Mechanistic studies of ethanol's interaction with the mesolimbic dopamine reward system.

Alcoholism is a chronic recurring brain disorder causing the afflicted a multitude of social and health problems and enormous costs to society. The psychosocial and pharmacological treatment options available have but small to moderate effect sizes, underlining the great need for new effective remedies. Alcohol like all other drugs of abuse acutely activates the mesolimbic dopamine system and, upon chronic administration, produces functional alterations of this important part of the brain reward system. Available data suggests that the mesolimbic dopamine system is involved both in the positive and negative reinforcing effects of ethanol. It hence becomes imperative to understand how ethanol interferes with this system. Increased knowledge about these mechanisms may open up for new targets for pharmacotherapies. We have investigated the tentative involvement of cys-loop ligand-gated ion-channels, which ethanol is known to interact with in relevant concentrations. Our data indicate that a neuronal circuitry involving glycine receptors in the nucleus accumbens, and, secondarily, nicotinic acetylcholine receptors in the ventral tegmental area is involved in the mesolimbic dopamine activating and reinforcing effects of ethanol. Manipulations of both these receptor populations have the potential to modulate ethanol consumption. The proposed neurocircuitry, has implications for understanding ethanol conditioned dopamine activation, chronic effects of ethanol on the mesolimbic dopamine system and the overall role/importance of dopamine and the nucleus accumbens for the reinforcing effects of ethanol. Computational neuroscience in conjunction with further emperical observations is likely to facilitate this process.

Age-contingent influence over accumbal neurotransmission and the locomotor stimulatory response to acute and repeated administration of nicotine in Wistar rats.

Nicotine addiction is one of the leading contributors to the global burden of disease, and early onset smokers report a more severe addiction with lower chance of cessation than those with a late onset. Preclinical research supports an age-dependent component to the rewarding and reinforcing properties of nicotine, and the aim of this study was to define behavioral adaptations and changes in accumbal neurotransmission that arise over 15 days of intermittent nicotine treatment (0.36 mg/kg/day) in rats of three different ages (5 weeks, 10 weeks, 36 weeks old). Repeated treatment increased the locomotor stimulatory response to nicotine in all age groups, but significantly faster in the two younger groups. In addition, nicotine decreased rearing activity in a way that sustained even after repeated administration in aged rats but not in the younger age groups. Electrophysiological field potential recordings revealed a decline in input/output function in the nucleus accumbens (NAc) of animals intermittently treated with nicotine starting at 5 weeks of age, but not in older animals. In drug naïve rats, acute administration of nicotine modulated both accumbal dopamine output and excitatory transmission in a partially age-dependent manner. Fifteen days of intermittent nicotine treatment did not alter the acute effect displayed by nicotine on dopamine levels or evoked field potentials. The data presented here show that both acute and repeated nicotine administration modulates accumbal neurotransmission and behavior in an age-contingent manner and that these age-dependent differences could reflect important neurobiological underpinnings associated with the increased vulnerability for nicotine-addiction in adolescents.

Bovine growth hormone transgenic mice display alterations in locomotor activity and brain monoamine neurochemistry.

Recent clinical and experimental data indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. In the present study we have investigated whether bovine GH (bGH) transgenic mice and nontransgenic controls differ in spontaneous locomotor activity, a behavioral response related to brain dopamine (DA) and reward mechanisms, as well as in locomotor activity response to drugs of abuse known to interfere with brain DA systems. The animals were tested for locomotor activity once a week for 4 weeks. When first exposed to the test apparatus, bGH transgenic animals displayed significantly more locomotor activity than controls during the entire registration period (1 h). One week later, after acute pretreatment with saline, the two groups did not differ in locomotor activity, whereas at the third test occasion, bGH mice were significantly more stimulated by d-amphetamine (1 mg/kg, ip) than controls. At the fourth test, a tendency for a larger locomotor stimulatory effect of ethanol (2.5 g/kg, ip) was observed in bGH transgenic mice. bGH mice displayed increased tissue levels of serotonin and 5-hydroxyindoleacetic acid in several brain regions, decreased DA levels in the brain stem, and decreased levels of the DA metabolite 3,4-dihydroxyphenylacetic acid in the mesencephalon and diencephalon, compared with controls. In conclusion, bGH mice display more spontaneous locomotor activity than nontransgenic controls in a novel environment and possibly also a disturbed habituation process. The finding that bGH mice were also more sensitive to d-amphetamine-induced locomotor activity may suggest that the behavioral differences observed are related to differences in brain DA systems, indicating a hyperresponsiveness of these systems in bGH transgenic mice. These findings may constitute a neurochemical basis for the reported psychic effects of GH in humans.

