Pre- and postsynaptic dopamine mechanisms after repeated nicotine: effects of adrenalectomy

The reinforcing properties of nicotine may be related to its ability to release dopamine in the nucleus accumbens and to increase locomotor activity in experimental animals. Both these effects are sensitized following repeated drug exposure, a phenomenon that may underlie important aspects of addiction. Adrenal steroids may be involved both in positive reinforcement and in sensitization. Adrenalectomy hampers, e.g., the induction of locomotor sensitization to nicotine, and cross-sensitization between stress and psychostimulants may develop. Here, the effect of adrenalectomy on postsynaptic and presynaptic changes of the mesolimbic dopamine system in association with nicotine sensitization was examined. Adrenalectomy or sham-operated rats received daily nicotine (0.4 mg/kg s.c.) or vehicle for 15 days, after which the locomotor responses to nicotine (0.2 mg/kg s.c.) and the dopamine D1/D2 receptor agonist apomorphine (1.0 mg/kg s.c. or 100 microM in the nucleus accumbens by reversed microdialysis) were recorded. In addition, accumbal dopamine output was monitored by in vivo microdialysis after nicotine challenge. Sham/nicotine animals showed a sensitized locomotor response to systemic and local apomorphine compared to all other groups, including the adrenalectomized/nicotine group. Nicotine increased accumbal dopamine output in all animals. In contrast, nicotine induced a pronounced increase in locomotor activity in the sham/nicotine animals compared to the other vehicle group and the adrenalectomized animals. These results indicate that adrenal steroids are involved in the induction of the postsynaptic component of nicotine sensitization, whereas their involvement in tentative presynaptic changes remains unclear.     

Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: comparison with caudate-putamen

Using in vivo dialysis and voltammetry, the effect of acute administration of (−)-nicotine (0.8 mg/kg free base, s.c.) on extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid and ascorbic acid in the nucleus accumbens and caudate-putamen of chloral hydrateanaesthetised rats has been examined. Nicotine stimulated release of dopamine only in the nucleus accumbens, measured using dialysis. After a short time delay levels of 3,4-dihydroxyphenylacetic acid in both the nucleus accumbens and caudate-putamen also increased. In both regions, 5-hydroxyindoleacetic acid was unaffected by nicotine. Using voltammetry the effect of nicotine on extracellular levels of 3,4-dihydroxyphenylacetic acid and ascorbic acid was examined. An increase in 3,4 dihydroxyphenylacetic acid was observed in both regions after nicotine. This increase was blocked by pretreatment with the central nicotinic receptor antagonist mecamylamine (5 mg/kg). Nicotine increased the level of ascorbic acid in the nucleus accumbens and caudate-putamen; while in animals pretreated with mecamylamine, nicotine decreased levels of ascorbate.

These results show that acute administration of nicotine stimulated release of dopamine in the nucleus accumbens and increased the levels of DOPAC and ascorbic acid in the nucleus accumbens and caudate-putamen. This effect is probably mediated by nicotinic receptors as it was antagonised by mecamylamine.     

Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: Comparison with caudate-putamen

Using in vivo dialysis and voltammetry, the effect of acute administration of (−)-nicotine (0.8 mg/kg free base, s.c.) on extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid and ascorbic acid in the nucleus accumbens and caudate-putamen of chloral hydrateanaesthetised rats has been examined. Nicotine stimulated release of dopamine only in the nucleus accumbens, measured using dialysis. After a short time delay levels of 3,4-dihydroxyphenylacetic acid in both the nucleus accumbens and caudate-putamen also increased. In both regions, 5-hydroxyindoleacetic acid was unaffected by nicotine. Using voltammetry the effect of nicotine on extracellular levels of 3,4-dihydroxyphenylacetic acid and ascorbic acid was examined. An increase in 3,4 dihydroxyphenylacetic acid was observed in both regions after nicotine. This increase was blocked by pretreatment with the central nicotinic receptor antagonist mecamylamine (5 mg/kg). Nicotine increased the level of ascorbic acid in the nucleus accumbens and caudate-putamen; while in animals pretreated with mecamylamine, nicotine decreased levels of ascorbate.These results show that acute administration of nicotine stimulated release of dopamine in the nucleus accumbens and increased the levels of DOPAC and ascorbic acid in the nucleus accumbens and caudate-putamen. This effect is probably mediated by nicotinic receptors as it was antagonised by mecamylamine.     

