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AbstractHuman alcoholics and animals that have received chronic ethanol treatment (CET) display memory deficits. Previous work in our laboratory has shown that CET produces damage to the hippocampus and a reduction in the magnitude of hippocampal long‐term synaptic potentiation. In the present report we examined the effects of CET on hippocampal long‐term depression (LTD). We used in vitro hippocampal slices to examine LTD after rats received 38–41 weeks of paired feeding on liquid diets containing ethanol or isocaloric sucrose. Stimulation delivered through electrodes in the CA3‐CA1 Schaffer collateral pathway activated synaptic population responses in CA1. LTD of CA1 stratum radiatum evoked field potential slope was not induced by 900 single pulses at 1 Hz, but was elicited by 900 pulse pairs separated by 50 or 200 msec delivered at 1 Hz (pLFS50, pLFS200). LTD evoked by pLFS200, but not by pLFS50, was significantly reduced in slices from ethanol‐treated rats. The N‐methyl D‐aspartate (NMDA) receptor antagonist 2‐amino‐5‐phosphonopentanoic acid (AP5) (50 μM) blocked LTD induced by pLFS50 and pLFS200 equally, but the L‐type calcium channel blocker nimodipine (10 μM) had no effect on either type of LTD. Thus, direct effects on these channels cannot explain how CET selectively reduces the magnitude of pLFS200 LTD. Finally, we describe a novel and robust LTD of the presynaptic afferent volley that is resistant to CET, NMDAR antagonists, GABA‐A receptor blockade, and blockade of L‐type calcium channels. Synapse 48:189–197, 2003. © 2003 Wiley‐Liss, Inc.

Acute administration of cyclo (His-Pro) to rats cause a dose-dependent decrease in ethanol-induced hypothermia. Bromination of the imidazole moiety of histidine in cyclo (His-Pro) resulted in a significant increase in its potency to attenuate ethanol hypothermia. In contrast, benzylation of the imidazole moiety of histidine or the substitution of one or both of the amino acids in cyclo(His-Pro) led to a total loss of its thermomodulatory activity. In conclusion, it appears from these preliminary data that it may be possible to design analogs of CHP that may be effective antagonists for ethanol hypothermia.

Our previous work indicated a role for fyn-kinase in mediating several ethanol- and GABA(A) agonist-mediated behaviors. In the present work we investigate behavioral sensitivity to ethanol and several GABA(A) compounds in mice that over-express fyn-kinase in forebrain to further characterize the role of this non-receptor tyrosine kinase in the mediation of ethanol sensitivity. Transgenic mice over-expressing fyn-kinase were tested for sensitivity to ethanol-induced loss of righting reflex and ethanol preference drinking using a two-bottle choice drinking paradigm. Loss of righting reflex induced by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; GABA(A) agonist) and etomidate (GABA(A) positive allosteric modulator) were also assessed. Fyn over-expressing mice exhibited shorter durations of ethanol-induced loss of righting reflex in the absence of differences in the rate of blood ethanol clearance, and exhibited reduced ethanol preference drinking. The genotypes did not differ in initial sensitivity to ethanol-induced loss of righting reflex suggesting development of greater acute tolerance to this ethanol action. Fyn over-expressing and wild-type mice also did not differ in sensitivity to loss of righting reflex induced by THIP and etomidate. The present results suggest regional specificity for fyn-kinase in the modulation of ethanol and GABAergic behavioral sensitivity. Fyn-kinase over-expression in forebrain structures modulates ethanol's hypnotic actions, as well as ethanol preference and consumption. Moreover, fyn over-expression in forebrain does not alter hypnotic sensitivity to THIP or etomidate, supporting data from fyn null mutant mice suggesting that cerebellar structures mediate the hypnotic actions of these GABAergic compounds.

