The action of glutamate in CNS is mediated by the activation of metabotropic and ionotropic receptors. The metabotropic glutamate receptors (mGluRs) are highly enriched in prefrontal cortex (PFC) -a brain region critically involved in the regulation of cognition and emotion. Emerging evidence has suggested that mGluRs are viable drug targets for neuropsychiatric disorders associated with PFC dysfunction. However, the mGluR-mediated signalling in PFC remains unclear. To understand the physiological functions of postsynaptic group II mGluRs (mGluR2/3) in PFC neurones, we investigated the molecular and cellular mechanisms underlying the regulation of NMDA receptor channels by group II mGluRs. We found that APDC, a highly selective and potent group II mGluR agonist, reversibly increased NMDAR currents in acutely dissociated PFC pyramidal neurones. Selective group II mGluR antagonists, but not group I mGluR antagonists, blocked APDC-induced enhancement of NMDAR currents, suggesting the mediation by mGluR2/3 receptors. The APDC effect on NMDAR currents was independent of Mg 2+ block or membrane voltages, and primarily targeted NR2A subunits containing NMDARs. While changing protein kinase A levels was without effect, inhibiting protein kinase C (PKC) or dialysis with Ca 2+ chelators largely blocked the mGluR2/3 modulation of NMDAR currents. In contrast, inhibiting protein tyrosine kinases, cyclin-dependent kinase 5, Ca 2+ /calmodulindependent kinase II or the Ca 2+ /calmodulin-dependent phosphatase calcineurin failed to do so. Moreover, treatment of PFC slices with APDC significantly increased the PKC activity and PKC phosphorylation of NMDA receptors. These findings suggest that activation of mGluR2/3 receptors potentiates NMDAR channel functions in PFC through a PKC-dependent mechanism. This modulation may be relevant for developing novel mGluR-related pharmacological agents for the treatment of mental illnesses.

Tyszkiewicz, Joanna P. and Zhen Yan. ␤-amyloid peptides impair PKC-dependent functions of metabotropic glutamate receptors in prefrontal cortical neurons. J Neurophysiol 93: 3102-3111, 2005. First published January 19, 2005 doi:10.1152/jn.00939.2004. The metabotropic glutamate receptors (mGluRs) have been implicated in cognition, memory, and some neurodegenerative disorders, including the Alzheimer's disease (AD). To understand how the dysfunction of mGluRs contributes to the pathophysiology of AD, we examined the ␤-amyloid peptide (A␤)-induced alterations in the physiological functions of mGluRs in prefrontal cortical pyramidal neurons. Two potential targets of mGluR signaling involved in cognition, the GABAergic system and the N-methyl-D-aspartate (NMDA) receptor, were examined. Activation of group I mGluRs with (S)-3,5-dihydroxyphenylglycine (DHPG) significantly increased the spontaneous inhibitory postsynaptic current (sIPSC) amplitude, and this effect was protein kinase C (PKC) sensitive. Treatment with A␤ abolished the DHPG-induced enhancement of sIPSC amplitude. On the other hand, activation of group II mGluRs with (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) significantly increased the NMDA receptor (NMDAR)-mediated currents via a PKC-dependent mechanism, and A␤ treatment also diminished the APDC-induced potentiation of NMDAR currents. In A␤-treated slices, both DHPG and APDC failed to activate PKC. These results indicate that the mGluR regulation of GABA transmission and NMDAR currents is impaired by A␤ treatment probably due to the A␤-mediated interference of mGluR activation of PKC. This study provides a framework within which the role of mGluRs in normal cognitive functions and AD can be better understood.

Taranabant is a highly selective and potent cannabinoid CB 1 receptor inverse agonist. We compared the pharmacological properties of taranabant with another inverse agonist, rimonabant, and determined the preclinical safety margins of taranabant. In vitro studies demonstrated that taranabant is $10-fold more potent than rimonabant at the CB 1 receptor, and taranabant is more selective based on offtarget in vitro screening. In vivo efficacy studies demonstrated that taranabant is $10-fold more potent than rimonabant in diet-induced obese rats. In repeat-dose toxicological studies, taranabant did not cause mortality in rodents and monkeys at exposure margins r6478 and 1922 times the estimated human exposure at 0.5 mg/day À1 . Taranabant did not produce CNS signs, including seizures, when administered to monkeys for 1 year at 10 mg/kg À1 day À1 (highest dose tested chronically), corresponding to an exposure margin of 974 times. In contrast to primates, taranabant produced brief handling-induced seizure-like activity in rodents, species predisposed to handling-induced seizures. Throughout the entire preclinical program, taranabant did not cause histopathological changes in the peripheral or central nervous system. In summary, the highly selective nature of taranabant is consistent with its generally favorable preclinical safety profile. Drug Dev Res 70 : 349-362, 2009. r

Dong, Yan, Joanna P. Tyszkiewicz, and Tung M. Fong. Galanin and galanin-like peptide differentially modulate neuronal activities in rat arculate nucleus neurons. J Neurophysiol 95: 3228 -3234, 2006. First published February 15, 2006 doi:10.1152/jn.01117.2005. Neuropeptides galanin and galanin-like peptide (GALP) share similar amino acid sequence and presumably interact with the same group of receptors, but they differentially regulate a variety of physiological and pathophysiological processes including metabolism and reproduction. Here we explored the neurophysiological basis of the in vivo differential effect between galanin and GALP by examining galanin and GALP modulation of neuronal activities of neurons in the arcuate nucleus (Arc), a brain region critically involved in energy homeostasis and reproductive function. We demonstrated that galanin and GALP inhibited excitatory and inhibitory postsynaptic currents in a similar way. In contrast, galanin and GALP differentially affected the intrinsic membrane property. In most recorded Arc neurons, galanin perfusion induced significant hyperpolarization of the resting membrane potential, which was not affected by GALP perfusion. In addition, galanin perfusion substantially suppressed the spontaneous spike firing in most Arc neurons, whereas in response to GALP perfusion, about half of the Arc neurons exhibited mild reduction in spontaneous spike firing and the other half showed enhancement. Furthermore, the Arc neurons that had been previously responsive to galanin perfusion no longer responded to galanin if co-applied with GALP, indicating that GALP can physiologically antagonize galanin effect. This differential effect appears to be mediated by G protein within the recorded cell, as the galanin effect on firing rate was abolished when the recorded cell was loaded with GDP-␤S, an agent that blocks G protein activity. Taken together, these differential effects of galanin and GALP may provide a neurophysiological mechanism through which galanin and GALP differentially regulate energy balance, reproductive function, and other physiological processes. I N T R O D U C T I O NGalanin and galanin-like peptide (GALP) are implicated in a variety of neuroendocrine processes (Hokfelt 2005). Although sharing a common sequence (Ohtaki et al. 1999) and presumably activating the same group of receptors (Gundlach 2002), galanin and GALP exert distinct in vivo effect, in particular in the regulation of feeding behaviors. Chronic intracerebral ventricular (icv) administration of galanin in rats persistently upregulates food intake (Kyrkouli et al. 1990) but does not affect body weight (Smith et al. 1994), whereas icv administration of GALP in rats produces a dichotomous effect: a transient orexigenic effect followed by either significantly reduced or unchanged feeding behaviors (Lawrence et al. 2002;Seth et al. 2003). The molecular and cellular basis for the differential in vivo effects of galanin and GALP has not been elucidated.The only known potential in vivo substrates for g...

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