Nucleus accumbens dopamine D1 receptors regulate the expression of ethanol-induced behavioural sensitization (original) (raw)
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Ethanol-induced sensitization depends preferentially on D1 rather than D2 dopamine receptors
Pharmacology Biochemistry and Behavior, 2011
Behavioral sensitization, defined as a progressive increase in the locomotor stimulant effects elicited by repeated exposure to drugs of abuse, has been used as an animal model for drug craving in humans. The mesoaccumbens dopaminergic system has been proposed to be critically involved in this phenomenon; however, few studies have been designed to systematically investigate the effects of dopaminergic antagonists on development and expression of behavioral sensitization to ethanol in Swiss mice. We first tested the effects of D 1 antagonist SCH-23390 (0-0.03 mg/kg) or D 2 antagonist Sulpiride (0-30 mg/kg) on the locomotor responses to an acute injection of ethanol (2.0 g/kg). Results showed that all tested doses of the antagonists were effective in blocking ethanol's stimulant effects. In another set of experiments, mice were pretreated intraperitoneally with SCH-23390 (0.01 mg/kg) or Sulpiride (10 mg/kg) 30 min before saline or ethanol injection, for 21 days. Locomotor activity was measured weekly for 20 min. Four days following this pretreatment, all mice were challenged with ethanol. Both antagonists attenuated the development of ethanol sensitization, but only SCH-23390 blocked the expression of ethanol sensitization according to this protocol. When we tested a single dose (30 min before tests) of either antagonist in mice treated chronically with ethanol, both antagonists attenuated ethanol-induced effects. The present findings demonstrate that the concomitant administration of ethanol with D 1 but not D 2 antagonist prevented the expression of ethanol sensitization, suggesting that the neuroadaptations underlying ethanol behavioral sensitization depend preferentially on D 1 receptor actions.
Pharmacology Biochemistry and Behavior, 2010
Several evidences have indicated the involvement of neuronal nicotinic acetylcholine receptors (nAChR) in behavioral effects of drugs of abuse, including ethanol. nAChRs are implicated in ethanol-induced behaviors as well as neurochemical responses to ethanol. Recently, it is demonstrated that mecamylamine, a nAChR antagonist blocks cocaine-, d-amphetamine-, ephedrine-, nicotine-, and methylphenidate-induced psychomotor sensitization. However, no reports are available on its role in ethanol-induced psychomotor sensitization. Therefore, an attempt was made to evaluate its effect on ethanol-induced locomotor sensitization using a model previously described by us. The results revealed that acute administration of mecamylamine (1 and 2 mg/kg, i.p.) blocked the acute stimulant effect of ethanol (2.0 g/kg, i.p.). In addition, treatment with mecamylamine (0.5-2.0 mg/kg, i.p.), 30 min prior to the challenge dose of ethanol (2.0 g/kg, i.p.) dose dependently attenuated expression of sensitization to locomotor stimulant effect of ethanol. Moreover, administration of mecamylamine (1 and 2 mg/kg, i.p.) during development (prior to each ethanol injection on days 1, 4, 7, and 10) blocked acquisition as well as expression (day 15) of sensitization to locomotor stimulant effect of ethanol. Mecamylamine per se did not affect locomotor activity. Further, it also did not influence blood ethanol levels and rotarod performance in mice. These results support the hypothesis that neuroadaptive changes in nAChRs may participate in the development and the expression of ethanolinduced locomotor sensitization.
PLoS ONE, 2014
In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens -a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/ kg/day) or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as ''sensitized'' and the 33% with the lowest levels as "non-sensitized''. The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 mg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in nonsensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of locomotor sensitization to ethanol.
MK-801 Blocks the Development of Behavioral Sensitization to Ethanol
Alcoholism: Clinical and Experimental Research, 2000
Background: Studies have indicatcd that MK-801 (a noncompetitive N-methyl-o-aspartate receptor antagonist) participates in the long-term neural changcs rcsponsible for sensitization to stimulant drugs. It is known that repeated administration of low doses of ethanol sensitizes animals to its stimulant effect. In this work we investigated whether MK-801 alters the development of behavioral sensitization to ethanol.
