The gamma-aminobutyric acid(B) (GABA(B)) receptor was first demonstrated on presynaptic terminals where it serves as an autoreceptor and also as a heteroreceptor to influence transmitter release by suppressing neuronal Ca(2+) conductance. Subsequent studies showed the presence of the receptor on postsynaptic neurones where activation produces an increase in membrane K(+) conductance and associated neuronal hyperpolarization. (-)-Baclofen is a highly selective agonist for GABA(B) receptors, whereas the established GABA(A) receptor antagonists, bicuculline and picrotoxin, do not block GABA(B) receptors. The receptor is G(i)/G(o) protein-coupled with mixed effects on adenylate cyclase activity. The receptor comprises a heterodimer with similar subunits currently designated 1 and 2. These subunits are coupled via coiled-coil domains at their C termini. The evidence for splice variants is critically reviewed. Thus far, no unique pharmacological or functional properties have been assigned to either subunit or the variants. The emergence of high-affinity antagonists for GABA(B) receptors has enabled a synaptic role to be established. However, the antagonists have generally failed to establish the existence of pharmacologically distinct receptor types within the GABA(B) receptor class. The advent of GABA(B1) knockout mice has also failed to provide support for multiple receptor types.

Corticotropin-releasing factor (CRF)-related peptides serve as hormones and neuromodulators of the stress response and play a role in affective disorders. These peptides are known to alter complex behaviors and neuronal properties, but their receptor-mediated effects at CNS synapses are not well described. Here we show that excitatory glutamatergic transmission is modulated by two endogenous CRFrelated peptide ligands, corticotropin-releasing factor [CRF rat/human (r/h)] and Urocortin I (Ucn I), within the central nucleus of the amygdala (CeA) and the lateral septum mediolateral nucleus (LSMLN). These limbic nuclei are reciprocally innervated, are involved in stress and affective disorders, and have high densities of the CRF receptors CRF 1 and CRF 2 . Activation of these receptors exerts diametrically opposed actions on glutamatergic transmission in these nuclei. In the CeA, CRF(r/h) depressed excitatory glutamatergic transmission through a CRF 1 -mediated postsynaptic action, whereas Ucn I facilitated synaptic responses through presynaptic and postsynaptic CRF 2 -mediated mechanisms. Conversely, in the LSMLN, CRF caused a CRF 1 -mediated facilitation of glutamatergic transmission via postsynaptic mechanisms, whereas Ucn I depressed EPSCs by postsynaptic and presynaptic CRF 2 -mediated actions. Furthermore, antagonists of these receptors also affected glutamatergic neurotransmission, indicating that endogenous ligands tonically modulated synoptic activity at these synapses.These data show that CRF receptors in CeA and LSMLN synapses exert and maintain a significant synaptic tone and thereby regulate excitatory glutamatergic transmission. The results also suggest that CRF receptors may provide novel targets in affective disorders and stress.

CIO-,. 7. Restoration of the GABA depolarization to its control level after augmentation by Cl-injection had a mean time constant of 27-8 + 2-6 min. Picrotoxin did not alter this value.8. When foreign anions were exchanged for Cl-in the perfusion solution, the ten anions smaller or equal to ClO3-, decreased the GABA depolarization by 50-90 % and increased its time course 1-5-20 x control. The only exception having a small radius was Br-which augmented the amplitude 10-30 %.9. The ten anions larger than C103-produced a biphasic effect, i.e. an initial Japan.J. P. GALLAGHER, H. HIGASHI AND S. NISHI augmentation followed by a marked (up to 100 %) depression of the response. Experiments with CH3COO-, CH3S04-, or HOCH2CH2SO3-, indicated that this depression was non-competitive.

