive motivational properties of nicotine, cocaine and food.
Rationale: The study of the effects of repeated amphetamine administration and withdrawal on brai... more Rationale: The study of the effects of repeated amphetamine administration and withdrawal on brain reward function has relevance to both amphetamine dependence and non-drug-induced depressions. Objectives: The purpose of this study was to investigate the effects of continuous amphetamine administration and withdrawal on brain stimulation reward thresholds, and the changes that occur with repeated amphetamine exposures. Methods: Rats were prepared with bipolar electrodes in the lateral hypothalamus and trained in a discrete-trial reward threshold procedure. Then, rats underwent two separate periods of amphetamine administration via subcutaneous osmotic mini-pumps. Results: Continuous amphetamine administration was associated with lowering in brain reward thresholds and decreases in response latencies, while withdrawal was associated with threshold elevations. These effects changed with subsequent amphetamine administration and withdrawal. Conclusions: The results of this study indicated that with the amphetamine administration regime used here, rats developed increased sensitivity to the effects of acute amphetamine administration and tolerance to the effects of amphetamine withdrawal.
Rationale Most nicotine self-administration (NSA) studies in rats are performed under limited-acc... more Rationale Most nicotine self-administration (NSA) studies in rats are performed under limited-access conditions. Few studies have examined the relationship between nicotine dependence and NSA. Objectives To determine how NSA access conditions affect NSA and the duration of nicotine dependence during abstinence, as reflected in somatic signs of withdrawal precipitated by administration of the nicotinic receptor antagonist mecamylamine. Methods The effects of different NSA access conditions (zero, 1 h/5 days, 1 h/7 days and 6 h/7 days per week) and non-contingent nicotine administration on NSA and somatic signs were examined. Results Daily NSA access (30 days) resulted in spontaneous and mecamylamine-induced somatic signs. Both daily access groups (1 h/day and 6 h/day, 7 days/week) exhibited spontaneous somatic signs on day 25 of NSA (17 h post-NSA) and sensitivity to mecamylamine up to 2 and 4 weeks of abstinence, respectively. In contrast, the 1 h/day, 5 days/week access group exhibited mecamylamine-induced somatic signs only up to 1 week of abstinence. NSA behavior was stable in rats with 1 h/day 5 days/week and 1 h/day 7 days/week access, but decreased from initially high rates in the 6 h/day 7 days/week access group, and decreased in rats receiving non-contingent nicotine. In contrast, extended cocaine self-administration access resulted in a gradual escalation in cocaine intake. Conclusion 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.
Rationale Nicotine withdrawal is characterized by depression-like symptomatology that may be medi... more Rationale Nicotine withdrawal is characterized by depression-like symptomatology that may be mediated by dysregulations in norepinephrine transmission. These aversive aspects of nicotine withdrawal and the rewarding effects of nicotine play major roles in maintaining nicotine dependence. Objectives The aim of this work was to evaluate the effects of desipramine (DMI), a preferential norepinephrine reuptake inhibitor and antidepressant, on preclinical models of nicotine dependence in rats. Materials and methods A rate-independent current-intensity discrete-trial threshold intracranial self-stimulation procedure was used to assess brain reward function during nicotine withdrawal induced by cessation of nicotine infusion via subcutaneous osmotic mini pumps (3.16 mg/kg/day, base). Nicotine withdrawal was also measured by somatic signs of withdrawal. DMI was administered acutely (2 or 5 mg/kg, salt) during nicotine/saline withdrawal. In other naïve rats, chronic DMI treatment via mini pump (15 mg/kg/day, salt) began after 7 days of nicotine/saline exposure and continued during administration of nicotine/saline for 14 days and during nicotine/saline withdrawal. Additional rats acquired intravenous nicotine- or food-maintained responding, were prepared with DMI/vehicle-containing mini pumps, and self-administered nicotine or food during 12 days of DMI/vehicle exposure. Results Acute DMI administration had no effect on threshold elevations observed in nicotine-withdrawing rats. Chronic DMI administration prevented the reward threshold elevations and the increased somatic signs of nicotine withdrawal. Although chronic DMI significantly decreased nicotine self-administration, it also decreased food-maintained responding. Conclusions The results suggest that norepinephrine reuptake inhibitors may be effective anti-smoking treatments that reduce the anhedonic depression-like and somatic components of nicotine withdrawal and may alter the rewarding effects of nicotine and food.
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Papers by Neil Paterson