Sex-Specific Regulation of Depression, Anxiety-Like Behaviors and Alcohol Drinking in Mice Lacking ENT1.
Sex-Specific Regulation of Depression, Anxiety-Like Behaviors and Alcohol Drinking in Mice Lacking ENT1.
Filed under: Depression Treatment
J Addict Res Ther. 2011 Dec 25; S4:
Ruby CL, Walker DL, An J, Kim J, Choi DS
OBJECTIVES: Adenosine signaling has been implicated in the pathophysiology of several psychiatric disorders including alcoholism, depression, and anxiety. Adenosine levels are controlled in part by transport across the cell membrane by equilibrative nucleoside transporters (ENTs). Recent evidence showed that a polymorphism in the gene encoding ENT1 is associated with comorbid depression and alcoholism in women. We have previously shown that deletion of ENT1 reduces ethanol intoxication and elevates alcohol intake in mice. Interestingly, ENT1 null mice display decreased anxiety-like behavior compared to wild-type littermates. However, our behavioral studies were performed only in male mice. Here, we extend our research to include female mice, and test the effect of ENT1 knockout on other behavioral correlates of alcohol drinking, including depressive and compulsive behavior, in mice. METHODS: To assess depression-like behavior, we used a forced swim test modified for mice. We examined anxiety-like behavior and locomotor activity in open field chambers, and perseverant behavior using the marble-burying test. Finally, we investigated alcohol consumption and preference in female mice using a two-bottle choice paradigm. RESULTS: ENT1 null mice of both sexes showed reduced immobility time in the forced swim test and increased time in the center of the open field compared to wild-type littermates. ENT1 null mice of both sexes showed similar locomotor activity levels and habituation to the open field chambers. Female ENT1 null mice displayed increased marble-burying compared to female wild-types, but no genotype difference was evident in males. Female ENT1 null mice showed increased ethanol consumption and preference compared to female wild-types. CONCLUSIONS: Our findings suggest that ENT1 contributes to several important behaviors involved in psychiatric disorders. Inhibition of ENT1 may be beneficial in treating depression and anxiety, while enhancement of ENT1 function may reduce compulsive behavior and drinking, particularly in females.
HubMed – depression
Two Decades of Smoking Cessation Treatment Research on Smokers with Depression: 1990-2010.
Filed under: Depression Treatment
Nicotine Tob Res. 2012 Oct 25;
Weinberger AH, Mazure CM, Morlett A, McKee SA
INTRODUCTION: Adults with depression smoke at higher rates than other adults leaving a large segment of this population, who already incur increased health-related risks, vulnerable to the enormous harmful consequences of smoking. Yet, the impact that depression has on smoking cessation is not clear due to the mixed results of past research. The primary aims of this review were to synthesize the research examining the relationship of depression to smoking cessation outcomes over a 20-year period, to examine the gender and racial composition of these studies, and to identify directions for future research. METHODS: Potential articles published between January 1, 2000 and December 31, 2010 were identified through a MEDLINE search of the terms “clinical trial,” “depression,” and “smoking cessation.” 68 studies used all three terms and met the inclusion criteria. RESULTS: The majority of studies examined either a past diagnosis of major depression or current depression symptoms. Within the few studies that examined the interaction of gender and depression on smoking cessation, depression had a greater impact on treatment outcomes for women than men. No study reported examining the interactive impact of race and depression on treatment outcomes. Conclusions:Although attention to the relationship of depression and smoking cessation outcomes has increased over the past 20 years, little information exists to inform a treatment approach for smokers with Current Major Depressive Disorder, Dysthymia, and Minor Depression and few studies report gender and racial differences in the relationship of depression and smoking cessation outcomes, thus suggesting major areas for targeted research.
HubMed – depression
AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca2+-Permeable AMPA Receptors.
Filed under: Depression Treatment
J Neurosci. 2012 Oct 24; 32(43): 15036-52
Sanderson JL, Gorski JA, Gibson ES, Lam P, Freund RK, Chick WS, Dell’acqua ML
AMPA receptors (AMPARs) are tetrameric ion channels assembled from GluA1-GluA4 subunits that mediate the majority of fast excitatory synaptic transmission in the brain. In the hippocampus, most synaptic AMPARs are composed of GluA1/2 or GluA2/3 with the GluA2 subunit preventing Ca(2+) influx. However, a small number of Ca(2+)-permeable GluA1 homomeric receptors reside in extrasynaptic locations where they can be rapidly recruited to synapses during synaptic plasticity. Phosphorylation of GluA1 S845 by the cAMP-dependent protein kinase (PKA) primes extrasynaptic receptors for synaptic insertion in response to NMDA receptor Ca(2+) signaling during long-term potentiation (LTP), while phosphatases dephosphorylate S845 and remove synaptic and extrasynaptic GluA1 during long-term depression (LTD). PKA and the Ca(2+)-activated phosphatase calcineurin (CaN) are targeted to GluA1 through binding to A-kinase anchoring protein 150 (AKAP150) in a complex with PSD-95, but we do not understand how the opposing activities of these enzymes are balanced to control plasticity. Here, we generated AKAP150?PIX knock-in mice to selectively disrupt CaN anchoring in vivo. We found that AKAP150?PIX mice lack LTD but express enhanced LTP at CA1 synapses. Accordingly, basal GluA1 S845 phosphorylation is elevated in AKAP150?PIX hippocampus, and LTD-induced dephosphorylation and removal of GluA1, AKAP150, and PSD-95 from synapses are impaired. In addition, basal synaptic activity of GluA2-lacking AMPARs is increased in AKAP150?PIX mice and pharmacologic antagonism of these receptors restores normal LTD and inhibits the enhanced LTP. Thus, AKAP150-anchored CaN opposes PKA phosphorylation of GluA1 to restrict synaptic incorporation of Ca(2+)-permeable AMPARs both basally and during LTP and LTD.
HubMed – depression
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