Key points Activation of oxytocin receptors (OXTRs) facilitates neuronal excitability in rat lateral nucleus of central amygdala (CeL). OXTR‐induced excitation is mediated by inhibition of inwardly rectifying K+ (Kir) channels. Phospholipase Cβ is necessary for OXTR‐mediated excitation of CeL neurons and depression of Kir channels. OXTR‐elicited depression of Kir channels and excitation of CeL neurons require the function of Ca2+‐dependent protein kinase C. Abstract Oxytocin (OXT) is a nonapeptide that exerts anxiolytic effects in the brain. The amygdala is an important structure involved in the modulation of fear and anxiety. A high density of OXT receptors (OXTRs) has been detected in the capsular (CeC) and lateral (CeL) nucleus of the central amygdala (CeA). Previous studies have demonstrated that activation of OXTRs induces remarkable increases in neuronal excitability in the CeL/C. However, the signalling and ionic mechanisms underlying OXTR‐induced facilitation of neuronal excitability have not been determined. We found that activation of OXTRs in the CeL increased action potential firing frequency recorded from neurons in this region via inhibition of the inwardly rectifying K+ channels. The functions of phospholipase Cβ and protein kinase C were required for OXTR‐induced augmentation of neuronal excitability. Our results provide a cellular and molecular mechanism whereby activation of OXTRs exerts anxiolytic effects.

Oxytocin (OXT) is a nonapeptide that serves as a neuromodulator in the brain and a hormone participating in parturition and lactation in the periphery. The subiculum is the major output region of the hippocampus and an integral component in the networks that process sensory and motor cues to form a cognitive map encoding spatial, contextual, and emotional information. Whilst the subiculum expresses the highest OXT-binding sites and is the first brain region to be activated by peripheral application of OXT, the precise actions of OXT in the subiculum have not been determined. Our results demonstrate that application of the selective OXT receptor (OXTR) agonist, [Thr4,Gly7]-oxytocin (TGOT), excited subicular neurons via activation of TRPV1 channels, and depression of K+ channels. The OXTR-mediated excitation of subicular neurons required the functions of phospholipase Cβ, protein kinase C, and degradation of phosphatidylinositol 4,5-bisphosphate (PIP2). OXTR-elicited excitation of subicular neurons enhanced long-term potentiation via activation of TRPV1 channels. Our results provide a cellular and molecular mechanism to explain the physiological functions of OXT in the brain.

Nociceptin (NOP) is an endogenous opioid-like peptide that selectively activates the opioid receptor-like (ORL-1) receptors. The entorhinal cortex (EC) is closely related to temporal lobe epilepsy and expresses high densities of ORL-1 receptors. However, the functions of NOP in the EC, especially in modulating the epileptiform activity in the EC, have not been determined. We demonstrated that activation of ORL-1 receptors remarkably inhibited the epileptiform activity in entorhinal slices induced by application of picrotoxin or by deprivation of extracellular Mg 2+. NOP-mediated depression of epileptiform activity was independent of synaptic transmission in the EC, but mediated by inhibition of neuronal excitability in the EC. NOP hyperpolarized entorhinal neurons via activation of K + channels and inhibition of cation channels. Whereas application of Ba 2+ at 300 μM which is effective for the inward rectifier K + (Kir) channels slightly inhibited NOP-induced hyperpolarization, the current-voltage (I-V) curve of the net currents induced by NOP was linear without showing inward rectification. However, a role of NOPinduced inhibition of cation channels was revealed after inhibition of Kir channels by Ba 2+. Furthermore, NOP-mediated augmentation of membrane currents was differently affected by application of the blockers selective for distinct subfamilies of Kir channels. Whereas SCH23390 or ML133 blocked NOP-induced augmentation of membrane currents at negative potentials, application of tertiapin-Q exerted no actions on NOP-induced alteration of membrane currents. Our results demonstrated a novel cellular and molecular mechanism whereby activation of ORL-1 receptors depresses epilepsy.

A sizeable portion of the societal drain from cocaine abuse results from the complications of in utero drug exposure. Because of challenges in using humans and mammalian model organisms as test subjects, much debate remains about the impact of in utero cocaine exposure. Zebrafish offer a number of advantages as a model in longitudinal toxicology studies and are quite sensitive physiologically and behaviorally to cocaine. In this study, we have used zebrafish to model the effects of embryonic pre-exposure to cocaine on development and on subsequent cardiovascular physiology and cocaine-induced conditioned place preference (CPP) in longitudinal adults. Larval fish showed a progressive decrease in telencephalic size with increased doses of cocaine. These treated larvae also showed a dose dependent response in heart rate that persisted 24 h after drug cessation. Embryonic cocaine exposure had little effect on overall health of longitudinal adults, but subtle changes in cardiovascular physiology were seen including decreased sensitivity to isoproterenol and increased sensitivity to cocaine. These longitudinal adult fish also showed an embryonic dose-dependent change in CPP behavior, suggesting an increased sensitivity. These studies clearly show that pre-exposure during embryonic development affects subsequent cocaine sensitivity in longitudinal adults.

Arginine vasopressin (AVP) is a hormone exerting vasoconstrictive and antidiuretic action in the periphery and serves as a neuromodulator in the brain. Although the hippocampus receives vasopressinergic innervation and AVP has been shown to facilitate the excitability of CA1 pyramidal neurons, the involved ionic and signaling mechanisms have not been determined. Here we found that AVP excited CA1

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Key points Activation of V1a vasopressin receptors facilitates neuronal excitability in the medial nucleus of central amygdala (CeM) V1a receptor activation excites about 80% CeM neurons by opening a cationic conductance and about 20% CeM neurons by suppressing an inwardly rectifying K+ (Kir) channel The cationic conductance activated by V1a receptors is identified as TRPC5 channels PLCβ‐mediated depletion of PIP2 is involved in V1a receptor‐elicited excitation of CeM neurons Intracellular Ca2+ release and PKC are unnecessary for V1a receptor‐mediated excitation of CeM neurons Abstract Arginine vasopressin (AVP) serves as a hormone in the periphery to modulate water homeostasis and a neuromodulator in the brain to regulate a diverse range of functions including anxiety, social behaviour, cognitive activities and nociception. The amygdala is an essential brain region involved in modulating defensive and appetitive behaviours, pain and alcohol use disorders. Whereas activation of V1a receptors in the medial nucleus of the central amygdala (CeM) increases neuronal excitability, the involved ionic and signalling mechanisms have not been determined. We found that activation of V1a receptors in the CeM facilitated neuronal excitability predominantly by opening TRPC5 channels, although AVP excited about one fifth of the CeM neurons via suppressing an inwardly rectifying K+ (Kir) channel. G proteins and phospholipase Cβ (PLCβ) were required for AVP‐elicited excitation of CeM neurons, whereas intracellular Ca2+ release and the activity of protein kinase C were unnecessary. Prevention of the depletion of phosphatidylinositol 4,5‐bisphosphate (PIP2) blocked AVP‐induced excitation of CeM neurons, suggesting that PLCβ‐mediated depletion of PIP2 is involved in AVP‐mediated excitation of CeM neurons. Our results may provide a cellular and molecular mechanism to explain the anxiogenic effects of AVP in the amygdala.

Title: PLCβ-mediated depletion of PIP 2 and ATP-sensitive K + channels are involved in arginine vasopressin-induced facilitation of neuronal excitability and LTP in the dentate gyrus