Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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Neuropsychopharmacology · May 2009
Association of changes in norepinephrine and serotonin transporter expression with the long-term behavioral effects of antidepressant drugs.
Previous work has shown that repeated desipramine treatment causes downregulation of the norepinephrine transporter (NET) and persistent antidepressant-like effects on behavior, ie effects observed 2 days after discontinuation of drug treatment when acute effects are minimized. The present study examined whether this mechanism generalizes to other antidepressants and also is evident for the serotonin transporter (SERT). Treatment of rats for 14 days with 20 mg/kg per day protriptyline or 7.5 mg/kg per day sertraline reduced NET and SERT expression, respectively, in cerebral cortex and hippocampus; these treatments also induced a persistent antidepressant-like effect on forced-swim behavior. ⋯ For all drugs tested, reductions of NET and SERT protein were not accompanied by reduced NET or SERT mRNA in locus coeruleus or dorsal raphe nucleus, respectively. Overall, the present results suggest an important, though not universal, role for NET and SERT regulation in the long-term behavioral effects of antidepressants. Understanding the mechanisms underlying transporter regulation in vivo may suggest novel targets for the development of antidepressant drugs.
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Neuropsychopharmacology · Apr 2009
Requirement of AQP4 for antidepressive efficiency of fluoxetine: implication in adult hippocampal neurogenesis.
Aquaporin-4 (AQP4), a key molecule for maintaining water homeostasis in the central nervous system, is expressed in adult neural stem cells (ANSCs) as well as astrocytes. Neural stem cells give rise to new hippocampal neurons throughout adulthood, and defects in neurogenesis may predispose an individual to depression. Nevertheless, the role of AQP4 in adult hippocampal neurogenesis and chronic mild stress (CMS)-induced depression remains unknown. ⋯ Notably, CMS procedure significantly increased the hippocampal AQP4 expression, which was reversed by 4-week fluoxetine treatment. Further investigation showed AQP4 knockout inhibited the proliferation of cultured ANSCs and eliminated the pro-proliferative effect of fluoxetine in vitro. Collectively, these findings suggest that AQP4 is required for the antidepressive action of fluoxetine via regulating adult hippocampal neurogenesis.
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Neuropsychopharmacology · Apr 2009
Cocaine- and amphetamine-regulated transcript peptide plays a role in the manifestation of depression: social isolation and olfactory bulbectomy models reveal unifying principles.
We investigated the effect of cocaine- and amphetamine-regulated transcript (CART) peptide on depression-like behavior in socially isolated and olfactory bulbectomized (OBX) rats. Administration of CART (54-102) into the lateral ventricle (50-100 ng) or central nucleus of amygdala (CeA) (10-20 ng) caused significant decrease in immobility time in the forced swim test (FST) without influencing locomotion, suggesting antidepressant-like effect. Social isolation as well as OBX models were undertaken to produce depression-like conditions. ⋯ However, dramatic increase in CART-immunoreactive fibers was noticed in the CeA in both the experimental models. The response by the cells and fibers in the periventricular area and perifornical nucleus in the OBX and socially isolated rats was variable. The study underscores the possibility that endogenous CART system might play a major role in mediating symptoms of depression.
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Neuropsychopharmacology · Apr 2009
Effect of cocaine on Fas-associated protein with death domain in the rat brain: individual differences in a model of differential vulnerability to drug abuse.
This study was designed to (1) assess the effects of cocaine on Fas-associated protein with death domain (FADD) system and its role in the activation of apoptotic vs nonapoptotic events and (2) ascertain whether animals selectively bred for their differential propensity to drug-seeking show differences in FADD levels or response to cocaine. Acute cocaine, through D(2) dopamine receptors, induced a dose-response increase in FADD protein in the cortex, with opposite effects over pFADD (Ser191/194), and no induction of apoptotic cell death (poly-(ADP-ribose) polymerase cleavage). FADD was increased by cocaine in cytosol (approximately 142%), membranes (approximately 23%) and nucleus (approximately 54%). ⋯ However, HR and LR rats showed similar rates of cocaine-induced apoptosis, and exhibited a parallel impact of cocaine over FADD within each phenotype. Thus, FADD is a signaling protein modulated by cocaine, regulating apoptosis/proliferative mechanisms in relation to its FADD/pFADD content. Interestingly, animals selectively bred for differential propensity to substance abuse show basal differences in the expression of this protein, suggesting FADD may also be a molecular correlate for the HR/LR phenotype.
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Neuropsychopharmacology · Mar 2009
A differential role for the adenosine A2A receptor in opiate reinforcement vs opiate-seeking behavior.
The adenosine A(2A) receptor is specifically enriched in the medium spiny neurons that make up the 'indirect' output pathway from the ventral striatum, a structure known to have a crucial, integrative role in processes such as reward, motivation, and drug-seeking behavior. In the present study we investigated the impact of adenosine A(2A) receptor deletion on behavioral responses to morphine in a number of reward-related paradigms. The acute, rewarding effects of morphine were evaluated using the conditioned place preference paradigm. ⋯ The acute locomotor response to morphine in the A(2A) knockout was similar to wild-type mice, yet A(2A) knockout mice did not display tolerance to chronic morphine under the present paradigm. Both genotypes display locomotor sensitization to morphine, implying a lack of a role for the A(2A) receptor in the drug-induced plasticity necessary for the development or expression of sensitization. Collectively, these data suggest a differential role for adenosine A(2A) receptors in opiate reinforcement compared to opiate-seeking.