Enhanced spontaneous locomotor activity in bovine GH transgenic mice involves peripheral mechanisms.

Clinical and experimental studies indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. Recently we showed that transgenic mice with general overexpression of bovine GH display increased spontaneous locomotor activity. In the present study, we investigated whether this behavioral change is owing to a direct action of GH in the central nervous system or to peripheral GH actions. A transgenic construct, containing the glial fibrillary acidic protein promoter directing specific expression of bovine GH to the central nervous system, was designed. The central nervous system-specific expression of bovine GH in the glial fibrillary acidic protein-bovine GH transgenic mice was confirmed, but no effect on spontaneous locomotor activity was observed. Serum bovine GH levels were increased in glial fibrillary acidic protein-bovine GH transgenic mice but clearly lower than in transgenic mice with general overexpression of bovine GH. In contrast to the transgenic mice with general overexpression of bovine GH, glial fibrillary acidic protein-bovine GH mice did not display any difference in serum IGF-I levels. The levels of free T(3) and the conversion of the free T(4) to free T(3) were only increased in transgenic mice with general overexpression of bovine GH, but serum corticosterone levels were similarly increased in both transgenic models. These results suggest that free T(3) and/or IGF-I, affecting dopamine and serotonin systems in the central nervous system, may mediate the enhanced locomotor activity observed in transgenic mice with general overexpression of bovine GH.

Naloxone reverses disinhibitory/aggressive behavior in 5,7-DHT-lesioned rats; involvement of GABA(A) receptor blockade?

Effective medical treatment for impulsive aggression and several impulse control disorders is needed. Disinhibited, impulsive behavior of e.g. murderers, arsonists, suicidal patients, and patients suffering from antisocial personality or substance abuse disorders has been associated with signs of a deficiency in brain serotonin (5-HT) systems. Depletion of brain 5-HT consistently produces disinhibition and aggression also in experimental animals. The present series of experiments using a modified Vogel's conflict test indicates that the disinhibitory behavior of 5-HT-lesioned rats can be reversed by the commonly used opiate receptor antagonist naloxone at doses (0.1-5.0 mg/kg, s.c.) that do not significantly affect behavior in sham-lesioned controls. Moreover, this effect of naloxone, which resembles that previously observed after administration of negative modulators of gamma-aminobutyric acidA (GABA(A))/benzodiazepine receptor complexes, was reversed by a low inert dose (2.0 mg/kg, i.p.) of amobarbital. Furthermore, both naloxone (5.0 mg/kg, s.c.) and Ro 15-4513 (1.0 mg/kg, p.o.; a partial inverse agonist at benzodiazepine receptors) significantly decreased the number of attacks and the time spent in aggressive acts in 5,7-DHT-lesioned male residents. These results taken together with previous behavioral and neurochemical data suggest that the behavioral effects of naloxone observed here may involve an antagonistic action at brain gamma-aminobutyric acidA (GABA(A))/benzodiazepine receptor complexes. Thus, naloxone, its stable analogue naltrexone or other weak negative modulators of brain GABA(A)/benzodiazepine receptor complexes may represent a new pharmacological principle for the treatment of impulse control disorders.

In vivo administration of the 5-HT1A receptor agonist 8-OH-DPAT interferes with brain GABA(A)/benzodiazepine receptor complexes.

