Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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Neuropsychopharmacology · Oct 2006
Comparative StudyActivation of adenosine A1 receptors reduces anxiety-like behavior during acute ethanol withdrawal (hangover) in mice.
Elevated signs of anxiety are observed in both humans and rodents during withdrawal from chronic as well as acute ethanol exposure, and it represents an important motivational factor for ethanol relapse. Several reports have suggested the involvement of brain adenosine receptors in different actions produced by ethanol such as motor incoordination and hypnotic effects. In addition, we have recently demonstrated that adenosine A1 receptors modulate the anxiolytic-like effect induced by ethanol in mice. ⋯ The acute administration of 'nonanxiolytic' doses of adenosine and the selective adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), but not the adenosine A2A receptor agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine (DPMA), at the onset of peak withdrawal (18 h), reduced this anxiogenic-like response. In addition, the effect of CCPA on the anxiety-like behavior of ethanol hangover was reversed by pretreatment with the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). These results reinforce the notion of the involvement of adenosine receptors in the anxiety-like responses and indicate the potential of adenosine A1 receptor agonists to reduce the anxiogenic effects during ethanol withdrawal.
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Neuropsychopharmacology · Oct 2006
Comparative StudyDopamine beta-hydroxylase knockout mice have alterations in dopamine signaling and are hypersensitive to cocaine.
Multiple lines of evidence demonstrate that the noradrenergic system provides both direct and indirect excitatory drive onto midbrain dopamine (DA) neurons. We used DA beta-hydroxylase (DBH) knockout (Dbh-/-) mice that lack norepinephrine (NE) to determine the consequences of chronic NE deficiency on midbrain DA neuron function in vivo. Basal extracellular DA levels were significantly attenuated in the nucleus accumbens (NAc) and caudate putamen (CP), but not prefrontal cortex (PFC), of Dbh-/- mice, while amphetamine-induced DA release was absent in the NAc and attenuated in the CP and PFC. ⋯ As a behavioral consequence of these neurochemical changes, Dbh-/- mice were hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, as measured by locomotor activity and conditioned place preference. Antagonists of DA, but not 5-HT, receptors attenuated the locomotor hypersensitivity to cocaine in Dbh-/- mice. As DBH activity in humans is genetically controlled and the DBH inhibitor disulfiram has shown promise as a pharmacotherapy for cocaine dependence, these results have implications for the influence of genetic and pharmacological DBH inhibition on DA system function and drug addiction.