Bupropion dose-dependently reverses nicotine withdrawal deficits in contextual fear conditioning

Bupropion, a norepinephrine and dopamine reuptake inhibitor and nicotinic acetylcholine receptor antagonist, facilitates smoking cessation and reduces some symptoms of nicotine withdrawal. However, the effects of bupropion on nicotine withdrawal-associated deficits in learning remain unclear. The present study investigated whether bupropion has effects on contextual and cued fear conditioning following withdrawal from chronic nicotine or when administered alone. Bupropion was administered alone for a range of doses (2.5, 5, 10, 20 or 40 mg/kg), and dose-dependent impairments in contextual and cued fear conditioning were observed (20 or 40 mg/kg). Follow-up studies investigated if bupropion disrupted acquisition or expression of fear conditioning. Bupropion (40 mg/kg) administration on training day only produced deficits in contextual fear conditioning. Alternatively, bupropion (20 or 40 mg/kg) administration during testing dose-dependently produced deficits in contextual and cued fear conditioning. To test the effect of bupropion on nicotine withdrawal, mice were withdrawn from 12 days of chronic nicotine (6.3 mg/kg/day) or saline treatment. Withdrawal from chronic nicotine disrupted contextual fear conditioning; however, 5 mg/kg bupropion reversed this deficit. Overall, these results indicate that a low dose of bupropion can reverse nicotine withdrawal deficits in contextual fear conditioning, but that high doses of bupropion produce deficits in fear conditioning.     

Effect of bupropion on nicotine self-administration in rats

RATIONALE AND OBJECTIVE: The mechanisms underlying the therapeutic efficacy of bupropion as a smoking cessation agent are unknown. Bupropion inhibits monoamine uptake as well as neuronal nicotinic receptor (nAChR) function. The present study compared effects of bupropion on nicotine self-administration to those of other stimulant drugs (methamphetamine and apomorphine) that lack nAChR activity in order to determine its mechanism of action. To determine the specificity of bupropion-induced changes in nicotine self-administration, the ability of bupropion to alter sucrose-maintained responding or amphetamine self-administration was determined. METHODS: In nicotine and amphetamine self-administration and sucrose-maintained responding experiments, rats responded for nicotine (0.01 or 0.02 mg/kg per infusion, IV), amphetamine (0.2 mg/kg per infusion, IV) and sucrose pellets (45 mg), respectively, on a fixed ratio 5 schedule. Once responding stabilized, rats were pretreated 15 min before the session with bupropion (1-78 mg/kg) or vehicle. The ability of methamphetamine (0.3-3 mg/kg) or apomorphine (0.01-0.2 mg/kg) to alter responding for nicotine (0.02 mg/kg per infusion, IV) was determined. RESULTS: Bupropion produced a biphasic dose-response pattern at both nicotine infusion doses, increasing infusions at low bupropion doses and decreasing infusions at high bupropion doses. Methamphetamine produced a similar biphasic pattern, whereas apomorphine only decreased nicotine infusions at high doses. Bupropion dose-dependently decreased responding for sucrose and amphetamine. CONCLUSIONS: These results suggest that high bupropion doses decrease responding nonspecifically; whereas low bupropion doses selectively increase responding for nicotine. The increase in nicotine self-administration is likely due to inhibition of dopamine and norepinephrine transporters, combined with inhibition of nAChRs.     

Adrenalectomy attenuates nicotine-induced dopamine release and locomotor activity in rats

Adrenalectomy (ADX) in mice can potentiate several physiological and behavioural responses to nicotine. The present experiments sought to examine this issue in the rat by characterising the influence of ADX upon the locomotor depressant, activating and dopamine-releasing properties of nicotine. Nicotine (0.8–1.2 mg/kg SC) dose-dependently depressed locomotor activity, an effect that was potentiated by ADX, while the locomotor activating effects of a smaller dose (0.4 mg/kg) were attenuated by ADX. In both SHAM and ADX rats chronically treated with nicotine for 5 days (daily injections of 0.4 mg/kg SC), the locomotor depressant effects of nicotine did not differ from saline-treated controls. Nicotine (0.4 mg/kg SC) increased extracellular levels of dopamine in the nucleus accumbens. This response was unaffected in rats pretreated with nicotine for 5 days (daily injections of 0.4 mg/kg SC). However, both ADX groups of rats showed smaller increases in dopamine following administration of nicotine. The results suggest that depletion of circulating corticosteroids can modulate sensitivity to nicotine in rats. The suppressant effects of ADX on nicotine-induced locomotor activity may be due to its effects on dopamine release in the nucleus accumbens. Received: 13 July 1995/Final version: 28 July 1996     

Which is the best primary medication for long-term smoking cessation--nicotine replacement therapy, bupropion or varenicline?