In the present study the influence of in vivo administration, or in vitro addition, of the prototypic 5-HT1A receptor agonist 8-OH-DPAT on in vitro characteristics of GABA(A)/benzodiazepine receptor complexes was examined. In vivo administration of 8-OH-DPAT at a dose (32 microg/kg, s.c. -10') that has been reported to produce anxiolytic-like effects in the elevated plus-maze doubled the Kd for in vitro binding of 3H-flunitrazepam to rat cortical membranes (Bmax was unchanged) and enhanced GABA-stimulated (3, 10, 30 and 100 microM) 36Cl- influx in corticohippocampal synaptoneurosomes. In synaptoneurosomes from vehicle treated rats, diazepam (1, 3 and 10 microM) potentiated GABA-stimulated (3 microM) 36Cl- influx. No such effect was observed in tissue from 8-OH-DPAT treated rats, in which the GABA-stimulated (3 microM) 36Cl- influx was similar to that caused by GABA + diazepam in tissue from vehicle treated rats. When added in vitro, 8-OH-DPAT failed to alter basal or GABA-stimulated 36Cl- uptake. In vivo administration of a low "anxiolytic" dose of 8-OH-DPAT thus appears to interfere with GABA(A)/benzodiazepine receptor complexes, whereas in vitro application does not. The underlying mechanism remains to be elucidated but could involve in vivo release of positive modulators of GABA(A)/benzodiazepine receptor complexes, e.g. GABA, endozepines or neurosteroids.

Biphasic effect of L-5-HTP in the Vogel conflict model.

The effect of L-5-HTP (25 400 mg/kg IP) following inhibition of the peripheral aromatic amino acid decarboxylase by means of benserazide (25 mg/kg IP) was investigated in a test modified from Vogel's drinking conflict model. At 50 mg/kg an anti-conflict action was detected, while higher doses (100-400 mg/kg) decreased punished responding. A lower dose (25 mg/kg) had no effect. Non-specific effects--such as alterations in muscle tone, in motivation to drink or in the sensitivity to electrical shock--could not explain the anxiolytic- and anxiogenic-like actions of 50 and 100 mg/kg, respectively. The bi-phasic effect of L-5-HTP is discussed in terms of different subpopulations of central serotoninergic receptors, possibly exerting opposing influences on conflict responding. The study emphasises the importance of 5-HT mechanisms in anxiety, and the possibility of finding novel anxiolytics among drugs selectively affecting central 5-HT neurotransmission.

Behavioral sensitization to nicotine is associated with behavioral disinhibition; counteraction by citalopram.

This study investigated the effects of repeated nicotine treatment on locomotor activity and behavioral inhibition, and the influence of citalopram on the behavioral effects obtained. Male rats received daily subcutaneous injections of vehicle + vehicle (veh + veh), citalopram (5.0 mg/kg) + vehicle (cit + veh), vehicle + nicotine (1.0 mg/kg; veh + nic) or citalopram + nicotine (cit + nic). Acutely, nicotine stimulated locomotor activity, and repeated daily nicotine injections sensitized veh + nic rats to the nicotine-induced locomotor stimulation after 5, 10 and 15 treatment days, whereas in cit + nic rats, the enhancement of nicotine-induced locomotion was suppressed. However, when challenged with nicotine after citalopram withdrawal (-36 h), the cit + nic treated animals were also observed to be sensitized. In the elevated plus-maze, repeated nicotine treatment produced behavioral disinhibition, measured as an increase of time spent in and entries made into open arms (%), and chronic citalopram treatment attenuated the expression of behavioral disinhibition. Moreover, the degree of nicotine sensitization correlated to the behavioral disinhibition observed. In summary, these findings suggest that behavioral sensitization to nicotine is associated with behavioral disinhibition and that chronic citalopram treatment counteracts the expression of both phenomena. Since citalopram is a highly selective serotonin reuptake inhibitor, the effects of citalopram may be due to a facilitation of serotonin neurotransmission caused by the chronic citalopram treatment.

Centrally administered neuropeptide Y (NPY) produces anxiolytic-like effects in animal anxiety models.

