Neil E. Paterson

The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats.

RationaleThe metabotropic glutamate (mGlu5) receptor subtype 5 antagonist MPEP attenuates self-administration of numerous drugs of abuse.ObjectivesThe 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.MethodsRats 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.ResultsResponding 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.ConclusionsThe mGlu5 receptor is implicated in mediating the reinforcing and incentive motivational properties of nicotine, cocaine and food.

The nicotinic antagonist methyllycaconitine has differential effects on nicotine self-administration and nicotine withdrawal in the rat

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.

Repeated administration of the GABAB receptor agonist CGP44532 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine-seeking in rats.

Acute administration of γ-aminobutyric acid B (GABAB) receptor agonists decreased nicotine, cocaine, ethanol, and heroin self-administration. GABAB receptor agonists also decreased cue-induced cocaine craving or seeking in humans and animals, respectively. The present study investigated the effects of repeated subcutaneous administration of the GABAB receptor agonist CGP44532 on nicotine- and food-maintained responding under a fixed ratio 5 schedule of reinforcement. The second part of the study determined whether contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior, and whether acute subcutaneous CGP44532 administration affected cue-induced reinstatement of extinguished nicotine-seeking behavior. The results indicated that repeated administration of 0.25 mg/kg CGP44532 selectively decreased nicotine self-administration compared to food-maintained responding during the first 7 days of treatment. Repeated administration of 0.5 mg/kg/day CGP44532 nonselectively decreased both nicotine- and food-maintained responding. Contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior. Further, acute CGP44532 administration (0.125 and 0.25 mg/kg) decreased cue-induced reinstatement of nicotine-seeking behavior. In summary, the present results indicated that 0.25 mg/kg/day CGP44532 selectively decreased nicotine self-administration compared to food-maintained responding, and acute administration of CGP44532 (0.125 and 0.25 mg/kg) dose-dependently decreased cue-induced reinstatement of nicotine-seeking behavior.

Extended Access to Nicotine Self-Administration Leads to Dependence: Circadian Measures, Withdrawal Measures, and Extinction Behavior in Rats

The present study characterized nicotine intake, circadian patterns of food and water intake, precipitated somatic signs of withdrawal, and extinction of nicotine-seeking behavior in rats with 23-h access to intravenous self-administration (IVSA). Separate groups of animals were allowed access to nicotine IVSA (0.015, n = 9; 0.03, n = 14; 0.06, n = 16; mg/kg/0.1 ml infusion/s; fixed ratio 1) and trained to nosepoke for food and water 23 h/day for 40 consecutive days. Somatic signs of nicotine withdrawal were examined following saline or mecamylamine administration (1.5 mg/kg i.p.), and extinction of nicotine-seeking behavior was assessed. A dose-dependent decrease in lever responding and an increase in nicotine intake were observed, with the highest nicotine dose producing the lowest amount of lever responding and the highest amount of nicotine intake. Nicotine acutely reduced diurnal and nocturnal food intake, producing smaller and fewer meals, and an increased rate of eating. Differences in rate of nicotine intake between the light and dark phase decreased significantly, especially in rats receiving higher unit nicotine doses (0.03 and 0.06 mg/kg), along with long-term decreases in the circadian profile and amplitude of feeding. Mecamylamine precipitated robust withdrawal signs, the magnitude of which was positively correlated with the total amount of self-administered nicotine. Extinction of nicotine-seeking behavior was observed and was facilitated by removal of nicotine-associated cues. The results demonstrate that rats will self-administer nicotine to the point of producing dependence, as measured by somatic signs, resistance to extinction, and measures of food intake.

Effects of repeated withdrawal from continuous amphetamine administration on brain reward function in rats

Abstract. 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.

Positive Modulation of GABAB Receptors Decreased Nicotine Self-Administration and Counteracted Nicotine-Induced Enhancement of Brain Reward Function in Rats

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

Chronic bupropion attenuated the anhedonic component of nicotine withdrawal in rats via inhibition of dopamine reuptake in the nucleus accumbens shell

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.

Role of γ‐Aminobutyric Acid (GABA) and Metabotropic Glutamate Receptors in Nicotine Reinforcement: Potential Pharmacotherapies for Smoking Cessation

Abstract: 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: γ‐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.

Sub-optimal performance in the 5-choice serial reaction time task in rats was sensitive to methylphenidate, atomoxetine and D-amphetamine, but unaffected by the COMT inhibitor tolcapone

Prefrontal cortical dopamine (DA) and norepinephrine (NE) are implicated in multiple aspects of cognitive function assessed via the 5-choice serial reaction time task (5-CSRTT) in rodents. The present studies assessed the effects of the NE reuptake inhibitor atomoxetine (0.5-2.0 mg/kg), the mixed DA/NE reuptake inhibitor methylphenidate (0.1-2.0 mg/kg), the catecholamine releaser D-amphetamine (0.1-1.0 mg/kg) and the catecholamine-o-methyl-transferase (COMT) inhibitor tolcapone (3.0-30.0 mg/kg) in rats that exhibited sub-optimal performance (reduced accuracy: <70% correct) in the 5-CSRTT. Increased ITI durations were associated with increased premature responding. Decreased ITI durations resulted in increased percent omissions, increased perseverative responses and increased response latencies, but had no effects on magazine latencies or percent correct. Atomoxetine decreased premature responding at prolonged ITI durations and methylphenidate decreased percent omissions at low doses (0.1 and 0.5 mg/kg). By contrast, D-amphetamine increased premature and perseverative responding in a dose-dependent manner (0.3-1.0 mg/kg). Finally, tolcapone had no effects on sub-optimal performance in the variable ITI 5-CSRTT. These results suggest minimal potential of tolcapone as a therapeutic agent for ADHD and implicate cortical NE, not DA, in impulsive action.

Psychostimulant-like discriminative stimulus and locomotor sensitization properties of the wake-promoting agent modafinil in rodents

UNLABELLED The present studies assessed the potential abuse liability and likely mechanism(s) of action of the wake-promoting agent modafinil. METHODS Experiments assessed the locomotor sensitization (LS) and discriminative stimulus (DS) properties of modafinil in mouse and rat, respectively. Comparative data were generated with a range of psychostimulants and monoamine reuptake inhibitors. RESULTS Repeated administration of d-amphetamine and cocaine, psychostimulants with high abuse liability, resulted in the induction and expression of LS in mice. Bupropion and caffeine, two psychostimulants not abused in humans, were not associated with LS. GBR12909 induced LS during repeated exposure, but there was no evidence of expression of LS after acute challenge following withdrawal. In contrast, repeated administration of modafinil resulted in the expression, but not induction, of LS. d-amphetamine, but not the mu-opioid agonist morphine or the nAChR agonist nicotine, fully substituted for the cocaine DS in rats. The selective dopamine transporter (DAT) inhibitor GBR12909 fully substituted, the preferential norepinephrine transporter (NET) inhibitor desipramine partially substituted, and the selective serotonin reuptake inhibitor citalopram failed to substitute for cocaine. Modafinil fully substituted for cocaine, similar to the mixed DAT/NET inhibitor bupropion. CONCLUSIONS Two preclinical assays indicated potential abuse liability of modafinil; drug discrimination studies suggest DAT blockade by modafinil is a likely mechanism of action in vivo.