Nicotine chewing gum has been available since 1982, when it was shown to increase smoking cessation rates by approximately 1.5- to 2-fold after 12 months. Despite the introduction of many other preparations of nicotine (sublingual, lozenge, transdermal, nasal spray and inhaler) and numerous other clinical trials, there has been no major improvement in effectiveness for smoking cessation, just an increase in the choice of how the nicotine replacement therapy (NRT) is administered. Smoking cessation rates with NRT are similar in subjects with serious chest and cardiovascular disorders. There is no evidence that intensive counselling improves the smoking cessation rates with NRT over standard counselling. The first major alternative to NRT introduced for smoking cessation was bupropion, an inhibitor of the neuronal uptake of noradrenaline and dopamine. Bupropion is effective for smoking cessation, and effectiveness is improved by a moderate level of counselling. A long-term direct comparison of bupropion with transdermal nicotine showed than bupropion was more effective than nicotine. Despite this, NRT remains the standard treatment for smoking cessation in many countries. An exciting new development for the treatment of smoking cessation is varenicline, a partial agonist at nicotinic alpha4beta2 receptors. A direct comparison of varenicline with bupropion has shown that varenicline is as least as good as and probably more effective than bupropion for smoking cessation. At present, the number of subjects who have used varenicline in clinical trial is relatively small, and probably does not allow assessment of any rare serious adverse effects. Thus, it may be premature to recommend varenicline for smoking cessation in preference to bupropion.     

The sensitizing effect of acute nicotine on amphetamine-stimulated behavior and dopamine efflux requires activation of β2 subunit-containing nicotinic acetylcholine receptors and glutamate N-methyl-D-aspartate receptors

Nicotine has been demonstrated to enhance the subsequent use of illicit drugs in animals and humans. We previously demonstrated in female, Holtzman rats that one low dose of nicotine will potentiate locomotor activity and dopamine (DA) efflux in response to a subsequent low dose of d-amphetamine (AMPH) given 1-4 h later. In the present study, we show this also occurs in male rats and characterize the receptors required for the rapid sensitizing effect of nicotine on AMPH-stimulated locomotor behavior and AMPH-induced DA efflux. Pretreatment of male, Holtzman rats with a low dose (0.1 mg/kg, i.p.) of nicotine 2-4 h before a challenge with AMPH (0.32 mg/kg, i.p.) enhanced locomotor behavior as compared to saline pretreatment. Dihydro-β-erythroidine (DHβE), a relatively selective antagonist at β2 subunit-containing (β2?) nicotinic acetylcholine receptors (nAChR), but not methyllycaconitine (MLA), a relatively selective antagonist at α7 nAChRs, blocked the sensitizing effect of nicotine on AMPH-stimulated locomotor activity. Pretreatment with varenicline, a partial agonist selective for β2? nAChRs, blocked the sensitizing effect of nicotine on AMPH-stimulated locomotor behavior. Nicotine pretreatment sensitized AMPH-induced DA overflow in slices from ventral (nucleus accumbens, NAc), but not dorsal striatum as compared to saline-pretreated rats. Nicotine sensitization of the DA overflow was blocked by DHβE. Pretreatment with the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801 (0.1 mg/kg, s.c.) 30 min before nicotine blocked sensitization of both locomotion and DA overflow in response to AMPH challenge. These results demonstrate that activation of the β2? nAChRs and NMDA receptors are required for the rapid sensitizing effect of nicotine on AMPH actions. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.     

