Cellular Mechanisms of the Brain Stress Systems in the Extended Amygdala

Elements of the brain stress and antistress systems can be hypothesized to act in series or in parallel on common mechanisms in the extended amygdala to affect emotional states. Cellular studies using electrophysiological techniques have the power to elucidate the common mechanisms. To date, most studies have explored either γ-aminobutyric acid (GABA) or glutamatergic activity within the extended amygdala, and some parallels can be found at the cellular level that appear at the behavioral-neuropharmacological level of analysis.

In the amygdala, CRF is localized within a subpopulation of GABAergic neurons in the bed nucleus of the stria terminalis and central nucleus of the amygdala that are different from those that colocalized with enkephalin (Day et al., 1999). In brain slice preparations, CRF enhanced GABA_A inhibitory postsynaptic potentials (IPSCs) in whole-cell recordings of the central nucleus of the amygdala, and this effect was blocked by CRF₁ antagonists and in CRF₁ knockout mice (Nie et al., 2004). Nociceptin had the opposite effects in the central nucleus of the amygdala?decreasing GABAergic IPSCs (Roberto and Siggins, 2006). Vasopressin also activated cells in the medial part of the central nucleus of the amygdala (Huber et al., 2005). These results show that CRF and vasopressin, which are anxiogenic-like, activate GABAergic interneurons in the central nucleus of the amygdala.

Most neurons in the central nucleus of the amygdala are GABAergic, either inhibitory interneurons with recurrent or feed-forward connections or inhibitory projection neurons to brainstem or downstream regions (e.g., bed nucleus of the stria terminalis). The central nucleus of the amygdala can be identified as a ?gate? that regulates the flow of information through the intra-amygdaloidal circuits, and the fine-tuning of the GABAergic inhibitory system in the central nucleus of the amygdala may be a prerequisite for controlling both local and output neurons to downstream nuclei. Because GABAergic drugs are typically robust anxiolytics, the fact that anxiogenic-like neurotransmitters would activate GABAergic neurotransmission and anxiolytic-like neurotransmitters would depress GABAergic transmission in a brain region known to be involved in stress-related behavior may seem paradoxical. However, local GABAergic activity within the central nucleus of the amygdala may functionally influence neuronal responsivity of inhibitory central nucleus of the amygdala gating that regulates information flow through the local intra-amygdaloidal circuits (i.e., by disinhibiting the central nucleus of the amygdala), leading to increased inhibition in downstream regions that mediate the behavioral response.

In the bed nucleus of the stria terminalis, whole-cell recordings from slice preparations demonstrated that CRF enhanced GABAergic neurotransmission, and the CRF effect appeared to be via the CRF₁ receptor similar to the effects in the amygdala, and NPY inhibited GABAergic neurotransmission (Kash and Winder, 2006). The predominant noradrenergic innervation of the bed nucleus of the stria terminalis is in the ventral part, and here norepinephrine decreases glutamatergic activity measured both electrophysiologically and with in vivo microdialysis (Egli et al., 2005; Forray et al., 1999). Norepinephrine also increased GABA_A IPSCs (Dumont and Williams, 2004). Thus, if one combines the data from the central nucleus of the amygdala and the bed nucleus of the stria terminalis, then certain consistencies evolve (Table 3). CRF, vasopressin, and norepinephrine increase GABAergic activity, and NPY and nociceptin decrease GABAergic activity, actions at the cellular level that are parallel to the behavioral effects described above with neuropharmacological studies (Table 3).

Table 3

Effects of Brain Stress Neurotransmitters on GABAergic Activity in the Extended Amygdala

Other researchers have argued that increasing excitability in the basolateral nucleus of the amygdala contributes to the anxiogenic-like effects of CRF (Rainnie et al., 2004). Using whole-cell patch-clamp recordings from basolateral amygdala neurons of animals chronically administered a CRF₁/CRF₂ agonist, urocortin, showed an N-methyl-D-aspartate (NMDA) receptor-mediated decrease in both spontaneous and stimulation-evoked IPSPs (Rainnie et al., 2004). Ethanol withdrawal, diazepam withdrawal, and uncontrollable stress also suppress IPSCs of the cells in the basolateral amygdala using a whole-cell patch-clamp preparation (Isoardi et al., 2007). These NMDA-mediated effects are the opposite of the GABA-mediated effects observed in the central nucleus of the amygdala and suggest that an integration of the role of the central and basolateral nuclei of the amygdala in stress and dependence responses will be required.

With the exception of recent studies with ethanol dependence, little work has been done at the cellular level in the extended amygdala on the changes in neurotransmission in the brain stress systems with the development of dependence. Chronic ethanol-induced changes in neuronal activity of GABA interneurons in the central nucleus of the amygdala have been linked to actions of CRF and nociceptin. Acute administration of doses of alcohol in the intoxicating range increased GABA_A receptor-mediated IPSCs in central nucleus of the amygdala neurons, and this effect has been hypothesized to be attributable to an increase in presynaptic GABA release (Roberto et al., 2003; Nie et al., 2004). Even more striking is that the augmented GABA release is increased even further in dependent animals, shown both by electrophysiological and in vivo microdialysis measures (Roberto et al., 2004). The ethanol-induced enhancement of GABAergic IPSCs was blocked by CRF₁ antagonists (Nie et al., 2004; Roberto et al., 2004) and was not observed in CRF₁ knockout mice (Nie et al., 2004). Nociceptin-induced inhibition of IPSCs was increased in dependent animals, suggesting an increased sensitivity to nociceptin (Roberto and Siggins, 2006). Thus, not only do the brain stress/antistress systems interact systematically with the hypothesized GABAergic interneurons of the central nucleus of the amygdala, but ethanol dependence also sensitizes these neurons to the actions of the brain stress/antistress systems.

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Date: 2016-06-12; view: 423