Effects of intracerebroventricular (ICV), neuropeptide Y (NPY) (0.2-5.0 nmol) and its C-terminal 13-36 amino acid (AA) fragment (0.4-2.0 nmol) have been examined with respect to anxiolytic properties in two rat anxiety models, Montgomery's conflict test (MT), and Vogel's drinking conflict test (VT). In the MT, 1.0 and 5.0 nmol NPY abolished the normal preference for the closed arms of the maze. At 5.0 nmol, the total number of entries made into both closed and open arms was decreased by 50%. In the VT, both 0.2 and 1.0 nmol NPY markedly increased the number of shocks accepted. The effect of 5.0 nmol NPY was less pronounced. In control experiments, NPY (0.2 nmol) did not affect pain sensitivity or thirst. Pretreatment with the selective alpha 2-adrenergic receptor antagonist idazoxan, at a dose which by itself did not affect behaviour (2.0 mg/kg), antagonized the effect of 1.0 nmol NPY in the VT. NPY 13-36 was without significant effect in both models. The results suggest that NPY exerts anxiolytic-like effects, and that these effects are mediated through an interaction with noradrenergic systems. Higher doses of NPY produce sedation and ataxia, which decrease overall activity in the MT, and interfere with the ability fully to express behaviourally the anxiolytic-like effect in the VT. The findings are discussed in relation to the noradrenaline hypothesis of anxiety, and to observations indicating involvement of NPY in the pathophysiology of major depression.

Repeated administration of amphetamine induces sensitisation to its disruptive effect on prepulse inhibition in the rat.

Male Sprague-Dawley rats were repeatedly treated with amphetamine (AMP, 1 mg/kg, SC) at 3- day intervals for 15 days and tested for prepulse inhibition of acoustic startle after each treatment. This treatment regimen induced sensitisation in the animals as evidenced by a progressive increase in the disruptive effect of AMP on prepulse inhibition. Persistent changes in brain function was indicated, since an increase in disruptive effect was observed in sensitised animals also after a 22-day-long drug- and test-free period. The development of sensitisation was blocked by pretreatment with haloperidol (HPD, 0.1 mg/kg, SC), which suggests that sensitisation to the disruptive effect of AMP was dependent on dopamine (DA) D2 receptor activation. Furthermore, the development of sensitisation was blocked by adrenalectomy, which suggests that sensitisation was dependent also on circulating adrenal hormones. Increased DA-ergic activity has been implicated in the pathophysiology of schizophrenia and AMP-induced sensitisation to the neuronal functions that modulate prepulse inhibition may be an experimental model to investigate this hypothesis.

Evidence for a role for dopamine in the diazepam locomotor stimulating effect.

It is well known that benzodiazepines produce dependence in humans and locomotor stimulation in experimental animals. In this study the possible involvement of catecholamines in the diazepam-induced locomotor stimulation in mice were investigated. Diazepam was found to have a biphasic effect; increasing locomotor activity at a low dose (0.25 mg/kg), while decreasing it at higher doses (greater than 0.5 mg/kg). The locomotor stimulating effect of diazepam was effectively blocked by pretreatment with the benzodiazepine receptor antagonist flumazenil, as well as with the catecholamine synthesis inhibitor alpha-methyltryrosine and the dopamine receptor antagonists haloperidol, spiperone and SCH 23390. Taken together, these data indicate that the locomotor stimulating effect observed after low doses of diazepam is due to activation of brain dopaminergic systems involved in locomotor activity. The observations are discussed in relation to the hypothesis that dependence-producing drugs activate specific brain reward systems.

Environment-dependent effects of ethanol on DOPAC and HVA in various brain regions of ethanol-tolerant rats.

The development of tolerance to the behavioral and biochemical effects of ethanol was studied. Rats were made tolerant to ethanol by the administration of daily ethanol injections (3 g/kg, IP) for 7 and 28 days. Tolerance developed both to the behavioral (hypothermic, sedative) and biochemical (accumulation of dopamine metabolites in various brain areas) actions of ethanol. However, it was found that this tolerance to both the behavioral and biochemical effects of ethanol was no longer present when previously ethanol-tolerant animals were moved from their home environment and given a challenge dose of ethanol (2.5 g/kg; IP) in a new, unfamiliar environment. Our findings confirm that ethanol tolerance cannot be explained on the basis of a singular neurochemical event. The development of ethanol tolerance is due to a complex interaction between environmental, learning, and biochemical factors.