Nicotine increases microdialysate brain amino acid concentrations and induces conditioned place preference

The action of nicotine on the nicotinic receptor-mediated release of inhibitory and excitatory acids in the nucleus accumbens, NAC, of freely moving rats was studied in order to clarify their effects' on reinforcing behavior as estimated by conditioned place preference (CPP). Using the technique of microdialysis, intraperitoneal (i.p.) injections of nicotine (0.15-0.3-0.6 mg/kg), significantly increased aspartate, glutamate, arginine, taurine, and alanine microdialysate content in the nucleus accumbens. The same doses of nicotine were able to elicit a reinforcing effect in a CPP paradigm which was probably associated with the increased brain levels of excitatory acids triggering additional dopamine release in the mesolimbic system.     

Which is the best primary medication for long-term smoking cessation – nicotine replacement therapy,bupropion or varenicline?

Nicotine chewing gum has been available since 1982, when it was shown to increase smoking cessation rates by ～ 1.5- to 2-fold after 12 months. Despite the introduction of many other preparations of nicotine (sublingual, lozenge, transdermal, nasal spray and inhaler) and numerous other clinical trials, there has been no major improvement in effectiveness for smoking cessation, just an increase in the choice of how the nicotine replacement therapy (NRT) is administered. Smoking cessation rates with NRT are similar in subjects with serious chest and cardiovascular disorders. There is no evidence that intensive counselling improves the smoking cessation rates with NRT over standard counselling. The first major alternative to NRT introduced for smoking cessation was bupropion, an inhibitor of the neuronal uptake of noradrenaline and dopamine. Bupropion is effective for smoking cessation, and effectiveness is improved by a moderate level of counselling. A long-term direct comparison of bupropion with transdermal nicotine showed than bupropion was more effective than nicotine. Despite this, NRT remains the standard treatment for smoking cessation in many countries. An exciting new development for the treatment of smoking cessation is varenicline, a partial agonist at nicotinic α₄β₂ receptors. A direct comparison of varenicline with bupropion has shown that varenicline is as least as good as and probably more effective than bupropion for smoking cessation. At present, the number of subjects who have used varenicline in clinical trial is relatively small, and probably does not allow assessment of any rare serious adverse effects. Thus, it may be premature to recommend varenicline for smoking cessation in preference to bupropion.     

The influence of nicotine pretreatment on mesoaccumbens dopamine overflow and locomotor responses to D-amphetamine

Pretreatment with psychostimulant drugs causes sensitisation of their effects on locomotor activity and dopamine (DA) overflow in the nucleus accumbens (NAcc) and there is evidence for similarities in the mechanisms involved. This study used in vivo microdialysis in conscious freely moving rats to investigate the extent to which pretreatment with nicotine causes sensitisation to D-amphetamine. Pretreatment with nicotine (0.4 mg/kg SC daily for 5 days) caused sensitisation of the locomotor responses to D-amphetamine (0.1–0.5 mg/kg SC) but not cocaine (15 mg/kg IP). Nicotine pretreatment did not influence the increase in DA overflow into dialysis probes, located in the core of the NAcc, evoked by systemic injections of D-amphetamine or cocaine (15 mg/kg IP) but decreased the overflow evoked by the administration of D-amphetamine (1 × 10^–6M) through the dialysis probe. The results provide further evidence for a dissociation between the expression of sensitised locomotor responses to psychostimulant drugs and sensitisation of their stimulatory effects on DA overflow in the core of the NAcc. The results suggest that the sensitisation of the effects of nicotine on DA overflow in this subdivision of the NAcc may be pharmacologically specific to nicotinic drugs. Received: 23 July 1997/Final version: 19 March 1998     

Locomotor activity in rats after administration of nicotinic agonists intracerebrally.

1. Nicotine (0.13 and 0.4 mg kg-1, s.c.) increased the ambulatory component of locomotor activity in rats previously exposed to the drug. Nicotine did not increase repeated movements reliably. 2. An infusion of either nicotine (8 micrograms) or the potent nicotinic agonist cytisine (4 micrograms) into the ventral tegmental area of the forebrain increased ambulation but not repeated movements. 3. An infusion of nicotine or cytisine into the nucleus accumbens, striatum, dorsal hippocampal formation or motor thalamus did not increase ambulatory or repeated movements. 4. Mecamylamine (0.1-1.0 mg kg-1, s.c.) blocked increases in locomotor activity produced by an infusion of nicotine or cytisine into the ventral tegmental area. 5. The locomotor activity produced by systemically administered nicotine may be mediated, in part, through nicotinic receptors located in the ventral tegmental area of the mesolimbic dopamine system.     

