• Energy Research
• US close
• CA close
• DE close
• Neuroscience close

Prenatal ethanol exposure is associated with, and is a risk factor for, developmental disorders with abnormal social behaviors, including autism spectrum disorders. We hypothesize that the specific effects of ethanol on social behavior are defined by the timing of the exposure as well as subsequent changes in brain regions such as the amygdala and ventral striatum. We recently reported that in utero ethanol exposure on gestational day 12 alters social behaviors of weanling [postnatal day (P) 28], adolescent (P42), and young adult (P75) rats. Male, but not female, offspring of the ethanol-exposed dams showed significant decreases in social investigation (sniffing of a social partner), contact behavior (grooming or crawling over/under the partner), and play fighting (following, chasing, nape attacks, or pinning) at all ages tested with maximal effects at P28 and P42. Furthermore, ethanol-exposed males and females showed evidence of social avoidance at P42 and P75. The present study sought to test whether a form of social enrichment could normalize any of the social deficits and what the molecular mechanisms of such effects might be. We found that housing rats with nonmanipulated control rats normalized the social avoidance phenotype normally seen when they are housed with sex-matched prenatal ethanol-exposed littermates. There was no mitigation of the other ethanol-induced behavioral deficits. Conversely, male control-treated rats housed with nonlittermates showed deficits in play fighting, social investigation and contact behavior. Molecular analyses of the amygdala and ventral striatum of adolescent rats following fetal ethanol exposure indicated several specific neurotransmitter systems and pathways that might underlie the social avoidance phenotype as well as its reversal.

The use of alcohol has been associated with both an increased risk of acquisition of HIV‐1 infection and an increased rate of disease progression among those already infected by the virus. The potential for alcohol to exacerbate the effects of HIV infection is especially important in the central nervous system (CNS) because this area is vulnerable to the combined effects of alcohol and HIV infection. The effects of alcohol on glial cells are mediated through receptors such as Toll‐like receptor 4 and N‐methyl‐d‐aspartate receptor. This causes the activation of signaling molecules such as interleukin‐1 receptor‐associated kinase and various members of the P38 mitogen‐activated protein kinase family and subsequent activation of transcription factors such as nuclear factor‐kappa beta and activator protein 1. The eventual outcome is an increase in pro‐inflammatory cytokine production by glial cells. Alcohol also induces higher levels of NADPH oxidase in glial cells, which leads to an increased production of reactive oxygen species (ROS). Viral invasion of the CNS occurs early after infection, and HIV proteins have also been demonstrated to increase levels of pro‐inflammatory cytokines and ROS in glial cells through activation of some of the same pathways activated by alcohol. Both cell culture systems and animal models have demonstrated that concomitant exposure to alcohol and HIV/HIV proteins results in increased levels of expression of pro‐inflammatory cytokines such as interleukin‐1 beta and tumor necrosis factor‐alpha, along with increased levels of oxidative stress. Clinical studies also suggest that alcohol exacerbates the CNS effects of HIV‐1 infection. This review focuses on the mechanisms by which alcohol causes increased CNS damage in HIV‐1 infection.

The opioid antagonist, naltrexone, reduces intake of, and operant responding for, ethanol, but reports of how the opioid agonist morphine alters these effects are conflicting. We examined the discrimination and plasma levels of ethanol with naltrexone and morphine pretreatments. Rats were trained to discriminate ethanol (1.5 g/kg; i.g.) from water, under a two-lever, food-reinforced procedure. Ethanol and pentobarbital, but not amphetamine, substituted for ethanol in a dose-related manner. Naltrexone reduced ethanol-induced, ethanol-appropriate responding to about 35%, but the peripherally-acting antagonist, naltrexone methobromide, was without effect. Morphine neither substituted for nor enhanced ethanol-appropriate responding. Rather, ethanol-induced, ethanol-appropriate responding was attenuated in a dose-related manner by morphine administration. Neither naltrexone nor morphine altered ethanol-appropriate responding to the substitution with pentobarbital. In another group of rats, both naltrexone and morphine decreased plasma ethanol levels, and delayed the time of peak concentrations, suggesting that opiates alter the behavioral effects of ethanol through both pharmacokinetic and pharmacodynamic mechanisms. The similarities between an opioid agonist and an antagonist suggest that either naltrexone has opioid agonist-like effects, or that these effects occur through non-opioidergic mechanisms.