Behavioral and neurochemical consequences of repeated nicotine treatment in the serotonin-depleted rat.

RATIONALE: Repeated exposure to addictive drugs causes neuroadaptive alterations that are proposed to increase the incentive motivation to consume drugs and to decrease the ability to inhibit such inappropriate motivational impulses and responses. Together, these behavioral consequences of drug intake may underlie the compulsive drug-seeking and -taking behaviors observed in drug abuse. OBJECTIVE: Brain serotonin (5-HT) has been implicated in these mechanisms and this study therefore investigated the consequences of brain 5-HT depletion on the behavioral and neurochemical effects induced by repeated daily nicotine treatment (15 days) in male rats. METHODS: The effects of the present pharmacological manipulations were evaluated behaviorally (locomotor activity, the elevated plus-maze) and neurochemically (microdialysis, brain biochemistry). RESULTS: Depletion of brain 5-HT produced behavioral disinhibition in the elevated plus-maze. In 5-HT-depleted animals, nicotine-induced locomotor sensitization was observed on treatment days 5, 10, and 15, but only on day 15 in the sham-operated rats. Postsensitization, the locomotor stimulatory effects of amphetamine and the dopamine receptor agonists SKF 38,393, apomorphine, and quinpirole were decreased in 5-HT-depleted animals, an effect that appeared to be more pronounced in nicotine-treated rats. Repeated nicotine treatment sensitized the nicotine-induced elevation of the extracellular accumbal dopamine levels in sham-operated, but not in 5-HT-depleted rats, and was also associated with decreased D2 autoreceptor function in both nicotine-treated experimental groups. CONCLUSIONS: Depletion of brain 5-HT, which produces behavioral disinhibition, may slightly facilitate the overall expression of locomotor sensitization to nicotine and differentially affect the pre- and postsynaptic neuroadaptive events involved in the expression of these phenomena.

Nicotinic mechanisms involved in the dopamine activating and reinforcing properties of ethanol.

Ethanol shares with all major dependence producing drugs the ability to activate brain mesocorticolimbic dopamine neurons, an important part of the brain reward systems. This dopamine activation may be involved in mediating the positive reinforcing effects of ethanol. The mechanisms of action of ethanol in its activation of this dopamine system remain, however, to be elucidated. A selective pharmacological interference with these mechanisms may offer a possibility to reduce the reinforcing properties of ethanol without simultaneously interfering with the reinforcing properties of natural rewards. Ethanol has been shown to directly influence the function of various ligand-gated ion-channels. Several of these are located on or nearby mesocorticolimbic dopamine neurons. One such receptor is the nicotinic acetylcholine receptor (nAChR). The present article reviews a series of investigations aimed at investigating whether nAChRs are involved in the dopamine activating and reinforcing properties of ethanol. To this end acute and chronic behavioral and neurochemical experiments were performed in mice and rats. The results obtained indicate that central nAChRs in the ventral tegmental area are involved in mediating the mesolimbic dopamine activating and reinforcing effects of ethanol. Furthermore, the ethanol-induced activation of these receptors is probably indirect, subsequent to a primary interference of ethanol in the nucleus accumbens. Moreover, subchronic nicotine treatment enhances the reinforcing and dopamine activating properties of ethanol. This long-term effect may, however, derive from autonomic adaptations in response to intermittent blockade of peripheral nAChRs (rather than from intermittent stimulation of central receptors), and appears to be associated with development of a disinhibitory behavior that could involve also other neurotransmitters, e.g. serotonin. Taken together, these findings could provide a neurobiological explanation to the often observed co-abuse of nicotine and ethanol in man. Furthermore, since the behavioral models applied previously have predicted therapeutic drug effects in the clinic, the results suggest that selective blockade of the ventral tegmental nAChRs that are involved in the above effects may provide a new pharmacological alternative in the treatment of alcoholism.

Sustained 5-hydroxytryptamine release-inhibitory and anxiolytic-like action of the partial 5-HT1A receptor agonist, buspirone, after prolonged chronic administration.