Bupropion enhances brain reward function and reverses the affective and somatic aspects of nicotine withdrawal in the rat

RATIONALE: Bupropion is an atypical antidepressant and the only non-nicotine-based therapy approved for smoking cessation. Its use has raised much debate as to how a non-nicotine-based agent can aid in smoking cessation. OBJECTIVES: We assessed the effects of bupropion on brain reward function under baseline conditions and subsequent to withdrawal from chronic nicotine administration in rats. METHODS: A discrete-trial intracranial self-stimulation paradigm procedure was used that provides one with current intensity thresholds, a measure of reward in rats under baseline conditions and subsequent to withdrawal from chronic nicotine (3.16 mg/kg per day for 7 days via osmotic minipump). Somatic signs were recorded based on a checklist of nicotine abstinence signs in animals withdrawn from nicotine. RESULTS: Bupropion (10-60 mg/kg) dose-dependently lowered reward thresholds in non-withdrawing subjects indicating an increase in reward. Interestingly, a sub-effective dose of bupropion (5 mg/kg) blocked completely the threshold lowering effects of acute nicotine (0.25 mg/kg). Animals withdrawn from chronic nicotine exhibited increases in somatic signs of withdrawal and elevated brain reward thresholds, which is indicative of "diminished interest or pleasure" (i.e. anhedonia) in the rewarding stimuli. Bupropion (10-40 mg/kg) reversed both the reward deficit and the somatic signs, with the highest dose (40 mg/kg) inducing a protracted reversal of the threshold elevation. CONCLUSIONS: Bupropion acts on multiple levels to alter brain reward circuits influenced by nicotine, in addition to reducing the expression of somatic signs of withdrawal. First, bupropion, unlike other antidepressants, increases brain reward function under baseline conditions in non-withdrawing subjects. Second, at low doses bupropion blocks the rewarding effects of nicotine. Third, bupropion reverses the negative affective aspects of nicotine withdrawal. Such actions are likely to act in concert to mediate the unique anti-smoking properties of bupropion.     

Comparison of the effects of bupropion on nicotinic receptor-evoked [(3)H]dopamine release from rat striatal synaptosomes and slices

Tobacco smoking is a nicotine addiction, mediated in part by the ability of nicotine to elicit dopamine release, as a result of the stimulation of nicotinic acetylcholine receptors associated with dopaminergic pathways. The smoking cessation agent bupropion is an inhibitor of the dopamine transporter, but has also been shown to inhibit nicotinic acetylcholine receptors. To assess the relative impact of its actions at these two targets, we have examined the effects of bupropion on nicotine-evoked [(3)H]dopamine release from rat striatal synaptosomes and slices, in the absence of any other transporter inhibitor. Bupropion (10 microM) significantly decreased nicotine-evoked [(3)H]dopamine release by approximately 50% in both preparations, consistent with the blockade of nicotinic receptors. In support of this interpretation, bupropion also selectively inhibited nicotine-evoked Ca(2+) increases in SH-SY5Y cells. In striatal slices (but not in synaptosomes) the concentration-response profile for bupropion has an inverted 'u' shape, with a decrease in nicotine-evoked [(3)H]dopamine release also observed in the presence of 0.1 microM bupropion. This effect of 0.1 microM bupropion (but not 10 microM bupropion) was reversed by the dopamine D(2) receptor antagonist raclopride. We propose that modest blockade of the dopamine transporter by low concentrations of bupropion results in feedback inhibition via dopamine D(2) autoreceptors. This is overcome at higher concentrations of bupropion, before inhibition of nicotinic receptors occurs. Therefore bupropion's inhibition of the dopamine transporter and nicotinic receptors appears to be separated with respect to concentration.     

Cholinergic modulation of dopaminergic reward areas: upstream and downstream targets of nicotine addiction

Nicotine reinforces smoking behaviour by activating nicotinic acetylcholine receptors in the midbrain dopaminergic reward centres. Upstream of the dopaminergic neurons nicotine induces long-term potentiation of the excitatory input to dopamine cells in the ventral tegmental area, and depresses inhibitory inputs. Both effects of nicotine were shown to last much longer than the nicotine exposure and together will activate the dopaminergic ventral tegmental area projection toward the nucleus accumbens. However, downstream of dopamine, effects of nicotine are also likely to occur. Cholinergic interneurons within the nucleus accumbens are important in the tonic control of the γ-amino buteric acid (GABA) nucleus accumbens output neurons, which project back to the ventral tegmental area. The nicotinic acetylcholine receptors that mediate this control are likely to desensitise upon preexposure to the nicotine concentrations found in the blood of smokers. Thus, synaptic mechanisms both upstream and downstream of dopamine release are potentially important factors contributing to the etiology of nicotine addiction.     

