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Anxiety disorders are one of the most common and debilitating mental illnesses worldwide. Growing evidence indicates an age-dependent rise in the incidence of anxiety disorders from adolescence through adulthood, suggestive of underlying neurodevelopmental mechanisms. Kappa opioid receptors (KORs) are known to contribute to the development and expression of anxiety; however, the functional role of KORs in the basolateral amygdala (BLA), a brain structure critical in mediating anxiety, particularly across ontogeny, are unknown. Using whole-cell patch-clamp electrophysiology in acute brain slices from adolescent (postnatal day (P) 30-45) and adult (P60+) male Sprague-Dawley rats, we found that the KOR agonist, U69593, increased the frequency of GABA A -mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in the adolescent BLA, without an effect in the adult BLA or on sIPSC amplitude at either age. The KOR effect was blocked by the KOR antagonist, nor-BNI, which alone did not alter GABA transmission at either age, and the effect of the KOR agonist was TTX-sensitive. Additionally, KOR activation did not alter glutamatergic transmission in the BLA at either age. In contrast, U69593 inhibited sIPSC frequency in the central amygdala (CeA) at both ages, without altering sIPSC amplitude. Western blot analysis of KOR expression indicated that KOR levels were not different between the two ages in either the BLA or CeA. This is the first study to provide compelling evidence for a novel and unique neuromodulatory switch in one of the primary brain regions involved in initiating and mediating anxiety that may contribute to the ontogenic rise in anxiety disorders., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We have previously reported that (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl]+ ++pyrrolidin-3-yl]thiazole (NRA0045) is a novel antipsychotic agent with affinities for dopamine D4, 5-hydroxytryptamine 2A (5-HT2A) and alpha1 receptors. In the present study, in vivo receptor occupancy of 5-HT2A, alpha1, dopamine D2 and D3 receptors by NRA0045 was assessed, based on in vivo and ex vivo receptor binding, and findings were compared to reference antipsychotic drugs (haloperidol, risperidone, clozapine). Intraperitoneal administration of haloperidol highly occupied the dopamine D2 receptor in the striatum and nucleus accumbens, and alpha1 adrenoceptors in the frontal cortex. Occupation of the 5-HT2A receptor in the frontal cortex and the dopamine D3 receptor in the nucleus accumbens and islands of Cajella was moderate. By contrast, atypical antipsychotics such as risperidone and clozapine dose-dependently occupied the 5-HT2A receptor in the frontal cortex, with moderate to negligible occupancy of the D2 receptor in the striatum and the nucleus accumbens. Clozapine and risperidone also occupied the alpha1 adrenoceptor in the frontal cortex, and clozapine did not occupy the dopamine D3 receptor. As seen with other atypical antipsychotics, intraperitoneal administration of NRA0045 dose-dependently occupied the 5-HT2A receptor and the alpha1 adrenoceptor in the frontal cortex, while it was without effect on dopamine D2 and D3 receptors in the striatum, nucleus accumbens and islands of Cajella. Thus, the strong occupancy of 5-HT2A and alpha1 receptors is involved in the pharmacological action of NRA0045.

Intracellular recordings were made from Retzius cells from the segmental ganglia of the leech, Hirudo medicinalis, gamma-D-Glutamylglycine, (50 microM), reversibly and preferentially antagonised the excitatory action of kainate, having no effect on actions of quisqualate or carbachol but at this concentration the antagonism was of short duration, reversing prior to washing off the gamma-D-glutamylglycine. However, higher concentrations of gamma-D-glutamylglycine (250-500 microM) reversibly antagonised both quisqualate and carbachol-induced excitatory responses, indicating a lack of specificity. The value of gamma-D-glutamylglycine in determining the possible site of action of kainate on leech Retzius cells is discussed.

beta-Endorphin-(1-27), administered intraventricularly has been previously reported to block the analgesia induced by beta-endorphin injected intraventricularly. The present study was to determine if the blocking effect of beta-endorphin-(1-27) was specific to beta-endorphin which stimulates epsilon receptors, but not to other opioids with activity at different opioid receptors. The antagonistic effects of beta-endorphin-(1-27) on the analgesia induced by beta-endorphin (epsilon-opioid receptor agonist), D-Ala2-NMePhe4-Gly-ol-enkephalin(DAGO) and morphine, (mu-opioid receptor agonists), D-Pen2-D-Pen5-enkephalin(DPDPE) and D-Ala2-D-Leu5-enkephalin(DADLE) (delta-opioid receptor agonists) and U-50, 488H (kappa-opioid receptor agonist) were studied. beta-Endorphin-(1-27) injected intraventricularly, at doses which, when injected alone did not produce analgesia, antagonized the analgesia induced by beta-endorphin given intraventricularly. However, the analgesia induced by DAGO, morphine, DPDPE, DADLE and U-50, 488H given intraventricularly was not antagonized by beta-endorphin-(1-27). The data suggest that beta-endorphin-(1-27) selectively blocks the analgesia induced by the stimulation of epsilon receptors but not by the stimulation of mu, delta, and kappa receptors. The results support the previously proposed hypothesis that beta-endorphin produces its analgesia by stimulating specific epsilon receptors.