Role of α6-Nicotinic Receptors in Alcohol-Induced GABAergic Synaptic Transmission and Plasticity to Cholinergic Interneurons in the Nucleus Accumbens.

The prevailing view is that enhancement of dopamine (DA) transmission in the mesolimbic system, consisting of DA neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc), underlies the reward properties of ethanol (EtOH) and nicotine (NIC). We have shown previously that EtOH and NIC modulation of DA release in the NAc is mediated by α6-containing nicotinic acetylcholine receptors (α6*-nAChRs), that α6*-nAChRs mediate low-dose EtOH effects on VTA GABA neurons and EtOH preference, and that α6*-nAChRs may be a molecular target for low-dose EtOH. However, the most sensitive target for reward-relevant EtOH modulation of mesolimbic DA transmission and the involvement of α6*-nAChRs in the mesolimbic DA reward system remains to be elucidated. The aim of this study was to evaluate EtOH effects on GABAergic modulation of VTA GABA neurons and VTA GABAergic input to cholinergic interneurons (CINs) in the NAc. Low-dose EtOH enhanced GABAergic input to VTA GABA neurons that was blocked by knockdown of α6*-nAChRs. Knockdown was achieved either by α6-miRNA injected into the VTA of VGAT-Cre/GAD67-GFP mice or by superfusion of the α-conotoxin MII[H9A;L15A] (MII). Superfusion of MII blocked EtOH inhibition of mIPSCs in NAc CINs. Concomitantly, EtOH enhanced CIN firing rate, which was blocked by knockdown of α6*-nAChRs with α6-miRNA injected into the VTA of VGAT-Cre/GAD67-GFP mice. The firing rate of CINs was not enhanced by EtOH in EtOH-dependent mice, and low-frequency stimulation (LFS; 1 Hz, 240 pulses) caused inhibitory long-term depression at this synapse (VTA-NAc CIN-iLTD) which was blocked by knockdown of α6*-nAChR and MII. Ethanol inhibition of CIN-mediated evoked DA release in the NAc was blocked by MII. Taken together, these findings suggest that α6*-nAChRs in the VTA-NAc pathway are sensitive to low-dose EtOH and play a role in plasticity associated with chronic EtOH.

The impact of cognitive challenges in major depression: the role of the primary care physician.

Nearly 1 in 5 Americans will struggle with major depression in their lives; some will have recurring bouts. Recent psychiatric research has given new attention to the prevalence of cognitive deficits in major depression and the impact such deficits have on remission and overall life functioning. When depression is partially treated i.e., leaving residual symptoms, patients have higher rates of relapse and lower functional outcomes. Impaired cognitive functioning is a frequent residual symptom, persisting in about 45% of patients even when emotional symptoms have improved, and results in a disproportionate share of the functional impairment, particularly in the workplace. Patients with depression have disrupted circuitry in brain regions responsible for cognition and it is therefore important to screen depressed patients for cognitive as well as emotional symptoms. Cognitive dysfunction should be evaluated in every mood disordered patient with validated self-report scales such as the Patient Health Questionnaire-9 or the Beck Depression Inventory and objective measures of cognitive function are also very very useful. Two easily administered tests are the Trails B Test and the Digit Symbol Substitution Test. Each take less than two minutes and measure working memory, executive function, and processing speed and can track cognitive improvement in depressed patients. Treatment of cognitive dysfunction in major depression is complicated by the 'serotonin conundrum': SSRI's frequently do not treat to full remission, and can cause cognitive blunting-actually adding to cognitive problems. Based on recent data including results from a recently completed meta-analysis by McIntyre and colleagues, an evidence-based algorithm for treating cognitive symptoms in depression is presented. A hierarchy of antidepressants and augmentation strategies based on the best available evidence is discussed. In conclusion, cognitive symptoms in major depressive disorder have been recognized as a target of therapeutic improvement by the FDA and have become a focus of clinical importance.