Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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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.
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Neuropsychopharmacology · Jul 2006
Comparative StudyElevated impulsivity and impaired decision-making in abstinent Ecstasy (MDMA) users compared to polydrug and drug-naïve controls.
Ecstasy (MDMA; 3,4-methylenedioxymethamphetamine) has a well-recognized neurotoxic effect on central serotonergic (5-HT) systems in animals, and there is some evidence of persistent serotonergic dysregulation in human ecstasy users. Serotonin is believed to mediate impulsive behavior and effective decision-making. Thus, the aim of the present study was to investigate impulsive behavior and decision-making in abstinent regular ecstasy users. ⋯ The groups did not differ on the CARROT measure of responsiveness to financial incentive; however, the ecstasy group displayed significantly elevated MFF20 impulsivity, and showed reduced discrimination between magnitudes of prospective gains and losses when making risky decisions, compared to the 'polydrug' and 'drug-naïve' control groups. These findings may reflect a vulnerability of 5-HT systems in the orbital prefrontal cortex and interconnected corticolimbic circuitry to the cumulative neurotoxic effects of ecstasy and have clinical significance for regular ecstasy users. The combination of elevated impulsivity and impaired use of reinforcement cues in uncertain decision-making may comprise risk factors for continued drug abuse and everyday functioning.
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Neuropsychopharmacology · Jun 2006
Comparative StudyMetabotropic glutamate receptor subtype 7 ablation causes dysregulation of the HPA axis and increases hippocampal BDNF protein levels: implications for stress-related psychiatric disorders.
Regulation of neurotransmission via group-III metabotropic glutamate receptors (mGluR4, -6, -7, and -8) has recently been implicated in the pathophysiology of affective disorders, such as major depression and anxiety. For instance, mice with a targeted deletion of the gene for mGluR7 (mGluR7-/-) showed antidepressant and anxiolytic-like effects in a variety of stress-related paradigms, including the forced swim stress and the stress-induced hyperthermia tests. Deletion of mGluR7 reduces also amygdala- and hippocampus-dependent conditioned fear and aversion responses. ⋯ These results indicate that mGluR7 deficiency causes dysregulation of HPA axis parameters, which may account, at least in part, for the phenotype of mGluR7-/- mice in animal models for anxiety and depression. In addition, we present evidence that protein levels of brain-derived neurotrophic factor are also elevated in the hippocampus of mGluR7-/- mice, which we discuss in the context of the antidepressant-like phenotype found in those animals. We conclude that genetic ablation of mGluR7 in mice interferes at multiple sites in the neuronal circuitry and molecular pathways implicated in affective disorders.
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Neuropsychopharmacology · May 2006
Systemic and intra-amygdala administration of glucocorticoid agonist and antagonist modulate extinction of conditioned fear.
We examined the effect of glucocorticoid agonists on the extinction of conditioned fear in rats by using fear-potentiated startle. Systemic injection of glucocorticoid receptor agonists dexamethasone (DEX) (0.1, 0.5, and 1.0 mg/kg) and intra-amygdala infusion of RU28362 (0.5, 1.0, and 3.0 ng/side) prior to extinction training facilitated extinction of conditioned fear in a dose-dependent manner. Extinction of conditioned fear and circulating corticosterone levels were attenuated by administration of corticosteroid synthesis inhibitor metyrapone (25 mg/kg s.c.) 90 min before extinction training. ⋯ The Dose of dexamethsone or metyrapone used here did not influence fear-potentiated startle when administered before testing. Thus, it is unlikely that these drugs influenced extinction by increasing or disrupting CS processing. All results suggested that amygdaloid glucocorticoid receptors were involved in the extinction of conditioned fear.