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.
BackgroundRapid-onset antidepressants could have important clinical impact if their benefits extended to ED patients. We examined preliminary feasibility, tolerability and efficacy of single-dose IV ketamine in depressed ED patients with suicide ideation (SI).MethodsFourteen depressed ED patients with SI received a single IV bolus of ketamine (0.2 mg/kg) over 1–2 minutes. Patients were monitored for 4 hours, then re-contacted daily for 10 days. Treatment response and time to remission were evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS) and Kaplan Meier survival analysis, respectively.ResultsBrief Psychiatric Rating Scale and Young Mania Rating Scale scores transiently increased in two subjects, consistent with ketamine's cognitive/behavioral effects in other populations. Mean MADRS scores fell significantly from 40.4 (SEM:1.8) at baseline to 11.5 (2.2) at 240 minutes. Median time to MADRS score ≤10 was 80 minutes (Interquartile Range: 0.67–24 hours). Suicide ideation scores (MADRS item 10) decreased significantly from 3.9 (SEM:0.4) at baseline to 0.6 (SEM:0.2) at 40 minutes post-administration, with improvements sustained over 10 days.ConclusionsThese data provide preliminary, open-label support for the feasibility and efficacy of ketamine as a rapid-onset antidepressant in the ED.
Long-term alterations in synaptic transmission are thought to underlie various types of alcohol-related brain disorders. While ethanol effects on synaptic potentiation are well documented, ethanol effects on synaptic depression have not been addressed. Herein, we performed experiments to assess the role of ethanol on long-term depression (LTD) formation. In rat hippocampal slices, prolonged low-frequency stimulation (LFS) of CA1 Schaffer collaterals (1 Hz for 7 min) induced saturable, long-lasting, reversible N-methyl-D-aspartate (NMDA) receptordependent LTD of stimulus-evoked dendritic population excitatory postsynaptic potentials. This depression (Ϫ26% LTD amplitude) was observed in young rats (12-20 days old), but not adult rats (28 -35 days old). Induction of LTD was blocked (Ϫ3% LTD amplitude) when the LFS was delivered in the presence of the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid. When the conditioning LFS was delivered in the presence of ethanol, there was a significant enhancement in the induction of NMDA receptor-dependent LTD versus control LTD (Ϫ36% LTD amplitude). Ifenprodil, an N-methyl-D-aspartate receptor subunit 2B (NR2B)-selective antagonist, also significantly facilitated the induction of LTD (Ϫ40% LTD amplitude). Consistent with this result, ifenprodil did not affect the NMDA receptor-dependent component of the baseline synaptic response, whereas D-2-amino-5-phosphonovaleric acid caused significant depression of the NMDA component. These data indicate that whereas ethanol is known to inhibit NMDA receptor function in a variety of systems, it significantly enhances the induction of NMDA receptor-dependent LTD. Furthermore, since ifenprodil is known to select for ethanol-sensitive subtypes of NR2B-NMDA receptors, these data also suggest that NR2B-containing NMDA receptor subpopulations do not contribute to LTD, but instead may actually play inhibitory roles in LTD induction.
Intoxicating concentrations of ethanol inhibit N-methyl-D-as-partate (NMDA) receptor-dependent long-term potentiation, an interaction thought to underlie a major component of the central nervous system actions of ethanol. Another form of synaptic potentiation involving activation of L-type dihydropyridinesensitive voltage-gated calcium channels (VGCCs) has been described, but very little information concerning ethanol effects on VGCC-dependent synaptic potentiation is available. Here, we assessed ethanol effects on VGCC-dependent synaptic potentiation using whole cell patch-clamp recordings of ␣-amino-3-hydroxy-5-methyl-4-soxazolepropionic acid (AMPA) receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in area CA1 of the rat hippocampus. No potentiation was observed in artificial cerebrospinal fluid containing 2 to 3 mM Ca 2ϩ , but marked potentiation of mEPSCs was consistently observed in 4 mM Ca 2ϩ and with patch pipettes containing an ATP-regenerating system. This potentiation was insensitive to the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid, whereas it was completely blocked the L-type VGCC antagonist nifedipine. Potentiation was also blocked dose dependently by bath application of ethanol (25-75 mM), which had no effect on baseline mEPSC amplitude or frequency. The synaptic potentiation involved enhancement of both presynaptic and postsynaptic components because significant increases in both the frequency and amplitude of AMPA mEPSCs were observed. Ethanol inhibition of VGCCdependent synaptic potentiation seemed to occur at the induction step because both the increases in mEPSC frequency and amplitude were affected. To address that question more directly, we used fluorescent imaging of synaptically evoked dendritic calcium events, which displayed a similarly marked ethanol sensitivity. Thus, ethanol modulates fast excitatory synaptic transmission by inhibiting the induction of an NMDA receptor-independent form of synaptic potentiation observed at excitatory synapses on central neurons.Efforts directed toward unraveling the synaptic basis for alcohol-related brain disorders have centered upon direct ethanol effects on the major excitatory and inhibitory ligandgated ion channels (LGICs) operated by GABA A and NMDA receptors (NMDARs). Indeed, the direct actions of ethanol on NMDARs impact the functional properties of neurons and profoundly alter the short-term processing and long-term storage of information in neural networks (Durand and
For many years, gender differences have been recognized as important factors in the etiology, pathophysiology, comorbidities, and treatment needs and outcomes associated with the use of alcohol, drugs, and tobacco. However, little is known about how these gender-specific differences affect ED utilization; responses to ED-based interventions; needs for substance use treatment and barriers to accessing care among patients in the ED; or outcomes after an alcohol-, drug-, or tobacco-related visit. As part of the 2014 Academic Emergency Medicine consensus conference on “Gender-Specific Research in Emergency Care: Investigate, Understand and Translate How Gender Affects Patient Outcomes,” a breakout group convened to generate a research agenda on priority questions related to substance use disorders.
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