Bupropion Increases Selection of High Effort Activity in Rats Tested on a Progressive Ratio/Chow Feeding Choice Procedure: Implications for Treatment of Effort-Related Motivational Symptoms

Background:

Depression and related disorders are characterized by deficits in behavioral activation, exertion of effort, and other psychomotor/motivational dysfunctions. Depressed patients show alterations in effort-related decision making and a bias towards selection of low effort activities. It has been suggested that animal tests of effort-related decision making could be useful as models of motivational dysfunctions seen in psychopathology.

Methods:

Because clinical studies have suggested that inhibition of catecholamine uptake may be a useful strategy for treatment of effort-related motivational symptoms, the present research assessed the ability of bupropion to increase work output in rats responding on a test of effort-related decision-making (ie, a progressive ratio/chow feeding choice task). With this task, rats can choose between working for a preferred food (high-carbohydrate pellets) by lever pressing on a progressive ratio schedule vs obtaining a less preferred laboratory chow that is freely available in the chamber.

Results:

Bupropion (10.0–40.0 mg/kg intraperitoneal) significantly increased all measures of progressive ratio lever pressing, but decreased chow intake. These effects were greatest in animals with low baseline levels of work output on the progressive ratio schedule. Because accumbens dopamine is implicated in effort-related processes, the effects of bupropion on markers of accumbens dopamine transmission were examined. Bupropion elevated extracellular dopamine levels in accumbens core as measured by microdialysis and increased phosphorylated dopamine and cyclic-AMP related phosphoprotein 32 kDaltons (pDARPP-32) immunoreactivity in a manner consistent with D1 and D2 receptor stimulation.

Conclusion:

The ability of bupropion to increase exertion of effort in instrumental behavior may have implications for the pathophysiology and treatment of effort-related motivational symptoms in humans.     

The effects of nicotine on locomotor activity and dopamine overflow in the alcohol-preferring AA and alcohol-avoiding ANA rats

The aim of the study was to investigate the importance of the interaction between central dopaminergic and cholinergic mechanisms for ethanol reinforcement. This was done by comparing the effects of nicotine on locomotor activity and release of dopamine in the nucleus accumbens of the alcohol-preferring Alko Alcohol (AA) and alcohol-avoiding alko non-alcohol (ANA) rats. Nicotine was administered acutely (0.25, 0.50 or 0.75 mg/kg, s.c.) or repeatedly once daily (0.5 mg/kg, s.c.) for 8 days. An acute dose of nicotine increased locomotor activity and the extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) measured with in vivo microdialysis suggesting stimulation of dopamine release by nicotine. No difference in the stimulation of locomotor activity or in the increase in the extracellular concentrations of dopamine or its metabolites by nicotine was found between the rat lines. The concentrations of nicotine in the plasma were also identical. The rats treated repeatedly with nicotine showed a progressive increase in locomotion. On the challenge day, 1 week after termination of nicotine or saline injections, rats previously treated with nicotine were activated more by nicotine than saline-treated rats. This behavioral sensitization was not accompanied by an increase in the amplitude of the neurochemical response to nicotine, but the duration of the increase in the levels of DOPAC was longer in the nicotine than saline-treated animals. The increases in locomotor activity and metabolite levels were, however, similar in both rat lines. These data suggest that differences in the interaction of central dopaminergic and cholinergic mechanisms probably do not contribute to the difference in ethanol self-administration between the AA and ANA rat lines.     