The effect of prolonged administration of high doses of buspirone on its 5-hydroxytryptamine (5-HT) release-inhibitory and anxiolytic-like properties was investigated. The 5-HT release-inhibitory effect of a challenge dose of buspirone (0.5 mg/kg, s.c.) was identical in rats chronically treated with vehicle or buspirone (10 mg/kg, b.i.d. for 10 weeks), as estimated by in vivo microdialysis in the ventral hippocampus. In the same set of animals there was a significant anxiolytic-like effect in the elevated plus-maze after 5 weeks of treatment with buspirone. The results indicate that the functional capacity of 5-HT release-controlling 5-HT1A autoreceptors is retained upon chronic administration of buspirone, and that this effect may well be associated with the anxiolytic-like action of the compound.

C-fos antisense in the nucleus accumbens blocks the locomotor stimulant action of cocaine.

Systemic cocaine induces c-fos expression in rat striatum. The functional role of this phenomenon remains unknown. Recently, selective inhibition of gene expression in the brain using antisense oligodeoxynucleotides became possible. Here, we report that bilateral administration of an antisense oligo against c-fos in the nucleus accumbens blocks cocaine induced locomotor stimulation, without affecting spontaneous exploratory activity. A control sense oligo was inactive. This finding suggests a role for c-fos in mediating psychostimulant effects of cocaine.

The mesolimbic dopamine-activating properties of ethanol are antagonized by mecamylamine.

It has been suggested that ethanol may interact with the central nicotinic acetylcholine receptor, thus providing a basis for the often observed high consumption of both ethanol and nicotine. In the present in vivo microdialysis study, ethanol (2.5 g/kg) moderately increased dopamine overflow in the rat nucleus accumbens. The central nicotinic acetylcholine receptor antagonist mecamylamine totally counteracted this effect in a dose (1.0 mg/kg) that did not alter dopamine overflow per se. Ethanol also increased the overflow of dihydroxyphenylacetic acid and homovanillic acid, but this effect was not altered by mecamylamine (1.0 mg/kg). Furthermore, the ethanol-induced enhancement of 3,4-dihydroxyphenylalanine accumulation in the mesolimbic dopamine terminal area after NSD 1015 (an inhibitor of l-aromatic amino acid decarboxylase) was completely antagonized by mecamylamine in doses (3.0 and 6.0 mg/kg) that exerted no effects per se. Neither ethanol nor mecamylamine changed the catecholamine synthesis rate in the striatum or the cerebral cortex. These results provide further evidence that ethanol-induced activation of the mesolimbic dopamine system (increased dopamine synthesis and release) may be mediated via stimulation of central nicotinic acetylcholine receptors. It is suggested that antagonists of central nicotinic acetylcholine receptors may be useful in the treatment of alcoholism.

Induction but not expression of behavioural sensitization to nicotine in the rat is dependent on glucocorticoids.

Behavioural sensitization has been implicated in the development of addictive behaviour, and several studies suggest that corticosteroids may be involved in this phenomenon. In the present study, the effects of adrenalectomy and steroid replacement treatments on the behavioural sensitization observed after daily injections of nicotine (0.4 mg/kg s.c.) were investigated in the rat. Adrenalectomy completely prevented sensitization to the locomotor stimulating effect of nicotine after repeated injections but did not influence the acute locomotor activating effect of the drug or an already established sensitization to nicotine. In adrenalectomized animals receiving replacement treatment with corticosterone or dexamethasone, but not aldosterone, repeated administration of nicotine produced behavioural sensitization. Repeated dexamethasone treatment per se failed, however, to sensitize rats to nicotine. Post mortem neurochemical studies showed that repeated administration of nicotine significantly increased homovanillic acid (HVA) levels, as well as the dihydroxyphenylacetic acid (DOPAC)/dopamine quotient, in the limbic forebrain. Adrenalectomy per se significantly increased HVA levels and tended to elevate the DOPAC/dopamine quotient. When repeatedly treated with nicotine, adrenalectomized rats displayed a higher DOPAC/dopamine quotient, but no significant difference in HVA levels, compared to nicotine-treated sham-operated controls. In the striatum and the cortex, no significant effects of nicotine treatment or adrenalectomy were observed on any of the neurochemical measures. The present results suggest that glucocorticoid (type II) receptor activation is required for induction of sensitization to the locomotor stimulatory effect of nicotine, whereas corticosteroids are not required for the expression of the behavioural sensitization once established. Provided that HVA levels and the DOPAC/dopamine quotient relatively well reflect the presynaptic dopamine activating effect of nicotine, it may be suggested that corticosteroid-related mechanisms associated with behavioural sensitization to nicotine are post- rather than presynaptically located in relation to mesolimbic dopamine neurons.

