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The effects of sodium bromide on the bullfrog sympathetic ganglion were studied by extracellular and intracellular recording techniques. Equimolar replacement of sodium chloride (112 mM) by sodium bromide in Ringer's solution caused hyperpolarization (means = 7.4 mV) of ganglion cells, and antidromically evoked spikes showed increased rates of rise as well as prolonged post-spike positivity. These effects, rapid in onset, returned to control values after approximately 30 min of continued exposure to bromide Ringer. Orthodromic synaptic transmission was not impaired by bromide (84-112 mM); instead it produced increased post-spike negativity and occasionally, stimulus-bound repetitive postganglionic responses (SBR) to each single preganglionic stimulus. This synaptic enhancement persisted as long as exposure to bromide continued. Since ethanol also causes responses, its interaction with bromide was tested and pronounced synergism was found in which 95% of ganglion cells displayed repetitive orthodromic responses to each single preganglionic stimulus. The present and previous studies suggest that bromide and ethanol act at the unmyelinated presynaptic nerve terminal to generate stimulus-bound repetitive responses. The transient nature of the hyperpolarization produced by bromide argues against a mechanistic role in its anticonvulsant action. The persistent synaptic excitatory effects of bromide, however, may have implications for the role of chloride channels in anticonvulsant mechanisms or in epileptogenesis.

The benzodiazepine--gamma-aminobutyric acid (GABA) receptor--ionophore system is an oligomeric complex, composed of at least three interacting components. These three components have been well characterized in vitro by radioreceptor binding assays. A variety of centrally acting anxiolytic, depressant, anticonvulsant and convulsant drugs, which affect GABAergic transmission, bind to one of the sites and modulate the binding of ligands at the other sites. Thus, depressant barbiturates, nonbarbiturate hypnotics (like etomidate) and pyrazolopyridines (like etazolate), while inhibiting the binding of alpha-dihydropicrotoxinin (DHP), enhance the binding of GABA and benzodiazepines. These enhancing effects are blocked by convulsant drugs that inhibit the binding of dihydropicrotoxinin and also by bicuculline. These interactions involving barbiturates and other modulatory drugs, exhibit stereoselectivity, anion dependence and brain regional selectivity. Several classes of drugs which facilitate GABAergic transmission appear to interact with the sites for GABA and benzodiazepines allosterically via the dihydropicrotoxinin site of the oligomeric complex. The GABA system has also been implicated in a variety of pathological conditions, including anxiety, seizure activity, movement disorders, cardiovascular control, pain and in drug dependence. Since most of the GABA agonists do not pass the blood-brain barrier, future trends in the pharmacology of GABA may be the development of drugs that will activate the GABA receptor system via picrotoxinin or benzodiazepine sites.

Short-term and long-term effects of ethanol on the fatty acid composition of mitochondrial, microsomal and myelin fractions in brain have been investigated. Microsomal membranes were not modified by treatment for 60 hr, while in mitochondrial membranes there was a significant decrease in arachidonic and docosahexaenoic acids, responsible for the decrease in the double-bond index. A clear decrease in the 18:1/18:0 ratio was found in myelin after short-term treatment, whereas no significant variations were observed in the other subcellular membranes under the same conditions. On the other hand, chronic exposure to ethanol for 18 days induced a significant increase in oleic and docosahexaenoic acids in microsomal membranes. However, no significant changes were detected in the composition of fatty acids of mitochondrial membranes after 18 days of administration of ethanol. Contrary to that found with short-term treatment, a significant increase was observed in the 18:1/18:0 ratio of the myelin fraction after chronic consumption of ethanol. These results suggest that alcohol intoxication of neonatal chicks induces different modifications in composition of fatty acids of different membranes in the brain, those observed in the myelin fraction being specially important.

The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) has been implicated in a number of neuropsychiatric disorders, including alcohol use disorder. Studies have shown that BDNF activity in cortical regions, such as the medial prefrontal cortex (mPFC) mediates various ethanol-related behaviors. We previously reported a significant down-regulation in Bdnf mRNA in mPFC following chronic ethanol exposure compared to control mice. The present study was conducted to extend these findings by examining whether chronic ethanol treatment reduces BDNF protein expression in mPFC and whether reversing this deficit via direct injection of BDNF or viral-mediated overexpression of BDNF in mPFC alters voluntary ethanol consumption in dependent and nondependent mice. Repeated cycles of chronic intermittent ethanol (CIE) exposure was employed to model ethanol dependence, which produces robust escalation of ethanol intake. Results indicated that CIE treatment significantly increased ethanol intake and this was accompanied by a significant decrease in BDNF protein in mPFC that lasted at least 72 h after CIE exposure. In a separate study, once dependence-related increased drinking was established, bilateral infusion of BDNF (0, 0.25, 0.50 μg) into mPFC significantly decreased ethanol intake in a dose-related manner in dependent mice but did not affect moderate drinking in nondependent mice. In a third study, viral-mediated overexpression of BDNF in mPFC prevented escalation of drinking in dependent mice but did not alter intake in nondependent mice. Collectively, these results provide evidence that adaptations in cortical (mPFC) BDNF activity resulting from chronic ethanol exposure play a role in mediating excessive ethanol drinking associated with dependence.

In rats exposed to ethanol either prenatally or both pre- and postnatally, the development of cardiac vesicular uptake of 3H-norepinephrine was nearly normal. However, the body and heart was lower than controls.