Clinical efficacy of bupropion in the management of smoking cessation

Nicotine addiction is a chronic relapsing condition that can be difficult to treat. Until recently, pharmacological options for the treatment of tobacco dependence were primarily limited to nicotine replacement therapy (NRT). Sustained-release bupropion (bupropion SR) is the first non-nicotine pharmacological treatment approved for smoking cessation. Bupropion SR is recommended for first-line pharmacotherapy alongside NRT in the updated US Clinical Practice Guidelines and the UK Health Education Authority Guidelines. The UK National Institute of Clinical Excellence recommends NRT and bupropion SR for smokers who have expressed a desire to quit smoking. This review presents evidence that bupropion SR is an effective first-line therapy for smoking cessation in a wide range of patient populations. It is associated with significantly higher smoking cessation rates compared with placebo in patients with or without a history of prior bupropion SR or NRT use, and its effect is independent of gender. Bupropion SR treatment is effective in the prevention of relapse to smoking in those patients who have successfully quit, and re-treatment is effective in smokers who recommence smoking after a previous course of bupropion SR. Bupropion SR treatment relieves the symptoms of craving and nicotine withdrawal, and attenuates the weight gain that often occurs after smoking cessation. Data collected from motivational support programmes and employer-based studies provide strong evidence of the effectiveness of bupropion SR as an aid to smoking cessation in 'real life' situations, and confirm the efficacy seen in clinical trials.     

Effect of ventral tegmental 6-hydroxydopamine lesions on the locomotor stimulant action of nicotine in rats

Convergent evidence suggests that the locomotor stimulant effect of nicotine is mediated by nicotinic receptors located on mesolimbic dopaminergic neurons. However, 6-hydroxydopamine lesions of the ventral tegmental area, resulting in substantial depletion of nucleus accumbens dopamine, were recently reported to have no effect on nicotine-induced locomotion. The present study sought to re-examine this issue. Rats received bilateral infusions of 6-hydroxydopamine or vehicle into the ventral tegmental area. Starting 3 weeks later, locomotor activity was tested after subcutaneous injection of saline, nicotine (0.4 mg/kg base), amphetamine (0.5 mg/kg) or scopolamine (0.5 mg/kg). In lesioned animals, the locomotor stimulant effects of nicotine and amphetamine were greatly reduced, whereas saline and scopolamine-induced activity was scarcely affected. Dopamine denervation was assessed by autoradiography, using [¹²⁵I]RTI-55 to label plasmalemmal dopamine transporters. Labelling was reduced in nucleus accumbens core and shell and in the ventral tegmental area (by 87, 81 and 70%, respectively), and in nigrostriatal areas (52–77%). The locomotor stimulant effects of nicotine and amphetamine were correlated with residual [¹²⁵I]RTI-55 labelling in mesolimbic and nigrostriatal regions (r=0.6–0.8). The present results provide further evidence that the locomotor stimulant effect of nicotine is dependent on the integrity of ascending dopamine neurons.     

Bupropion attenuates nicotine abstinence syndrome in the rat

Rationale Bupropion reduces discomfort and craving associated with smoking cessation. This study determined whether a rat model of nicotine dependence could detect such nicotine abstinence-alleviating effects. Objectives Experiments determined whether the abstinence-alleviating effects of bupropion were detectable by (1) behavioral abstinence signs precipitated by the nicotinic antagonist mecamylamine, (2) place aversion conditioned to mecamylamine-precipitated nicotine abstinence, and (3) spontaneous behavioral abstinence signs after abrupt nicotine withdrawal. Methods In experiments 1 and 2, nicotine-dependent rats were coinfused for 7 days with 3.15 mg/kg/day nicotine and 20 mg/kg/day bupropion or with nicotine alone. They were then challenged with 1 mg/kg mecamylamine and observed for behavioral abstinence signs (experiment 1) or place aversion conditioned to precipitated abstinence (experiment 2). In experiment 3, rats were nicotine-infused for 7 days as above. A day after termination of nicotine infusion, rats were observed for spontaneous nicotine abstinence signs before and after injection with saline or bupropion. Results In experiment 1, rats coinfused with nicotine and bupropion had significantly fewer mecamylamine-precipitated abstinence signs than rats infused with nicotine alone but similar numbers to rats infused with saline alone. In experiment 2, bupropion pretreatment significantly reduced the aversiveness of mecamylamine-precipitated nicotine abstinence. In experiment 3, a single bupropion injection dose-dependently alleviated spontaneous nicotine abstinence syndrome. Conclusions These results suggest that these rat models of nicotine dependence and abstinence syndrome may be useful in detecting nicotine abstinence-alleviating effects of potential medications for smoking cessation. The effects of acute bupropion administration raise interesting questions regarding bupropion's mechanism of action.