Stress andVTAsynapses: implications for addiction and depression

Abstract

While stressful experiences are a part of everyone’s life, they can also exact a major toll on health. Stressful life experiences are associated with increased substance abuse, and there exists significant co-morbidity between mental illness and substance use disorders (Volkow & Li, 2004; Koob & Kreek, 2007; Sinha, 2008). The risk for development of mood or anxiety disorders after stress is positively associated with the risk for substance use disorders (Sinha, 2008), suggesting that there are common substrates for vulnerability to addictive and affective disorders. Understanding the molecular and physiological substrates of stress may lead to improved therapeutic interventions for the treatment of substance use disorders and mental illnesses.

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

“…In fact, a form of NMDARindependent LTD has been demonstrated in VTA-DA neurons that is induced by the activation of group I metabotropic glutamate receptors (mGluRs), a switch in the subunit composition of AMPARs and a redistribution of AMPARs from synaptic to extrasynaptic or intracellular locations. 66,67 Interestingly, group I mGluRs, in particular mGluR5, are potential targets for the development of antidepressants. 68 Both NMDARs and AMPARs are regulated by mGluR5 through intracellular mechanisms, 69 and mGluR5 deletion induces anti-depressive-like behavior in young mice.…”

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

“…Although both the nicotinic antagonist mecamylamine and the low efficacy partial agonist cytisine can decrease c-fos activity in the amygdala (Mineur et al, 2007), it is not known where in the brain nAChRs are required to alter behaviors relevant to stress and depression. Many brain areas that receive significant ACh innervation, including hippocampus, prefrontal cortex, habenuala, IPN, ventral tegmental area, and nucleus accumbens/striatum (Leao et al, 2015;Mineur et al, 2013Mineur et al, , 2015Picciotto and Mineur, 2014;Polter and Kauer, 2014;Zhao-Shea et al, 2013 could be involved in nAChR-related mood regulation. We demonstrate here that the non-selective nAChR antagonist mecamylamine can induce antidepressant-like effects when infused locally into the amygdala, suggesting that nAChR signaling is critical for baseline neuronal activity in this brain region, and that decreasing nAChR activity in amygdala is sufficient for an antidepressant-like response.…”

Environmental enrichment blocks reinstatement of ethanol-induced conditioned place preference in mice

“…In contrast, other studies have animals housed in socially impoverished conditions as control groups [1,11,21,22,32]. In this case, IE condition can be considered to be a chronic stress which has profound effects on brain and behavior [18], in particular, dramatically increases the vulnerability to addiction [6,23]. The behavioral differences between EE and IE could actually be caused by the stressful impact associated with IE rather than the protective effects of EE.…”

“…Epidemiological and preclinical studies suggest that negative environmental conditions such as stress increases the vulnerability to addiction [23], while positive conditions such as environmental enrichment (EE) can reduce the activating and reinforcing effects of psychostimulants and may prevent the development of drug addiction [30]. Studies (SA) to cocaine [14,29], heroin [12], morphine [35], ethanol [9,11], sucrose [5], amphetamine [32], but not to methamphetamine [34].…”