There is considerable evidence of interactions between adenosine A 2A receptors and dopamine D 2 receptors in striatal areas, and antagonists of the A 2A receptor have been shown to reverse the motor effects of DA antagonists in animal models. The D 2 antagonist haloperidol produces parkinsonism in humans, and also induces motor effects in rats, such as suppression of locomotion. The present experiments were conducted to study the ability of the adenosine A 2A antagonist MSX-3 to reverse the locomotor effects of acute or subchronic administration of haloperidol in rats. Systemic (i.p.) injections of MSX-3 (2.5-10.0 mg/kg) were capable of attenuating the suppression of locomotion induced by either acute or repeated (i.e., 14 day) administration of 0.5 mg/kg haloperidol. Bilateral infusions of MSX-3 directly into the nucleus accumbens core (2.5 µg or 5.0 µg in 0.5 µl per side) produced a dose-related increase in locomotor activity in rats treated with 0.5 mg/kg haloperidol either acutely or repeatedly. There were no overall significant effects of MSX-3 infused directly into the dorsomedial nucleus accumbens shell or the ventrolateral neostriatum. These results indicate that antagonism of adenosine A 2A receptors can attenuate the locomotor suppression produced by DA antagonism, and that this effect may be at least partially mediated by A 2A receptors in the nucleus accumbens core. These studies suggest that adenosine and dopamine systems interact to modulate the locomotor and behavioral activation functions of nucleus accumbens core.

Rationale Naltrexone, a non-selective opioid antagonist, decreases the euphoria and positive subjective responses to alcohol in heavy drinkers. It has been proposed that the μ-opioid receptor plays a role in ethanol reinforcement through modulation of ethanol-stimulated mesolimbic dopamine release. Objective To investigate the ability of naltrexone and β-funaltrexamine, an irreversible μ-opioid specific antagonist, to inhibit ethanol-stimulated and morphine-stimulated mesolimbic dopamine release and to determine whether opioid receptors on mesolimbic neurons contribute to these mechanisms. Methods Ethanol-naïve male Long Evans rats were given opioid receptor antagonists either intravenously, subcutaneously, or intracranially into the ventral tegmental area (VTA), followed by intravenous administration of ethanol or morphine. We measured extracellular dopamine in vivo using microdialysis probes inserted into the nucleus accumbens shell (n=114). Results Administration of naltrexone (intravenously) and β-funaltrexamine (subcutaneously), as well as intracranial injection of naltrexone into the VTA did not prevent the initiation of dopamine release by intravenous ethanol administration, but prevented it from being as prolonged. In contrast, morphine-stimulated mesolimbic dopamine release was effectively suppressed. Conclusions Our results provide novel evidence that there are two distinct mechanisms that mediate ethanol-stimulated mesolimbic dopamine release (an initial phase and a delayed phase), and that opioid receptor activation is required to maintain the delayed-phase dopamine release. Moreover, μ-opioid receptors account for this delayed-phase dopamine response, and the VTA is potentially the site of action of this mechanism. We conclude that μ-opioid receptors play different roles in the mechanisms of stimulation of mesolimbic dopamine activity by ethanol and morphine.

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Background Among the evidence implicating neuroimmune signaling in alcohol use disorders are increased levels of the chemokine monocyte chemoattractant protein-1 (MCP-1) in the brains of human alcoholics and animal models of alcohol abuse. However, it is not known whether neuroimmune signaling can directly increase ethanol consumption, and whether MCP-1 is involved in that mechanism. We designed experiments to determine if MCP-1 signaling itself is sufficient to accelerate or increase ethanol consumption. Our hypothesis was that increasing MCP-1 signaling by directly infusing it into the brain would increase operant ethanol self-administration. Methods We implanted osmotic minipumps to chronically infuse either one of several doses of MCP-1 or vehicle into the cerebral ventricles of Long-Evans rats and then tested them in the operant self-administration of a sweetened ethanol solution for 8 weeks. Results There was a significant interaction between dose of MCP-1 and sweetened ethanol consumed across the first 4 weeks (while pumps were flowing) and across the 8-week experiment. Animals receiving the highest dose of MCP-1 (2 μg/day) were the highest consumers of ethanol during weeks 3 through 8. MCP-1 did not influence the acquisition of self-administration (measured across the first 5 days), the motivation to consume ethanol (time to lever press or progressive ratio), withdrawal-induced anxiety, or the consumption of sucrose alone. Conclusion We provide novel evidence that neuroimmune signaling can directly increase chronic operant ethanol self-administration, and that this increase persists beyond the administration of the cytokine. These data suggest that ethanol-induced increases in MCP-1, or increases in MCP-1 due to various other neuroimmune mechanisms, may further promote ethanol consumption. Continued research into this mechanism, particularly using models of alcohol dependence, will help determine if targeting MCP-1 signaling has therapeutic potential in the treatment of alcohol use disorders.

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