Corticotropin Releasing Hormone (CRH) or Corticotropin Releasing Factor (CRF) and its family of related naturally occurring endogenous peptides and receptors are becoming recognized for their actions within central (CNS) and peripheral (PNS) nervous systems. It should be recognized that the term 'CRH' has been displaced by 'CRF' (Guillemin 2005). However, to maintain uniformity among contributions to this special issue we have used the original term, CRH. The term 'CRF' has been associated recently with CRH receptors and designated with subscripts by the IUPHAR nomenclature committee (Hauger R.L. et al. 2003) to denote the type and subtype of receptors activated or antagonized by CRH ligands. CRH, as a hormone, has long been identified as the regulator of basal and stress-induced ACTH release within the hypothalamo-pituitary-adrenal axis (HPA axis). But the concept, that CRH and its related endogenous peptides and receptor ligands have non-HPA axis actions to regulate CNS synaptic transmission outside the HPA axis, is just beginning to be recognized and identified . It is especially noteworthy that since the synapse has become a prime focus for a variety of mental diseases, e.g. schizophrenia (Fischbach 2007), and neurological disorders, e.g., Alzheimer's disease (Bell and Cuello 2006), we suggest that "THE STRESSED SYNAPSE" has been overlooked (c.f., Kim and Diamond 2002; Radley and Morrison 2005) as a major contributor to many CNS disorders. We present data demonstrating CRH neuroregulatory and neuromodulatory actions at three limbic synapses, the basolateral amygdala to central amygdala synapse; the basolateral amygdala to medial prefrontal cortex synapse, and the lateral septum mediolateral nucleus synapse. A novel stress circuit is presented involving these three synapses. We suggest that CRH ligands and their receptors are significant etiological factors that need to be considered in the pharmacotherapy of mental diseases associated with CNS synaptic transmission.

Cocaine addiction is an enduring, relapsing, behavioural disorder in which stressors reinstate cocaine-seeking even after prolonged abstinence. Evidence suggests that the 'anxiety-like' behaviour and stress associated with protracted withdrawal may be mediated by increased corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA), a part of the limbic circuitry engaged in the coding and transmission of stimulus-reward associations. In the present study we describe a long-lasting potentiation of glutamatergic transmission induced at lateral amygdala (LA)-to-CeA synapses by rat/human CRF. After 2 weeks of withdrawal from repeated intermittent exposure to cocaine, CRF-induced long-term potentiation (LTP) was greatly enhanced compared to the respective saline control group while, after short-term withdrawal (24 h), there was no significant difference between the two treatment groups, indicating alterations in CRF systems during protracted withdrawal from chronic cocaine. After prolonged withdrawal, CRF-induced LTP was dependent on activation of CRF2, CaV2.3 (R-type) calcium channels and intracellular signalling through protein kinase C in both saline- and cocaine-treated groups. The enhanced CRF-induced LTP after 2 weeks of withdrawal was mediated through augmented CRF1 receptor function, associated with an increased signalling through protein kinase A, and required N-methyl-D-aspartate (NMDA) receptors. Accordingly, single-cell recordings revealed a significantly increased NMDA/AMPA ratio after prolonged withdrawal from the cocaine treatment. These results support a role for CRF1 receptor antagonists as plausible treatment options during withdrawal from chronic cocaine and suggest Ca(V)2.3 blockers as potential candidates for pharmaceutical modulation of CRF systems.

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Corticotropin-releasing factor (CRF) and urocortin (Ucn I) are endogenous members among a family of CRF-related peptides that activate two different and synaptically localized G-protein-coupled receptors, CRF 1 and CRF 2 . These peptides and their receptors have been implicated in stress responses and stress with cocaine abuse.In this study, we observed significant alterations in excitatory transmission and CRF-related peptide regulation of excitatory transmission in the lateral septum mediolateral nucleus (LSMLN) after chronic cocaine administration. In brain slice recordings from the LSMLN of control (saline-treated) rats, glutamatergic synaptic transmission was facilitated by activation of CRF 1 receptors with CRF but was depressed after activation of CRF 2 receptors with Ucn I. After acute withdrawal from a chronic cocaine administration regimen, CRF 1 activation remained facilitatory, but CRF 2 activation facilitated rather than depressed LSMLN EPSCs. These alterations in CRF 2 effects occurred through both presynaptic and postsynaptic mechanisms. In saline-treated rats, CRF 1 and CRF 2 coupled predominantly to protein kinase A signaling pathways, whereas after cocaine withdrawal, protein kinase C activity was more prominent and likely contributed to the CRF 2 -mediated presynaptic facilitation. Neither CRF nor Ucn I altered monosynaptic GABA A -mediated IPSCs before or after chronic cocaine administration, suggesting that loss of GABA A -mediated inhibition could not account for the facilitation. This switch in polarity of Ucn I-mediated neuromodulation, from a negative to positive regulation of excitatory glutamatergic transmission after chronic cocaine administration, could generate an imbalance in the brain reward circuitry associated with the LSMLN.