Action of Ethanol and Zolpidem on gamma-Aminobutyric Acid Responses from Cerebellar Purkinje Neurons: Relationship to beta-Adrenergic Receptor Input

The observation that cerebellar Purkinje cells contain type-l benzodiazepine-sensitive GABAA receptors is consistent with findings in the present work that the majority of Purkinje neurons are sensitive to enhancement of GABA by the type-1 benzodiazepine agonist, zolpidem. Previous work has demonstrated a relation between zolpidem and ethanol enhancement of GABA responses in several brain regions, but had not tested Purkinje neurons. Therefore, given that a majority of Purkinje neurons were found to be sensitive to zolpidem, ethanol would have been expected to enhance GABA responses from this cell type. However, in agreement with earlier electrophysiological studies, ethanol enhanced GABA inhibitory responses from only a small proportion of these cerebellar Purkinje neurons. Rather than enhancement of GABA, local application of ethanol either inhibited or did not affect responses to GABA from a majority of cerebellar-Purkinje neurons. Nonetheless, as previously reported, a portion of the Purkinje neurons initially insensitive to ethanol enhancement of GABA became sensitive to this action of ethanol with co-application of the β-adrenergic agonist, isoproterenol. Thus, these results collectively implicate a β-adrenergic input dependency for ethanol enhancement of GABA from some, but not all, cerebellar Purkinje neurons sensitive to zolpidem. Because a β-adrenergic input did not allow ethanol enhancement of GABA from all Purkinje neurons, future studies should explore the possibility that other auxiliary neural inputs to zolpidem-sensitive cerebellar Purkinje neurons may be required for ethanol enhancement of GABA responsiveness when a β-adrenergic input does not have this action. Likewise, knowing that the action of zolpidem can predict ethanol enhancement of GABA in other brain regions, the present findings suggest that a future determination be made concerning whether zolpidem-sensitive neurons in these other regions of brain require a β-adrenergic or an alternative neural input for ethanol enhancement of GABA responses

Comparison of Basal Neuropeptide Y and Corticotropin Releasing Factor Levels Between the High Ethanol Drinking C57BL/6J and Low Ethanol Drinking DBA/2J Inbred Mouse Strains

Recent genetic and pharmacological evidence indicates that low neuropeptide Y (NPY) levels in brain regions involved with neurobiological responses to ethanol promote increased ethanol consumption. Because of their opposing actions, it has been suggested that NPY and corticotropin releasing factor (CRF) exert a reciprocal regulation on drug self-administration. It has been widely reported that inbred C57BL/6 mice consume significantly higher amounts of ethanol than do DBA/2 mice. Therefore, we used immunohistochemical techniques to determine if basal NPY and/or CRF levels differed in predicted directions between C57BL/6J and DBA/2J mice

The PLC/IP3R/PKC pathway is required for ethanol-enhanced GABA release

Research on the actions of ethanol at the GABAergic synapse has traditionally focused on postsynaptic mechanisms, but recent data demonstrate that ethanol also increases both evoked and spontaneous GABA release in many brain regions. Using whole-cell voltage-clamp recordings, we previously showed that ethanol increases spontaneous GABA release at the rat interneuron-Purkinje cell synapse. This presynaptic ethanol effect is dependent on calcium release from internal stores, possibly through activation of inositol 1,4,5-trisphosphate receptors (IP3Rs). After confirming that ethanol targets vesicular GABA release, in the present study we used electron microscopic immunohistochemistry to demonstrate that IP3Rs are located in presynaptic terminals of cerebellar interneurons. Activation of IP3Rs requires binding of IP3, generated through activation of phospholipase C (PLC). We find that the PLC antagonist edelfosine prevents ethanol from increasing spontaneous GABA release. Diacylglycerol generated by PLC and calcium released by activation of the IP3R activate protein kinase C (PKC). Ethanol-enhanced GABA release was blocked by two PKC antagonists, chelerythrine and calphostin C. When a membrane impermeable PKC antagonist, PKC (19-36), was delivered intracellularly to the postsynaptic neuron, ethanol continued to increase spontaneous GABA release. Overall, these results suggest that activation of the PLC/IP3R/PKC pathway is necessary for ethanol to increase spontaneous GABA release from presynaptic terminals onto Purkinje cells

Differential Effects of Chronic Antidepressant Treatment on Swim Stress- and Fluoxetine-Induced Secretion of Corticosterone and Progesterone