Neuropharmacology
Striatal dopamine D2 receptors have been implicated in the development of behavioral sensitization after repeated exposure to drugs of abuse. There are clear individual differences in the level of sensitization to ethanol among species and even among individuals from the same strain. Albino Swiss mice treated with ethanol (2.2 g/kg) have been shown to present clear variations in the development of sensitization. While some mice developed ethanol (EtOH) induced sensitization, others did not. This variability was associated with differences in D2 dopaminergic receptor binding. In the present study, we evaluated the functional relevance of dopamine D2 receptor by measuring, in sensitized and non-sensitized mice, the locomotor response to a D2 receptor agonist (quinpirole, 0.5 and 2.0 mg/kg i.p. or 0.01 and 0.2 μg/side intra-accumbens) or antagonist (sulpiride, 10 or 50 mg/kg i.p. or 0.02 μg/side intra-accumbens + ethanol i.p.). Whereas the systemic administration of quinpirole decreased locomotor activity in a similar way in all the groups, intra-nucleus accumbens (NAc) administration induced significantly higher locomotor stimulation in the sensitized group alone. Our data show that functionally hyperresponsive D2 receptors are present in the NAcs of sensitized but not non-sensitized mice, suggesting that this could be a biomarker of behavioral sensitization. Furthermore, i.p. administration of sulpiride blocked the expression of sensitization in the sensitized group, and intra-NAc administration attenuated it, indicating that the activation of accumbal D2 receptors is essential for the expression of EtOH behavioral sensitization.This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.► There is significant individual variability in the development of ethanol sensitization. ► D2 receptor hyperfunctionality in the NAc is associated with ethanol sensitization. ► Activation of NAc D2 receptors is important for the expression of ethanol sensitization. ► Individual variations in susceptibility to ethanol sensitization are related to differences in accumbal D2 receptor function.
Fuel and Energy Abstracts
Behavioral sensitization to the stimulating effect of ethanol (EtOH) or other drugs, which can be observed in mice as an increase in locomotor activity after repeated administration, has been associated with neuroadaptations within the dopaminergic mesolimbic pathway. In the nucleus accumbens (NAc), an afferent region of the mesolimbic pathway, dopamine (DA) release can be modulated by serotonergic 2C receptors (5-HT2CR). The aim of the present study was to evaluate the function of 5-HT2CR in the expression of EtOH-induced behavioral sensitization in Albino Swiss mice with various levels of sensitization to EtOH. In the four experiments that we performed, the mice were given saline or 2.2 g/kg EtOH daily for 21 days. Based on their locomotion on day 21, the EtOH-pretreated mice were assigned to one of two groups, highly sensitized or weakly sensitized to the stimulating effect of EtOH. In each experiment, 2 weeks after the 21-day treatment (withdrawal period), the mice were submitted to four pharmacological challenges of two drug treatments each. The mice in experiments 1 and 2 received two i.p. injections, whereas the mice in experiments 3 and 4 received an intra-NAc administration followed by an i.p. injection. The challenges were: saline+saline; saline+EtOH; SB-242084 (a 5-HT2CR antagonist; 0.5, 1.0 or 2.0 mg/kg i.p. or 1.0 or 2.0 μg/side intra-NAc)+EtOH; and SB-242084 (0.5, 1.0 or 2.0 mg/kg i.p. or 1.0 or 2.0 μg/side intra-NAc)+saline. At all tested doses, i.p. administration of SB-242084 did not affect the stimulating effect of EtOH in the highly sensitized mice. However, when delivered by intra-NAc administration, SB-242084 reduced (at 1.0 μg/side) or completely blocked (at 2.0 μg/side) the expression of EtOH-induced behavioral sensitization in the highly sensitized mice. These findings suggest that the expression of behavioral sensitization to the stimulating effect of EtOH depends on accumbal 5-HT2CR activity.▶Some mice treated 3 weeks with EtOH developed high sensitization to its stimulant effect. ▶Other mice under the same treatment (2.2 g/kg EtOH) developed weak sensitization. ▶SB-242084 intra-NAc reduced sensitization expression only in highly sensitized mice. ▶SB-242084 i.p. did not affect the expression of EtOH-induced sensitization. ▶Expression of behavioral sensitization to EtOH depends on accumbal 5-HT2CR activity.