AbstractActivation of potassium (K+) currents plays a critical role in the control of programmed cell death. Because pituitary adenylate cyclase‐activating polypeptide (PACAP) has been shown to inhibit the apoptotic cascade in the cerebellar cortex during development, we have investigated the effect of PACAP on K+ currents in cultured cerebellar granule cells using the patch‐clamp technique in the whole‐cell configuration. Two types of outward K+ currents, a transient K+ current (IA) and a delayed rectifier K+ current (IK) were characterized using two different voltage protocols and specific inhibitors of K+ channels. Application of PACAP induced a reversible reduction of the IK amplitude, but did not affect IA, while the PACAP‐related peptide vasoactive intestinal polypeptide had no effect on either types of K+ currents. Repeated applications of PACAP induced gradual attenuation of the electrophysiological response. In the presence of guanosine 5′‐[γthio]triphosphate (GTPγS), PACAP provoked a marked and irreversible IK depression, whereas cell dialysis with guanosine 5′‐[βthio]diphosphate GDPβS totally abolished the effect of PACAP. Pre‐treatment of the cells with pertussis toxin did not modify the effect of PACAP on IK. In contrast, cholera toxin suppressed the PACAP‐induced inhibition of IK. Exposure of granule cells to dibutyryl cyclic adenosine monophosphate (dbcAMP) mimicked the inhibitory effect of PACAP on IK. Addition of the specific protein kinase A inhibitor H89 in the patch pipette solution prevented the reduction of IK induced by both PACAP and dbcAMP. PACAP provoked a sustained increase of the resting membrane potential in cerebellar granule cells cultured either in high or low KCl‐containing medium, and this long‐term depolarizing effect of PACAP was mimicked by the IK specific blocker tetraethylammonium chloride (TEA). In addition, pre‐incubation of granule cells with TEA suppressed the effect of PACAP on resting membrane potential. TEA mimicked the neuroprotective effect of PACAP against ethanol‐induced apoptotic cell death, and the increase of caspase‐3 activity observed after exposure of granule cells to ethanol was also significantly inhibited by TEA. Taken together, the present results demonstrate that, in rat cerebellar granule cells, PACAP reduces the delayed outward rectifier K+ current by activating a type 1 PACAP (PAC1) receptor coupled to the adenylyl cyclase/protein kinase A pathway through a cholera toxin‐sensitive Gs protein. Our data also show that PACAP and TEA induce long‐term depolarization of the resting membrane potential, promote cell survival and inhibit caspase‐3 activity, suggesting that PACAP‐evoked inhibition of IK contributes to the anti‐apoptotic effect of the peptide on cerebellar granule cells.

Alcoholism and alcohol abuse represent a significant medical and societal problem, and have been thoroughly investigated in humans as well as using animal models. A less well understood aspect of alcohol related disorders is the possible effect of this drug on offspring whose parents were exposed prior to conception. The zebrafish has been successfully employed in alcohol research, however, the effect of exposing the parents to alcohol before fertilization of the eggs on offspring has not been demonstrated in this species. In this proof of concept study, we attempt to address this hiatus. We exposed both adult male and female zebrafish to 0.0% (control) or 0.5% (vol/vol) alcohol chronically for 7 days, subsequently bred the fish within their respective treatment group, collected the fertilized eggs, allowed them to develop, and tested the behavior of free-swimming offspring at their age of 7-9 days post-fertilization. We conducted the analysis in two genetically distinct quasi-inbred strains of zebrafish, AB and TL. Although gross morphology and general activity of the fish appeared unaffected, we found significant behavioral alterations in offspring of alcohol exposed parents compared to offspring of control parents in both strains. These alterations included robustly increased duration and reduced frequency of immobility, increased turn angle, and increased intra-individual variance of turn angle in offspring of alcohol exposed parents in both strains. The mechanisms underlying these behavioral effects or whether the effects are due to exposure of the father, the mother, or both to alcohol are unknown. Nevertheless, our results now set the stage for future studies with zebrafish that will address these questions.

To demonstrate the applicability of optimal control theory for designing minimum energy charge-balanced input waveforms for single periodically-firing in vitro neurons from brain slices of Long-Evans rats.The method of control uses the phase model of a neuron and does not require prior knowledge of the neuron's biological details. The phase model of a neuron is a one-dimensional model that is characterized by the neuron's phase response curve (PRC), a sensitivity measure of the neuron to a stimulus applied at different points in its firing cycle. The PRC for each neuron is experimentally obtained by measuring the shift in phase due to a short-duration pulse injected into the periodically-firing neuron at various phase values. Based on the measured PRC, continuous-time, charge-balanced, minimum energy control waveforms have been designed to regulate the next firing time of the neuron upon application at the onset of an action potential.The designed waveforms can achieve the inter-spike-interval regulation for in vitro neurons with energy levels that are lower than those of conventional monophasic pulsatile inputs of past studies by at least an order of magnitude. They also provide the advantage of being charge-balanced. The energy efficiency of these waveforms is also shown by performing several supporting simulations that compare the performance of the designed waveforms against that of phase shuffled surrogate inputs, variants of the minimum energy waveforms obtained from suboptimal PRCs, as well as pulsatile stimuli that are applied at the point of maximum PRC. It was found that the minimum energy waveforms perform better than all other stimuli both in terms of control and in the amount of energy used. Specifically, it was seen that these charge-balanced waveforms use at least an order of magnitude less energy than conventional monophasic pulsatile stimuli.The significance of this work is that it uses concepts from the theory of optimal control and introduces a novel approach in designing minimum energy charge-balanced input waveforms for neurons that are robust to noise and implementable in electrophysiological experiments.