Hypersecretion of cortisol occurs in numerous patients with major depression and normalizes with clinical recovery during the course of chronic antidepressant treatment. These clinical data suggest that investigation of the effects of antidepressant treatments on the regulation of the brain-pituitary-adrenal axis may assist in elucidating the therapeutic basis of antidepressant actions. In the present investigation, both swim stress and acute fluoxetine challenge increased release of corticosterone and progesterone to reflect an activation of the brain pituitary-adrenal axis. The effects of chronic antidepressant treatment (21 days) on corticosterone and progesterone secretion induced by these challenges were investigated. Chronic fluoxetine treatment (5 mg/kg/day) completely blocked the increased secretion of corticosterone and progesterone in response to the acute fluoxetine challenge. Chronic treatment with desipramine, imipramine or amytriptyline (15 mg/kg/day) also markedly attenuated fluoxetine-induced corticosterone and progesterone secretion. However, chronic treatment with the monoamine oxidase inhibitors, phenelzine (5 mg/kg) and tranylcypromine (5 mg/kg), did not affect this hormonal response to acute fluoxetine challenge. Plasma levels of fluoxetine after acute challenge were not significantly different for the various chronic antidepressant treatment conditions from the chronic saline controls; therefore, an increase in the metabolism of fluoxetine can not explain the antagonism of the fluoxetine-induced hormonal response after chronic antidepressant treatment. In contrast to the effects of selected antidepressants on acute fluoxetine-induced steroid release, chronic treatment with imipramine (20 mg/kg/day), fluoxetine (5 mg/kg/day) or phenelzine (5 mg/kg) did not significantly alter this swim stress-induced corticosterone or progesterone secretion. Because chronic fluoxetine and tricyclic antidepressant drugs blocked the acute action of fluoxetine to increase adrenal cortical secretion, but did not alter swim stress-induced secretion of these steroids, we propose that distinct neurochemical mechanisms control fluoxetine and swim stress-induced steroid release. We speculate that the substantial adaptive response to those chronic antidepressant treatments, which minimize the effect of acute fluoxetine challenge to increase in corticosterone and progesterone secretion, may be relevant to the therapeutic actions of these drugs

Decreased Immunoreactivity of the Melanocortin Neuropeptide α-Melanocyte-Stimulating Hormone (α-MSH) After Chronic Ethanol Exposure in Sprague-Dawley Rats

The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor proopiomelanocortin (POMC). Recent pharmacologic and genetic evidence suggests that MC receptor (MCR) signaling modulates neurobiologic responses to ethanol and ethanol intake. Because ethanol decreases POMC mRNA levels, we determined if exposure to an ethanol-containing diet (ED) would significantly reduce central immunoreactivity of the MC peptide α-MSH in rats. We also determined if ethanol exposure would alter the immunoreactivity of agouti-related protein (AgRP), an endogenous MCR antagonist

Patterning light emitting porous silicon using helium beam irradiation

ABSTRACT High energy helium beam has been utilized to pattern silicon prior to electrochemical etching in hydrofluoric acid. Photoluminescence (PL) studies carried out on medium resistivity silicon showed that the PL wavelength of the irradiated regions is continuously red-shifted by up to 150 nm with increasing dose. On the lower resistivity silicon, the intensity is shown to increase by more than twenty times with dose. Atomic force microscopy (AFM) and scanning electron microscopy (SEM) have been used to determine the surface morphology of the irradiated structure. This technique is potentially important for producing an integrated silicon based optoelectronic device

Involvement of protein kinase A in ethanol-induced locomotor activity and sensitization

Mutant mice lacking the RIIβ subunit of protein kinase A (regulatory subunit II beta−/−) show increased ethanol preference. Recent evidence suggests a relationship between heightened ethanol preference and susceptibility to ethanol-induced locomotor sensitization. It is currently unknown if protein kinase A signaling modulates the stimulant effects and/or behavioral sensitization caused by ethanol administration. To address this question, we examined the effects of repeated ethanol administration on locomotor activity RIIβ−/− and littermate wild-type (RIIβ+/+) mice on multiple genetic backgrounds

The CRF-1 Receptor Antagonist, CP-154,526, Attenuates Stress-Induced Increases in Ethanol Consumption by BALB/cJ Mice

Corticotropin-releasing factor (CRF) signaling modulates neurobiological responses to stress and ethanol, and may modulate observed increases in ethanol consumption following exposure to stressful events. The current experiment was conducted to further characterize the role of CRF1 receptor (CRF1R) signaling in stress-induced increases in ethanol consumption in BALB/cJ and C57BL/6N mice

Elevated anxiety-like behavior following ethanol exposure in mutant mice lacking neuropeptide Y (NPY)

Neuropeptide Y (NPY) is a neuromodulator with anxiolytic properties. Recent evidence suggests that NPY modulates neurobiological responses to ethanol. Because withdrawal from ethanol is associated with elevated anxiety-like behavior, and because central NPY modulates anxiety, we assessed anxiety-like behavior in mutant mice lacking normal production of NPY (NPY−/−) and in normal wild-type mice (NPY+/+) 6-hours after removal of a liquid diet containing 4.5% ethanol