Nicotine induces disinhibitory behavior in the rat after subchronic peripheral nicotinic acetylcholine receptor blockade.

The present study investigated the effects of subchronic nicotine, mecamylamine and hexamethonium, alone or in combinations, on locomotor activity and behavioral inhibition. Rats were divided into groups and tested for locomotor activity after acute nicotine. The different groups received vehicle, nicotine, mecamylamine, mecamylamine+nicotine, hexamethonium (two different concentrations) and hexamethonium+nicotine injections once a day for 15 days after which they were tested for nicotine-induced locomotor activity again. Acutely, nicotine stimulated locomotor activity, and repeated daily nicotine or hexamethonium+nicotine administration sensitized the animals to this nicotine-induced locomotor stimulation (locomotor sensitization). Mecamylamine administered subchronically in combination with nicotine was able to block the induction to locomotor sensitization to nicotine. None of the nicotinic receptor antagonists induced locomotor sensitization to nicotine by themselves. In the elevated plus-maze, subchronic nicotine treatment demonstrated a nicotine-induced behavioral disinhibition, measured as an increase of time spent in and entries made into open arms. In contrast to the findings regarding locomotor sensitization, none of the antagonists counteracted the induction of this nicotine-induced behavioral disinhibition after subchronic co-treatment with nicotine. In addition, both antagonists by themselves produced a similar effect as subchronic nicotine, i.e. promoted the development of nicotine-induced disinhibitory behavior. It was concluded that the induction of locomotor sensitization to nicotine involves stimulation of central nicotinic acetylcholine receptors, whereas the development of nicotine-induced behavioral disinhibition involves blockade of peripheral nicotinic acetylcholine receptors, and that the latter, but not the former, phenomenon from a pharmacological point of view appears to be related to the increased ethanol consummatory behavior observed after subchronic nicotine administration.

Accumbal dopamine overflow after ethanol: localization of the antagonizing effect of mecamylamine.

It has been suggested that ethanol exerts its mesolimbic dopamine activating effects and its reinforcing effects via interaction with central nicotinic acetylcholine receptors, thus providing a basis for the often observed covariation between ethanol and nicotine consumption. We have previously demonstrated that the central nicotinic acetylcholine receptor antagonist mecamylamine totally counteracts the ethanol-induced elevation of extracellular dopamine in the nucleus accumbens, as measured by in vivo microdialysis. A contribution of peripheral nicotinic receptor blockade could, however, not be excluded. In the present study, mecamylamine (1.0 mg/kg, i.p.) again totally counteracted the ethanol-induced dopamine overflow, as measured by in vivo microdialysis, while the quarternary nicotinic receptor antagonist hexamethonium (10 mg/kg, i.p.) did not. Furthermore, the increase in accumbal dopamine overflow after systemic ethanol (2.5 g/kg, i.p.) was counteracted by local perfusion of mecamylamine (50 microM) in the ipsilateral ventral tegmental area, but not by mecamylamine perfusion in the nucleus accumbens. Ethanol-induced accumbal dopamine overflow was also counteracted by perfusion of hexamethonium (250 microM) in the ventral tegmental area. These results provide further evidence that ethanol-induced activation of the mesolimbic dopamine system is mediated via stimulation of central nicotinic acetylcholine receptors, and that the receptor population within the ventral tegmental area may be the most important in this regard. It is suggested that antagonists of central nicotinic acetylcholine receptors may be useful in the treatment of alcoholism.