Thirty-two pregnant Long-Evans rats were divided into 10 groups of 3 or 4 pregnant rats, and each rat was given a single dose of 4 ml ethanol/kg (20 ml/kg of a 20% solution) between d 6 and 15 of gestation. An 11th group of 50 pregnant rats received distilled water and served as controls. Offspring body weights were decreased in groups of rats given ethanol as compared to controls (3.0-3.6 g, versus 3.9 g for controls). Total litter weight was decreased in dams given ethanol on d 6. Skeletal variants were seen in 13-78% of the offspring given ethanol, compared to 0.6% of the controls. Variations may be considered as additional signs of embryotoxicity. Malformations such as hydronephrosis, pelvic kidney, microcephalus, cranioschisis, and microphthalmia occurred in 72-100% of the ethanol treated offspring, as compared to 12% of controls. Hydronephrosis was most frequent on d 9 or 14, pelvic kidney on d 8 and 11, and microphthalmia from d 10-12. Cranioschisis was maximal on d 7, 11, and 15, and microcephalic offspring were most frequently born to dams given ethanol on d 7 or 14. Skeletal defects were usually single entities, while soft-tissue anomalies occurred in a consistent pattern. These results suggest that ethanol is a stage-specific teratogen in the rat at comparable exposure levels attained by many humans.

The population of most countries is increasing and the United Nations predicts that by the year 2050 those over the age of 60 years old will increase from 900 million individuals to approximately 2.1 billion individuals (United Nations, 2015). The increase in the number of older individuals will place a strain on many national health care systems making it important to investigate behaviors in the aged that may negatively impact general health in this demographic. Recent work has shown that older adults consume alcohol, often at levels that exceed the legal limit of intoxication. Unfortunately, consumption of high levels of ethanol in the older population is associated with many health consequences and may negatively impact the brain. Given ethical constraints found in many biomedical studies, animal models are needed to investigate the possible negative impact of high ethanol use in aged populations. However, few studies have investigated the effect of ethanol exposure in aged animals compared to ethanol exposure in younger animals and consequently the impact of ethanol in the aged population is not well understood. The current review summarizes initial work establishing the impact of ethanol in aged animals. The reviewed research studies support the working hypothesis that ethanol exposure produces significantly greater effects in aged animals compared to younger animals on many, if not all, behavioral tasks. In addition, the review proposes several initial, promising avenues of research to explore the neurobiological mechanisms that underly greater effects on ethanol-induced ataxia, cognition and sleep time. It is hoped that this effort will not only lead to a better understanding of behaviors impacted by ethanol in aged animals, but also improve the understanding brain mechanisms of the reported increased sensitivity to ethanol in the aged population.

Rats that were selectively bred for differences in alcohol‐induced sleep time (alcohol neurosensitivity) were tested for differences in formation and extinction of alcohol‐ and LiCl‐induced conditioned taste aversions. Male rats bred for high, control, or low alcohol sensitivity (HAS, CAS, and LAS rats, respectively) were deprived of water and given daily 30 min access to water for a baseline period of 7 days. Rats were then given a novel 0.125% sodium saccharin solution, followed by an intraperitoneal injection of either saline, 2 g/kg of ethanol (at 10% w/v), or 50.9 mg/kg of LiCl(0.15 M) on 3 conditioning days. Each saccharin exposure was followed by a recovery day of BCCBSS to water. The ethanol‐induced saccharin aversion extinguished more rapidly in LAS rats than in CAS or HAS rats (p < 0.05), but LiCl conditioned equivalent aversions in each group. Also, ethanol injection results in large differences in observed resting behavior in these rats (HAS > CAS > LAS), but LiCl injection produced no reliable group differences in resting. The weaker alcohol‐Induced M e aversion in LAS rats accords with their previously measured higher oral consumption of alcohol (Kulkosky et al., Alcoholism 17: M‐651, 1993) and the idea that alcohol intake is limited by an expectancy of postingestive consequences. The weaker ethanol induced aversion in LAS rats reflects selective breeding of an alcohol‐specific trait and not a general difference In aversive conditioning or chemical neurosensitivity.

In humans and in animal models the most frequently observed alcohol‐related birth defect (ARBD) is intrauterine growth retardation (IUGR). The central nervous system (CNS) is sensitive to the growth inhibitory effects of in utero ethanol exposure and neonatal CNS alterations with associated behavioral deficits are a likely result of maternal ethanol consumption. Presently, little information exists as to the biochemical mechanism by which ethanol inhibits fetal CNS growth. Further, it is unknown if there are genetic differences in maternal or fetal responses to ethanol. Ongoing research using a chick model indicates that pharmacologically appropriate doses of ethanol (< 30 mm) inhibit brain growth and reduce CNS 3′,5′‐cyclic adenosine monophosphate (cyclic AMP) with an associated 50% decrease in the binding of cyclic AMP by the regulatory subunit (RII) of protein kinase A. Furthermore, there is a specific loss of phosphorylation of RII by kinase catalytic subunit as a result of ethanol exposure. Because tissue cyclic AMP content and the degree of RII phosphorylation are important parameters for the regulation of protein kinase A catalytic activity, it is hypothesized that these alterations may be biochemical transformations that underlie ethanol‐induced growth suppression.