Many volatile organic compounds (VOCs) are significant environmental irritants that stimulate somatosensory nerve endings to produce pain and irritation. We measured intracellular calcium in cultured trigeminal ganglion neurons to characterize the cellular mechanisms and chemical structural determinants underlying sensitivity to VOCs. Trigeminal neurons responded to homologous series of alcohols (C4-C7) as well as saturated and unsaturated aldehydes in a concentration dependent manner. Ranked in terms of threshold to recruit neurons by compounds of the same carbon chain length, enaldehyde

The development of alcohol use disorder (AUD) involves binge or heavy drinking to high levels of intoxication that leads to compulsive intake, the loss of control in limiting intake, and a negative emotional state when alcohol is removed. This cascade of events occurs over an extended period within a three-stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These three heuristic stages map onto the dysregulation of functional domains of incentive salience/habits, negative emotional states, and executive function, mediated by the basal ganglia, extended amygdala, and frontal cortex, respectively. Sleep disturbances, alterations of sleep architecture, and the development of insomnia are ubiquitous in AUD and also map onto the three stages of the addiction cycle. During the binge/intoxication stage, alcohol intoxication leads to a faster sleep onset, but sleep quality is poor relative to nights when no alcohol is consumed. The reduction of sleep onset latency and increase in wakefulness later in the night may be related to the acute effects of alcohol on GABAergic systems that are associated with sleep regulation and the effects on brain incentive salience systems, such as dopamine. During the withdrawal/negative affect stage, there is a decrease in slow-wave sleep and some limited recovery in REM sleep when individuals with AUD stop drinking. Limited recovery of sleep disturbances is seen in AUD within the first 30 days of abstinence. The effects of withdrawal on sleep may be related to the loss of alcohol as a positive allosteric modulator of GABAA receptors, a decrease in dopamine function, and the overactivation of stress neuromodulators, including hypocretin/orexin, norepinephrine, corticotropin-releasing factor, and cytokines. During the preoccupation/anticipation stage, individuals with AUD who are abstinent long-term present persistent sleep disturbances, including a longer latency to fall asleep, more time awake during the night, a decrease in slow-wave sleep, decreases in delta electroencephalogram power and evoked delta activity, and an increase in REM sleep. Glutamatergic system dysregulation that is observed in AUD is a likely substrate for some of these persistent sleep disturbances. Sleep pathology contributes to AUD pathology, and vice versa, possibly as a feed-forward drive to an unrecognized allostatic load that drives the addiction process.

The actuation of micro- and nanostructures controlled by external stimuli remains one of the exciting challenges in nanotechnology due to the wealth of fundamental questions and potential applications in energy harvesting, robotics, sensing, biomedicine, and tunable metamaterials. Photoactuation utilizes the conversion of light into motion through reversible chemical and physical processes and enables remote and spatiotemporal control of the actuation. Here, we report a fast light-to-motion conversion in few-nanometer thick bare polydopamine (PDA) membranes stimulated by visible light. Light-induced heating of PDA leads to desorption of water molecules and contraction of membranes in less than 140 μs. Switching off the light leads to a spontaneous expansion in less than 20 ms due to heat dissipation and water adsorption. Our findings demonstrate that pristine PDA membranes are multiresponsive materials that can be harnessed as robust building blocks for soft, micro-, and nanoscale actuators stimulated by light, temperature, and moisture level.

A consistent preclinical finding is that exposure to alcohol during adolescence produces a persistent hyperdopaminergic state during adulthood. The current experiments determine that effects of Adolescent Intermittent Ethanol (AIE) on the adult neurochemical response to EtOH administered directly into the mesolimbic dopamine system, alterations in dendritic spine and gene expression within the nucleus accumbens shell (AcbSh), and if treatment with the HDACII inhibitor TSA could normalize the consequences of AIE. Rats were exposed to the AIE (4 g/kg ig; 3 days a week) or water (CON) during adolescence, and all testing occurred during adulthood. CON and AIE rats were microinjected with EtOH directly into the posterior VTA and dopamine and glutamate levels were recorded in the AcbSh. Separate groups of AIE and CON rats were sacrificed during adulthood and Taqman arrays and dendritic spine morphology assessments were performed. The data indicated that exposure to AIE resulted in a significant leftward and upward shift in the dose-response curve for an increase in dopamine in the AcbSh following EtOH microinjection into the posterior VTA. Taqman array indicated that AIE exposure affected the expression of target genes (Chrna7, Impact, Chrna5). The data indicated no alterations in dendritic spine morphology in the AcbSh or any alteration in AIE effects by TSA administration. Binge-like EtOH exposure during adolescence enhances the response to acute ethanol challenge in adulthood, demonstrating that AIE produces a hyperdopaminergic mesolimbic system in both male and female Wistar rats. The neuroadaptations induced by AIE in the AcbSh could be part of the biological basis of the observed negative consequences of adolescent binge-like alcohol exposure on adult drug self-administration behaviors.