A common feature of drugs of abuse is their ability to increase extracellular dopamine levels in key brain circuits. The actions of dopamine within these circuits are thought to be important in reward and addiction-related behaviors. Current theories of addiction also posit a central role for corticotrophin-releasing factor (CRF) and an interaction between CRF and monoaminergic signaling. One region where drugs of abuse promote robust rises in extracellular dopamine levels is the bed nucleus of the stria terminalis (BNST), a CRF-rich component of the extended amygdala. We find that dopamine rapidly enhances glutamatergic transmission in the BNST through activation of a combination of D 1 -and D 2 -like receptors. This enhancement is activity-dependent and requires the downstream action of CRF receptor 1 (CRF-R1), suggesting that dopamine induces CRF release through a local network mechanism. Furthermore, we found that both in vivo and ex vivo cocaine induced a dopamine receptor and CRF-R1-dependent enhancement of a form of NMDA receptordependent short-term potentiation in the BNST. These data highlight a direct and rapid interaction between dopamine and CRF systems that regulates excitatory transmission and plasticity in a brain region key to reinforcement and reinstatement. Because a rise in extracellular dopamine levels in the BNST is a shared consequence of multiple classes of drugs of abuse, this suggests that the CRF-R1-dependent enhancement of glutamatergic transmission in this region may be a common key feature of substances of abuse.

These findings confirm a functional connection between the amygdala and respiratory control in humans. Moreover, they suggest specific amygdalar nuclei may be critical in mediating this effect and that attentional state is critical to apnea mediated by amygdala activation-perhaps alluding to future development of strategies for the prevention of SUDEP. Ann Neurol 2018;83:460-471.

Long-term depression (LTD) is an important synaptic mechanism for limiting excitatory influence over circuits subserving cognitive and emotional behavior. A major means of LTD induction is through the recruitment of signaling via G q -linked receptors activated by norepinephrine (NE), acetylcholine, and glutamate. Receptors from these transmitter families have been proposed to converge on a common postsynaptic LTD maintenance mechanism, such that hetero-and homosynaptic induction produce similar alterations in glutamate synapse efficacy. We report that in the dorsolateral and ventrolateral bed nucleus of the stria terminalis (BNST), recruitment of G q -linked receptors by glutamate or NE initiates mechanistically distinct forms of postsynaptically maintained LTD and these LTDs are differentially regulated by stress exposure. In particular, we show that although both mGluR5-and α 1 -adrenergic receptor (AR)-dependent LTDs involve postsynaptic endocytosis, the α 1 -AR-initiated LTD exclusively involves modulation of signaling through calcium-permeable AMPA receptors. Further, α 1 -AR-but not mGluR5-dependent LTD is disrupted by restraint stress. α 1 -AR LTD is also impaired in mice chronically exposed to ethanol. These data thus suggest that in the BNST, NE-and glutamate-activated G q -linked signaling pathways differentially tune glutamate synapse efficacy in response to stress.addiction | norepinephrine | metabotropic glutamate receptor | calcium-permeable AMPA receptor | ethanol A lterations in key amygdalar and reward circuitries have been proposed as potential mechanisms underlying interrelated anxiety disorders and addiction. The bed nucleus of the stria terminalis (BNST) is a nucleus within a series of structures known as the "extended amygdala," which receives a mix of glutamatergic inputs from cognitive and systemic brain centers and projects to key nuclei in both the reward and stress circuitries (1, 2). Consistent with this anatomy, a large literature indicates key roles of this region in anxiety-related behaviors, addiction, and other affective disorders (3).The BNST receives intense noradrenergic innervation through the ventral noradrenergic bundle (VNAB) (4). Disruption of the VNAB or noradrenergic signaling in the BNST alters responses to stressors, preference for opiates, and stress-induced reinstatement to drug seeking (5, 6). α 1 -Adrenergic receptors (ARs) are G qlinked G-protein-coupled receptors (GPCRs) that participate in shaping responses to stressors. Signaling through BNST α 1 -ARs within the BNST potently regulates the hypothalamic-pituitaryadrenal (HPA) stress axis and anxiety responses after stressors (7). The α 1 -AR antagonist prazosin has been shown to attenuate ethanol self-administration (SA) in ethanol-dependent rats (8) and reduces opiate SA (9). Furthermore, data from clinical trials have demonstrated that prazosin alleviates symptoms of posttraumatic stress disorder (PTSD) (10) and reduces alcohol drinking behavior in alcoholics (11).Like α 1 -ARs, group I metabotropic glutamat...

Background-Evidence suggests that the noradrenergic and corticotrophin-releasing factor (CRF) systems play critical roles in relapse and stress related behaviors. In particular, behavioral studies point to a serial signaling process initiated by β-adrenergic receptors that requires CRF receptor (CRFR)-dependent signaling in the bed nucleus of the stria terminalis (BNST) to produce stress-induced relapse to cocaine seeking.

OBJECTIVESudden unexpected death in epilepsy (SUDEP) is the leading cause of death for patients with refractory epilepsy, and there is increasing evidence for a centrally mediated respiratory depression as a pathophysiological mechanism. The brain regions responsible for a seizure’s inducing respiratory depression are unclear—the respiratory nuclei in the brainstem are thought to be involved, but involvement of forebrain structures is not yet understood. The aim of this study was to analyze intracranial EEGs in combination with the results of respiratory monitoring to investigate the relationship between seizure spread to specific mesial temporal brain regions and the onset of respiratory dysfunction and apnea.METHODSThe authors reviewed all invasive electroencephalographic studies performed at Northwestern Memorial Hospital (Chicago) since 2010 to identify those cases in which 1) multiple mesial temporal electrodes (amygdala and hippocampal) were placed, 2) seizures were captured, and 3) patients’ respiration was monitored. They identified 8 investigations meeting these criteria in patients with temporal lobe epilepsy, and these investigations yielded data on a total of 22 seizures for analysis.RESULTSThe onset of ictal apnea associated with each seizure was highly correlated with seizure spread to the amygdala. Onset of apnea occurred 2.7 ± 0.4 (mean ± SEM) seconds after the spread of the seizure to the amygdala, which was significantly earlier than after spread to the hippocampus (10.2 ± 0.7 seconds; p < 0.01).CONCLUSIONSThe findings suggest that activation of amygdalar networks is correlated with central apnea during seizures. This study builds on the authors’ prior work that demonstrates a role for the amygdala in voluntary respiratory control and suggests a further role in dysfunctional breathing states seen during seizures, with implications for SUDEP pathophysiology.