Despite the pervasiveness of alcohol (ethanol) use, it is unclear how the multiple molecular targets for ethanol contribute to its many behavioral effects. The function of GABA type A receptors (GABA A -Rs) is altered by ethanol, but there are multiple subtypes of these receptors, and thus far, individual subunits have not been definitively linked with specific behavioral actions. The ␣1 subunit of the GABA A -R is the most abundant ␣ subunit in the brain, and the goal of this study was to determine the role of receptors containing this subunit in alcohol action. We designed an ␣1 subunit with serine 270 to histidine and leucine 277 to alanine mutations that was insensitive to potentiation by ethanol yet retained normal GABA sensitivity and constructed knockin mice containing this mutant subunit. Hippocampal slice recordings from these mice indicated that the mutant receptors were less sensitive to ethanol's potentiating effects. Behaviorally, we observed that mutant mice recovered more quickly from the motor-impairing effects of ethanol and etomidate, but not pentobarbital, and showed increased anxiolytic effects of ethanol. No differences were observed in ethanol-induced hypnosis, locomotor stimulation, cognitive impairment, or in ethanol preference and consumption. Overall, these studies demonstrate that the postsynaptic effects of ethanol at GABAergic synapses containing the ␣1 subunit are important for specific ethanol-induced behavioral effects.Alcohol (ethanol) has a prominent role in society and is one of the most frequently used and abused drugs. Despite the prevalence of alcohol use, the molecular mechanisms underlying its behavioral effects remain unclear. Ethanol intoxication elicits a diverse array of behavioral effects including cognitive impairment and motor incoordination, and these behavioral effects are likely due to actions of ethanol on multiple brain proteins (Harris, 1999). GABA type A receptors (GABA A -Rs) are ligand-gated ion channels that mediate
Abstract-Hypertension in (mRen2)27 transgenic rats is partly dependent on activation of the sympathetic nervous system, but the role of ganglionic transmission is unknown. We assessed indices of synaptic plasticity (post-tetanic short-term potentiation [PTP] and long-term potentiation [LTP]) and sympathetic ganglionic transmission without tetany in superior cervical ganglia (SCG) of Hannover Sprague-Dawley rats (HnSD) versus (mRen2)27 rats. Key Words: angiotensin II Ⅲ rats, transgenic Ⅲ autonomic nervous system Ⅲ hypertension Ⅲ arterial Ⅲ receptors I n the mammalian autonomic ganglia, post-tetanic potentiation (PTP) and long-term potentiation (LTP) of synaptic transmission are examples of activity-dependent forms of synaptic plasticity. A few seconds of repetitive presynaptic stimulation producing profound changes in the efficacy of chemical synaptic transmission that can last for seconds or minutes is designated PTP, whereas increased synaptic strength persisting for hours or days is termed LTP. Activitydependent LTP is dependent on activation of serotonin 5-HT 3 receptors in rat superior cervical ganglia (SCG) 1 and is independent of activation of either cholinergic or adrenergic receptors 2,3 in rats. In addition to activity-dependent mechanisms, enduring changes in the synaptic strength also occur through activity-independent mechanisms. For example, specific antigen challenges of isolated sympathetic ganglia activates resident mast cells to release substances that initiate long-lasting increases in synaptic efficacy. 4 Also, application of exogenous catecholamines induces LTP of cholinergic 5 or peptidergic synaptic transmission in sympathetic ganglia. 6 Although the role of ganglionic LTP in the physiology of autonomic ganglia is not understood, recent reports show a positive relationship between ganglionic LTP and blood pressure in ouabain-dependent hypertension that favors the possibility that ganglionic LTP contributes to increased sympathetic nerve activity (SNA) in hypertension or vice versa. 7 Captopril reversed both hypertension and ganglionic abnormalities, suggesting a role for angiotensin (Ang) II in an ouabain-dependent model of hypertension. Other studies show alterations in ganglionic function in spontaneously hypertensive rats (SHRs). 8,9 For example, postsynaptic spike frequency adaptation is curtailed in SHRs. 9 Presynaptically, there is enhanced release of acetylcholine. 10 Collectively, these changes in ganglionic function may contribute to increased SNA in the development and maintenance of hypertension observed in human and experimental hypertension. 11,[12][13][14][15][16][17][18][19] However, less well understood is how enhanced SNA contributes to elevated blood pressure or alters ganglionic synaptic plasticity. In the ouabain-dependent rat, SHRs, and renin-transgenic rat, Ang II acting centrally to increase sympathetic nervous system (SNS) outflow appears to be a common feature; but increased peripheral levels of Ang II, or local increases in the peptide, cannot be excluded. In fact,
The phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway in brain of spontaneously hypertensive rats (SHR), but not Wister-Kyoto (WKY) rats, contributes to elevated mean arterial pressure (MAP). The role of PI3K in regulation of blood pressure or autonomic function in the nucleus solitary tract (NTS) is yet to be established in other AngII-dependent models of hypertension. Thus, we microinjected PI3K inhibitors, wortmannin or LY294002, into the NTS, and measured MAP, baroreflex sensitivity (BRS) for heart rate control, and heart rate variability (HRV) in mRen2.Lewis congenic and (mRen2)27 transgenic rats. Bilateral NTS microinjections of wortmannin (100 nmol/L; 50 nL) reduced MAP in (mRen2)27 and mRen2.Lewis rats (33±5 mmHg, n=7, and 32±6 mmHg, n=9, respectively) for ~90 minutes. Spectral and sequence analysis showed improvements in spontaneous BRS and HRV (50–100%) following treatment in both hypertensive strains. Injections of wortmannin into NTS of Hannover Sprague-Dawley or Lewis control rats failed to alter MAP, BRS or HRV. In mRen2.Lewis, but not control Lewis rats, LY294002 (50 µmol/L) reduced MAP and increased BRS and HRV similar to wortmannin. Thus, pharmacologic blockade of the PI3K signaling pathway in NTS reveals an important contribution to resting MAP and BRS in rats with over expression of the Ren2 gene.
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