Psychopharmacology, 2005
Rationale: Novelty associated with behavioral testing has been shown to enhance psychostimulant-and morphine-induced locomotor stimulation. Evidence has demonstrated that novelty increases dopamine (DA) activity, and habituation to a novel environment reduces such activation. However, it is not clear whether novelty modulates ethanol-induced behavioral stimulation and whether DA plays a role in this effect. Objectives: The present work sought to demonstrate a role of habituation to test procedure as a factor that could modulate the involvement of DA in ethanol-induced locomotor stimulation. Methods: Non-habituated (NH) and habituated (H) Swiss mice pretreated with DA D1-(SCH23390; 0-0.045 mg/kg) or D2receptor (sulpiride; 0-50 mg/kg) antagonists were tested for ethanol (0-2.5 g/kg)-induced locomotor stimulation. Experiments with amphetamine (0-4 mg/kg), morphine (0-5 mg/kg) and caffeine (0-15 mg/kg) were designed to compare their results to those obtained with ethanol. The effect of the non-selective opioid receptor antagonist naltrexone (0-1.5 mg/kg) was also tested on ethanolinduced locomotor stimulation. Results: NH and H animals did not differ in their locomotor response to ethanol or caffeine; however, amphetamine-and morphine-induced stimulation was greater in NH than in H mice. SCH23390 only reduced ethanol-induced stimulation at doses that also reduced spontaneous activity in both NH and H mice. Sulpiride decreased ethanol-stimulated behavior only in the NH condition. Habituation did not modify the effect of sulpiride on amphetamine-, morphine-or caffeine-induced activation. Naltrexone reduced ethanol-induced stimulation regardless of habituation. Conclusions: The present data suggest that the participation of DA D2-receptors in ethanol-induced behavioral stimulation requires the presence of novelty. Results also support the involvement of neurotransmitter systems other than DA (i.e., endogenous opioid system) as important substrates mediating ethanol-induced locomotor activation.
Pharmacology Biochemistry and Behavior, 1999
GEVAERD, M. S. AND R. N. TAKAHASHI. Involvement of dopamine receptors on locomotor stimulation and sensitization elicited by the interaction of ethanol and mazindol in mice. PHARMACOL BIOCHEM BEHAV 63 (3) 395-399, 1999.-We have previously observed that the combination of ethanol (EtOH) and the anorectic drug mazindol (MZ) produces more marked effects on behavior than either substance alone. In the present study we examined whether the repeated administration of the drug combination could induce sensitization to its motor activating effects in mice and, if so, whether this response could be affected by dopamine (DA) receptors antagonists. Male Swiss albino mice were treated daily for 7 days with combined EtOH ϩ MZ (1.2 g/kg, 5.0 mg/kg IP), EtOH (1.2 g/kg IP), MZ (5.0 mg/kg IP), or control solution coadministered with the D 1 dopamine antagonist SCH-23390 (0.025 or 0.05 mg/kg IP), the mixed dopamine antagonist haloperidol (0.05 or 0.075 mg/kg IP), or vehicle. After the injections on days 1, 7, and 10, mice were assessed in activity cages at different time intervals. Repeated administration of MZ resulted in an enhancement of its locomotor activating effects, behavioral sensitization. Further, the combined EtOH ϩ MZ treatment also resulted in sensitization to its locomotor effects. Moreover, the development of MZ and EtOH ϩ MZ sensitization was attenuated by both SCH-23390 and haloperidol. These data demonstrate that following repeated MZ or EtOH ϩ MZ exposure mice show locomotor sensitization through DA receptor stimulation. Also, these findings suggest that a major determinant of combined anorectic-alcohol misuse may be the increased stimulating effects produced by such combination.
Behavioural Pharmacology, 2015
The behavioural effects of high-frequency electrical stimulation (HFS) are often similar to the effects of lesions, with the advantage of being reversible. The present study examined the effects of HFS of the nucleus accumbens (NAc), an area that has been shown to be important for sensitization to several psychostimulants, on the development and expression of EtOH sensitization. Male DBA/2 mice received five biweekly injections of EtOH (2.2 g/kg, intraperitoneally) or saline (SAL) immediately before assessments of locomotor activity (LMA). For some of the mice, each EtOH or SAL injection was preceded by 2 h of bilateral NAc HFS, whereas the remaining mice received no stimulation. Seven days after the last injection, LMA was again measured after the mice received a challenge dose of EtOH (1.8 g/kg, intraperitoneally) or SAL, either preceded or not preceded by 2 h of HFS. Mice receiving NAc HFS before EtOH injections during the sensitization period showed progressive increases in LMA that were not different from the LMA scores of EtOH-injected mice which had received no HFS. However, when the latter group was subsequently challenged after receiving HFS, a strong suppression of LMA was observed, in comparison with their own previous LMA scores (-72%) and compared with EtOH-sensitized groups challenged in the absence of HFS (-70%). A separate cohort of mice that were surgically implanted but not stimulated showed a robust EtOH sensitization response that did not differ from that of EtOH-treated mice without electrodes, demonstrating that HFS behavioural effects were not merely a result of the presence of electrodes in the NAc. These results suggest that NAc HFS may have different effects at different stages of the EtOH sensitization process, specifically suppressing expression, but not the development of EtOH sensitization. This pattern of distinct effects of NAc manipulations on different aspects of sensitization is similar to what has been reported for other drugs of abuse, suggesting a commonality of mechanisms. Our findings also suggest that the sensitization may provide a useful paradigm for the investigation of mechanisms of clinical effectiveness of HFS in humans.