AbstractAdolescent alcohol exposure is associated with many negative outcomes that persist into adulthood, including altered affective and reward-related behaviors. However, the long-term neurological disruptions underlying these behavioral states are not fully understood. The basolateral amygdala (BLA) plays a critical role in many of these behaviors, and shifts in the excitatory/inhibitory balance in this area are capable of directly modulating their expression. While changes to BLA physiology have been demonstrated during the acute withdrawal phase following adolescent ethanol exposure, no studies to date have examined whether these persist long-term. The kappa opioid receptor (KOR) system is a neuromodulatory system that acts as a prominent mediator of negative affective behaviors, and alterations of this system have been implicated in the behavioral profile caused by chronic alcohol exposure in adulthood. Notably, in the BLA, the KOR system undergoes functional changes between adolescence and adulthood, but whether BLA KORs are functionally disrupted by adolescent ethanol exposure has not been examined. In this study, we exposed male and female Sprague-Dawley rats to a vapor inhalation model of moderate adolescent chronic intermittent ethanol (aCIE) and examined the long-term effects on GABAergic and glutamatergic neurotransmission within the adult BLA using whole-cell patch-clamp electrophysiology. We also assessed how KOR activation modulated these neurotransmitter systems in aCIE versus control rats using the selective KOR agonist, U69593. This investigation revealed that aCIE exposure disrupted basal glutamate transmission in females by increasing spontaneous excitatory postsynaptic current (sEPSC) frequency, while having no effects on glutamate transmission in males or GABA transmission in either sex. Interestingly, we also found that aCIE exposure unmasked a KOR-mediated suppression of spontaneous inhibitory postsynaptic current (sIPSC) frequency and sEPSC amplitude only in males, with no effects of aCIE exposure on KOR function in females. Together, these data suggest that moderate-level adolescent ethanol exposure produces long-term changes to BLA physiology and BLA KOR function, and that these changes are sex-dependent. This is the first study to examine persistent adaptations to both BLA physiology and KOR function following adolescent alcohol exposure, and opens a broad avenue for future investigation into other neurobiological and behavioral consequences of adolescent ethanol exposure-induced disruptions of these systems.

Alcohol consumption is mediated by several important neuromodulatory systems, including the endocannabinoid and neuropeptide Y (NPY) systems in the limbic brain circuitry. However, molecular mechanisms through which cannabinoid-1 (CB1) receptors regulate alcohol consumption are still unclear. Here, we investigated the role of the CB1 receptor-mediated downstream regulation of NPY via epigenetic mechanisms in the amygdala. Alcohol drinking behavior was measured in adult male C57BL/6J mice treated with a CB1 receptor neutral antagonist AM4113 using a two-bottle choice paradigm while anxiety-like behavior was assessed in the light-dark box (LDB) test. The CB1 receptor-mediated changes in the protein levels of phosphorylated cAMP-responsive element binding protein (pCREB), CREB binding protein (CBP), H3K9ac, H3K14ac and NPY, and the mRNA levels of Creb1, Cbp, and Npy were measured in amygdaloid brain structures. Npy-specific changes in the levels of acetylated histone (H3K9/14ac) and CBP in the amygdala were also measured. We found that the pharmacological blockade of CB1 receptors with AM4113 reduced alcohol consumption and, in an ethanol-naïve cohort, reduced anxiety-like behavior in the LDB test. Treatment with AM4113 also increased the mRNA levels of Creb1 and Cbp in the amygdala as well as the protein levels of pCREB, CBP, H3K9ac and H3K14ac in the central and medial nucleus of amygdala, but not in the basolateral amygdala. Additionally, AM4113 treatment increased occupancy of CBP and H3K9/14ac at the Npy gene promoter, leading to an increase in both mRNA and protein levels of NPY in the amygdala. These novel findings suggest that CB1 receptor-mediated CREB signaling plays an important role in the modulation of NPY function through an epigenetic mechanism and further support the potential use of CB1 receptor neutral antagonists for the treatment of alcohol use disorder.

Depression-alcohol addiction comorbidity is a common clinical phenomenon. Alcohol exposure in adolescence has been shown to induce depression-like behaviors in rodents. However, the mechanism of action for this type of depression remains unclear. Previous studies have reported that several different types of stress, such as chronic unpredictable stress and early social isolation, trigger depression-like symptoms in mice by inducing hippocampal microglial decline, which is mediated by the initial activation of the microglial cells. Since alcohol also activates microglia, we evaluated the dynamic changes in hippocampal microglia in mice receiving adolescent intermittent alcohol exposure (AIE). Our results showed that 14 days of AIE, followed by 21 days period of no treatment, induced behavioral abnormalities as well as a significant loss and dystrophy of hippocampal microglia in mice. We found that this AIE-induced decline in hippocampal microglia was mediated by both microglial activation and apoptosis, as (i) 1 day of alcohol exposure induced a distinct activation of hippocampal microglia followed by their apoptosis, and (ii) blocking the initial activation of hippocampal microglia by pretreatment with minocycline suppressed the AIE-induced apoptosis and loss of hippocampal microglia as well as the AIE-induced depression-like symptoms. Lipopolysaccharide (LPS), a classical activator of microglia, ameliorated the AIE-induced depression-like symptoms by reversing the decline in the hippocampal microglia. These results reveal a possible mechanism for AIE-induced depression and demonstrate that the restoration of hippocampal microglial homeostasis may be a therapeutic strategy for depression induced by alcohol intake and withdrawal.