The role of metabotropic glutamate receptors and associated cell signaling pathways in the acute sedative-hypnotic effects of ethanol

Metabotropic glutamate receptors (mGluRs) mediate the slower, modulatory effects of glutamate neurotransmission. In this capacity, mGluRs can alter signaling at both NMDA and GABAA receptors, the receptors which are thought to mediate the majority of ethanol's sedative-hypnotic properties. The goal of the present study was to examine the role of mGluRs, and the intracellular signaling pathways with which they associate, in mediating the acute sedative-hypnotic properties of ethanol. The first set of experiments examines the effects of three selective mGluR antagonists on the sedative and hypnotic effects of acutely administered high doses of ethanol. Inhibition of mGluR5 increased both ethanol-induced locomotor deficits and loss of righting reflex (LORR). Inhibition of mGluR5 also produced an increase in ketamine-induced LORR, but did not alter pentobarbital or midazolam-induced LORR. These data suggest that inhibition of mGluR5 selectively enhances the sedative-hypnotic effects of ethanol, and that this enhancement may be related to decreased mGluR5-NMDAR interactions. The second set of experiments examines the effects of acute ethanol treatment on protein kinase C-gamma (PKC[gamma]) phosphorylation over time. Acute ethanol treatment increased phosphorylated PKC[gamma] (pPKC[gamma]) immunoreactivity in the nucleus accumbens and the central amygdala and decreased pPKC[gamma] immunoreactivity in the basolateral amygdala. Moreover, these effects were time dependent. These data suggest that acute ethanol alters the abundance of the catalytically competent form of PKC[gamma] and these changes may mediate some of the acute behavioral effects of ethanol. The third set of experiments examines the effects of acute ethanol treatment and mGluR5 inhibition on extracellular-signal regulated kinase (ERK) phosphorylation. Acute ethanol treatment rapidly increased pERK immunoreactivity in the nucleus accumbens shell and the central amygdala and produced delayed increases in the basolateral amygdala, thalamus, and hypothalamus. pERK immunoreactivity was decreased in the nucleus accumbens core. Following mGluR5 inhibition, the effects of ethanol in the nucleus accumbens were reduced and the effects of ethanol in the basolateral amygdala and the hypothalamus were enhanced. Finally, inhibition of ERK phosphorylation reduced ethanol-induced LORR, suggesting that these changes in pERK may be related to the sedative-hypnotic effects of ethanol. These studies identified signaling pathways that may mediate the sedative-hypnotic effects of ethanol

Differential Modulation of Ethanol-Induced Sedation and Hypnosis by Metabotropic Glutamate Receptor Antagonists in C57BL/6J Mice

Emerging evidence implicates metabotropic glutamate receptor (mGluR) function in the neurobiological effects of ethanol. The recent development of subtype specific mGluR antagonists has made it possible to examine the roles of specific mGluRs in biochemical and behavioral responses to ethanol. The purpose of the present study was to determine if mGluRs modulate the acute sedative-hypnotic properties of ethanol in mice

Metabotropic Glutamate Receptor 5 Activity in the Nucleus Accumbens Is Required for the Maintenance of Ethanol Self-Administration in a Rat Genetic Model of High Alcohol Intake

Systemic modulation of Group I and II metabotropic glutamate receptors (mGluRs) regulate ethanol self-administration in a variety of animal models. Although these receptors are expressed in reward-related brain regions, the anatomical specificity of their functional involvement in ethanol self-administration remains to be characterized. This study sought to evaluate the functional role of Group I (mGluR5) and Group II (mGluR2/3) in mesocorticolimbic brain regions in ethanol self-administration

Alcohol Alters the Activation of ERK1/2, a Functional Regulator of Binge Alcohol Drinking in Adult C57BL/6J Mice

Binge alcohol drinking is a particularly risky pattern of alcohol consumption that often precedes alcohol dependence and addiction. The transition from binge alcohol drinking to alcohol addiction likely involves mechanisms of synaptic plasticity and learning in the brain. The mitogen-activated protein kinase (MAPK) signaling cascades have been shown to be involved in learning and memory, as well as the response to drugs of abuse, but their role in binge alcohol drinking remains unclear. The present experiments were designed to determine the effects of acute alcohol on extracellular signaling related kinases (ERK1/2) expression and activity, and to determine whether ERK1/2 activity functionally regulates binge-like alcohol drinking

The mGluR5 antagonist MPEP selectively inhibits the onset and maintenance of ethanol self-administration in C57BL/6J mice

Many of the biochemical, physiological, and behavioral effects of ethanol are known to be mediated by ionotropic glutamate receptors. Emerging evidence implicates metabotropic glutamate receptors (mGluRs) in the biobehavioral effects of ethanol and other drugs of abuse, but there is little information regarding the role of mGluRs in the reinforcing effects of ethanol

The Inhibition of CDK8/19 Mediator Kinases Prevents the Development of Resistance to EGFR-Targeting Drugs

Drug resistance is the main obstacle to achieving cures with both conventional and targeted anticancer drugs. The emergence of acquired drug resistance is initially mediated by non-genetic transcriptional changes, which occur at a much higher frequency than mutations and may involve population-scale transcriptomic adaptation. CDK8/19 kinases, through association with transcriptional Mediator complex, regulate transcriptional reprogramming by co-operating with different signal-responsive transcription factors. Here we tested if CDK8/19 inhibition could prevent adaptation to drugs acting on epidermal growth factor receptor (EGFR/ERBB1/HER1). The development of resistance was analyzed following long-term exposure of BT474 and SKBR3 breast cancer cells to EGFR-targeting small molecules (gefitinib, erlotinib) and of SW48 colon cancer cells to an anti-EGFR monoclonal antibody cetuximab. In all cases, treatment of small cell populations (~10 cells) with a single dose of the drug initially led to growth inhibition that was followed by the resumption of proliferation and development of drug resistance in the adapted populations. However, this adaptation was always prevented by the addition of selective CDK8/19 inhibitors, even though such inhibitors alone had only moderate or no effect on cell growth. These results indicate that combining EGFR-targeting drugs with CDK8/19 inhibitors may delay or prevent the development of tumor resistance to therapy

The Inhibition of CDK8/19 Mediator Kinases Prevents the Development of Resistance to EGFR-Targeting Drugs

Drug resistance is the main obstacle to achieving cures with both conventional and targeted anticancer drugs. The emergence of acquired drug resistance is initially mediated by non-genetic transcriptional changes, which occur at a much higher frequency than mutations and may involve population-scale transcriptomic adaptation. CDK8/19 kinases, through association with transcriptional Mediator complex, regulate transcriptional reprogramming by co-operating with different signal-responsive transcription factors. Here we tested if CDK8/19 inhibition could prevent adaptation to drugs acting on epidermal growth factor receptor (EGFR/ERBB1/HER1). The development of resistance was analyzed following long-term exposure of BT474 and SKBR3 breast cancer cells to EGFR-targeting small molecules (gefitinib, erlotinib) and of SW48 colon cancer cells to an anti-EGFR monoclonal antibody cetuximab. In all cases, treatment of small cell populations (~105 cells) with a single dose of the drug initially led to growth inhibition that was followed by the resumption of proliferation and development of drug resistance in the adapted populations. However, this adaptation was always prevented by the addition of selective CDK8/19 inhibitors, even though such inhibitors alone had only moderate or no effect on cell growth. These results indicate that combining EGFR-targeting drugs with CDK8/19 inhibitors may delay or prevent the development of tumor resistance to therapy