In this study we addressed whether certain behavioural measures, endocrine levels and specific stress-related proteins exhibit long-term alterations in adult rats following repeated postnatal maternal separation. Rats were subjected to daily maternal separation for 15 min (HMS15) or 180 min (HMS180) from postnatal day 2-14. Adult HMS180 animals were hypoactive and had increased levels of stereotypy compared to HMS15 and normal animal facility-reared (AFR) animals. HMS180 animals also had augmented plasma adrenocorticotropin (ACTH) and corticosterone (CORT) concentrations following an acute stressor, compared to the other two groups. We assessed persistent changes in proteins regulated by stress in hippocampus, cortex, ventral tegmental area, nucleus accumbens, striatum and amygdala. Western blotting analysis revealed a decrease in the levels of mature brain-derived neurotrophic factor (BDNF) in hippocampus and striatum, but an increase in the ventral tegmental area in the HMS180 rats. Levels of pro-BDNF were significantly increased in the ventral tegmental area of HMS180 animals but were unchanged in other brain regions compared to the other two groups. Levels of the transcription factors cAMP response element binding protein (CREB) and DeltaFosB were unchanged in all of the brain regions studied in the maternally separated rats. These data show that maternal separation induces long-term changes in BDNF expression, and more specifically the processing of BDNF, in the hippocampus, striatum and ventral tegmental area. Recognition of these adaptations begins to define the brain regions, and neural circuitry, associated with persistent alterations induced by early life stressors and the development of mood disorders.

The medium spiny neurons of the nucleus accumbens receive both an excitatory glutamatergic input from forebrain and a dopaminergic input from the ventral tegmental area. This integration point may constitute a locus whereby the N-methyl-D-aspartate (NMDA)-subtype of glutamate receptors promotes drug reinforcement. Here we investigate how dopaminergic inputs alter the ethanol sensitivity of NMDA receptors in rats and mice and report that previous dopamine receptor-1 (D1) activation, culminating in dopamine and cAMP-regulated phosphoprotein-32 kD (DARPP-32) and NMDA receptor subunit-1 (NR1)-NMDA receptor phosphorylation, strongly decreases ethanol inhibition of NMDA responses. The regulation of ethanol sensitivity of NMDA receptors by D1 receptors was absent in DARPP-32 knockout mice. We propose that DARPP-32 mediated blunting of the response to ethanol subsequent to activation of ventral tegmental area dopaminergic neurons initiates molecular alterations that influence synaptic plasticity in this circuit, thereby promoting the development of ethanol reinforcement.

The burden of mental illness is profound and growing. Coupled with large gaps in extant psychiatric services, this mental health burden has often forced emergency departments (EDs) to become the de facto primary and acute care provider of mental health care in the United States. An expanded emergency medical and mental health research agenda is required to meet the need for improved education, screening, surveillance, and ED-initiated interventions for mental health problems. As an increasing fraction of undiagnosed and untreated psychiatric patients passes through the revolving doors of U.S. EDs, the opportunities for improving the art and science of acute mental health care have never been greater. These opportunities span macroepidemiologic surveillance research to intervention studies with individual patients. Feasible screening, intervention, and referral programs for mental health patients presenting to general EDs are needed. Additional research is needed to improve the quality of care, including the attitudes, abilities, interests, and virtues of ED providers. Research that optimizes provider education and training can help academic settings validate psychosocial issues as core components and responsibilities of emergency medicine. Transdisciplinary research with federal partners and investigators in neuropsychiatry and related fields can improve the mechanistic understanding of acute mental health problems. To have lasting impact, however, advances in ED mental health care must be translated into real-world policies and sustainable program enhancements to assure the uptake of best practices for ED screening, treatment, and management of mental disorders and psychosocial problems.