Bipolar disorder, characterized by extreme manic and depressive moods, is a prevalent debilitating disease of unknown etiology. Because mood stabilizers, antipsychotics, antidepressants, and mood-regulating neuromodulators increase the inhibitory serine-phosphorylation of glycogen synthase kinase-3 (GSK3), we hypothesized that deficient GSK3 serine-phosphorylation may increase vulnerability to mood-related behavioral disturbances. This was tested by measuring behavioral characteristics of GSK3α/β21A/21A/9A/9A knockin mice with serine-to-alanine mutations to block inhibitory serine-phosphorylation of GSK3. GSK3 knockin mice displayed increased susceptibility to amphetamine-induced hyperactivity and to stress-induced depressive-like behaviors. Furthermore, serine-phosphorylation of GSK3 was reduced during both mood-related behavioral responses in wild-type mouse brain and in blood cells from patients with bipolar disorder. Therefore, proper control of GSK3 by serine-phosphorylation, which is targeted by agents therapeutic for bipolar disorder, is an important mechanism that regulates mood stabilization, and mice with disabled GSK3 serine-phosphorylation may provide a valuable model to study bipolar disorder.

This article traces the history of peer review of scientific publications, plotting the development of the process from its inception to its present-day application. We discuss the merits of peer review and its weaknesses, both perceived and real, as well as the practicalities of several major proposed changes to the system. It is our hope that readers will gain a better appreciation of the complexities of the process and, when serving as reviewers themselves, will do so in a manner that will enhance the utility of the exercise. We also propose the development of an international on-line training program for accreditation of potential referees.

Serotonin is an influential monoamine neurotransmitter that signals through a number of receptors to modulate brain function. Among different serotonin receptors, the serotonin 1A (5-HT1A) receptors has been tied to a variety of physiological and pathological processes, notably in anxiety, mood, and cognition. 5-HT1A receptors couple not only to the classical inhibitory G-protein-regulated signaling pathway, but also to signaling pathways traditionally regulated by growth factors. Despite the importance of 5-HT1A receptors in brain function, little is known about how these signaling mechanisms link 5-HT1A receptors to regulation of brain physiology and behavior. Following a brief summary of the known physiological and behavioral effects of 5-HT1A receptors, this article will review the signaling pathways regulated by 5-HT1A receptors, and discuss the potential implication of these signaling pathways in 5-HT1A receptor-regulated physiological processes and behaviors.

Summary Stress facilitates reinstatement of addictive drug-seeking in animals and promotes relapse in humans. Acute stress has marked and long-lasting effects on plasticity at both inhibitory and excitatory synapses on dopamine neurons in the ventral tegmental area (VTA), a key region necessary for drug reinforcement. Stress blocks long-term potentiation at GABAergic synapses on dopamine neurons in the VTA (LTPGABA), potentially removing a normal brake on activity. Here we show that blocking kappa opioid receptors (KORs) prior to forced-swim stress rescues LTPGABA. In contrast, blocking KORs does not prevent stress-induced potentiation of excitatory synapses nor morphine-induced block of LTPGABA. Using a kappa receptor antagonist as a selective tool to test the role of LTPGABA in vivo, we find that blocking KORs within the VTA prior to forced-swim stress prevents reinstatement of cocaine-seeking. These results suggest that KORs may represent a useful therapeutic target for treatment of stress-triggered relapse in substance abuse.

The ventral tegmental area (VTA) is best known for its robust dopaminergic projections to forebrain regions and their critical role in regulating reward, motivation, cognition, and aversion. However, the VTA is not only made of dopamine (DA) cells, as approximately 30% of cells in the VTA are GABA neurons. These neurons play a dual role, as VTA GABA neurons provide both local inhibition of VTA DA neurons and long-range inhibition of several distal brain regions. VTA GABA neurons have increasingly been recognized as potent mediators of reward and aversion in their own right, as well as potential targets for the treatment of addiction, depression, and other stress-linked disorders. In this review article, we dissect the circuit architecture, physiology, and behavioral roles of VTA GABA neurons and suggest critical gaps to be addressed.

Background-The mammalian FoxO transcription factors function to regulate diverse physiological processes. Emerging evidence that both BDNF and lithium suppress FoxO activity suggests a potential role of FoxOs in regulating mood-relevant behavior. Here, we investigated whether brain FoxO1 and FoxO3a can be regulated by serotonin and antidepressant, and whether their genetic deletion affects behaviors.

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.

Background Dopaminergic neurons in the ventral tegmental area (VTA) of the brain are an important site of convergence of drugs and stress. We previously identified a form of long-term potentiation of GABAergic synapses on these neurons (LTPGABA). Our studies have shown that exposure to acute stress blocks this LTP, and that reversal of the block of LTPGABA is correlated with prevention of stress-induced reinstatement of cocaine-seeking. Methods Sprague-Dawley rats were subjected to cold-water swim stress. Midbrain slices were prepared following stress, and whole-cell patch clamp recordings of IPSCs were performed from VTA dopamine neurons. Antagonists of glucocorticoid and kappa opioid receptors were administered at varying time points after stress. Additionally, the ability of a post-stress kappa antagonist to block FSS-induced reinstatement of cocaine self-administration was tested. Results We report that an acute stressor blocks LTPGABA for five days after stress through a transient activation of glucocorticoid receptors and more lasting contribution of kappa opioid receptors. Pharmacological block of kappa opioid receptors beginning as late as 4 days after stress has occurred can reverse the block of LTPGABA. Furthermore, post-stress administration of a kappa opioid antagonist prevents reinstatement of cocaine-seeking. Conclusions Our results show that a brief stressor can cause days-long changes in the reward circuitry and reveal roles for glucocorticoid and kappa opioid receptors as mediators of the lasting effects of stress on synaptic plasticity. These results indicate that kappa opioid receptor antagonists reverse the neuroadaptations underlying stress-induced drug-seeking behavior and may be useful in the treatment of cocaine addiction.