• Energy Research
• CA close
• FR close
• Energy Research close
• Neuroscience close

Altered dopamine (DA) transporter densities have been implicated in mechanisms of vulnerability and relapse in human alcoholics. The regional distribution and density of the DA transporter was studied in alcohol-preferring vervet monkeys to investigate baseline status and regulation of the DA transporter at different stages of chronic alcohol drinking. Combined ligand binding and in vitro autoradiography of the cocaine congener [125I]RTI-55 (beta-CIT) demonstrated a significant increase in DA transporter densities in abstinent alcohol-preferring monkeys over those in alcohol-avoiding monkeys. Chronic alcohol consumption down-regulated DA transporter densities, and this effect was reversed by acute withdrawal. These results demonstrate that the DA transporter is regulated by alcohol exposure and suggest that increased DA transporter densities may be a phenotypic marker of alcohol preference in vulnerable monkeys.

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.

When rats are presented with a novel saccharin solution and immediately injected with either morphine or ethanol, they subsequently develop a conditioned taste aversion (CTA) to the saccharin solution which reflects the aversive component of the conditioning drug. The present study provides evidence which suggests that both morphine-induced and ethanol-induced CTAs can be blocked by the specific high-affinity binding opiate antagonist, naloxazone.

The perinate is particularly risk-prone to chemical species which have the potential of inducing neuronal apoptosis or necrosis and thereby adversely altering development of the brain, to produce life-long functional and behavioral deficits. This paper is an overview for many substances of abuse, but the purview is much more broadened by the realization that even elevated levels of estrogens and corticosteroids in the pregnant mother can act as neuroteratogens, by passing via the placenta and altering neural development or inducing apoptosis in the perinate. Finally, therapeutic risks of anesthetics are highlighted, as these too induce neuronal apoptosis in the neonate by either blocking N-methyl-D-aspartate receptors or by acting as gamma-aminobutyric acid agonists. By understanding the mechanisms involved it may ultimately be possible to interrupt the mechanistic scheme and thereby prevent neuroteratological processes.

γ-aminobutyric acid (GABA) is an amino acid used for mitigating the detrimental effects of heat stress in broilers. In addition, a growing body of literature suggests that the in ovo feeding of various nutrients can enhance the post-hatch thermotolerance of broilers. Therefore, we hypothesized that the supplementation of GABA during incubation might have positive effects in heat-stressed broilers. Chicks hatched from eggs were divided into three groups described as follows: chicks hatched from eggs incubated at normal temperature and then raised under thermoneutral temperature (CON); chicks hatched from eggs incubated at normal temperature but raised under cyclic heat stress (HS) (CON+HS); and chicks hatched from eggs injected with 60 mg of GABA dissolved in 0.6 mL of distilled water but raised under cyclic HS (G10+HS). The HS was applied between 28 and 31 days of age with ambient temperatures raised from 22 ± 1 °C to 33 ± 1 °C for 6 h daily. Compared to the CON group, average daily weight gain was significantly lower in the CON+HS but not in the G10+HS group. Feed intake was significantly decreased in both the CON+HS and G10+HS groups. Compared to the CON group, plasma corticosterone levels were significantly increased in the CON+HS group, but not the G10+HS group. Hepatic mRNA levels of the acetyl-CoA carboxylase gene (ACC) were significantly reduced in the G10+HS group compared to the CON group. In addition, positive Pearson correlation coefficients were found in mRNA levels between fatty acid synthase (FAS) and nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) (r = 0.55, p < 0.05), NOX1 and NOX4 (r = 0.65, p < 0.01), and catalase (CAT) and superoxide dismutase (SOD) (r = 0.62, p < 0.05). Taken together, the results suggest that this study can serve as a basis for future work focusing on the in ovo feeding of GABA as a technique to combat heat stress in broilers.

Both genetic and environmental factors, such as stress, are important in determining alcohol consumption. Furthermore, both stress and alcohol influence the activity of the hypothalamic-pituitary-adrenal (HPA)-axis. Thus, the present studies investigated the response of the HPA axis to stress and the effect of ethanol on the stress response, in subjects at high (HR) and low (LR) risk of alcoholism as determined from their family history. Twenty HR and 20 LR subjects performed a stress-inducing task 30 min following the ingestion of either a placebo drink or a low dose of ethanol. The levels of plasma adrenal corticotropic hormone (ACTH) and cortisol were measured prior to and for four hours following initiation of the treatment. Changes with time in the plasma hormone levels following ingestion of either a placebo or an ethanol drink, without the performance of the stress task, served as controls to compare the stress-induced changes. Neither the placebo nor the ethanol drink altered the plasma ACTH and cortisol concentrations. High risk subjects presented lower basal ACTH, but not cortisol, levels and a lower stress-induced increase in plasma ACTH concentration than LR subjects. Furthermore, the HR subjects presented a delayed post-stress recovery of the plasma ACTH and cortisol levels. Ethanol consumption prior to the stress task attenuated (ACTH) or abolished (cortisol) the stress-induced increase in the plasma hormone concentrations of both LR and HR subjects. Thus, there are quantitative differences on the response of the HPA-axis to stress between HR and LR subjects, while ingestion of low amounts of ethanol prior to the performance of the stress task had a similar effect on HR and LR individuals.

Male mice of the BALB/c strain were given a solution of 15% ethanol as their only source of fluid for periods varying from 5 weeks to 8 months. For behavioral testing, they were compared with control groups which had received either an isocaloric solution of sucrose or tap water. Memory was tested by using spontaneous alternation behavior in a T maze. Each test consisted of two forced trials (acquisition) followed by a free trial (test) given at different acquisition--test intervals (from 30 s to 24 h). Results from two independent experiments showed that after 25 weeks of ethanol administration there was an accelerated rate of decay of spontaneous alternation as a function of the acquisition--test interval. Such a phenomenon persisted after ethanol was omitted from the diet. A third experiment showed that when tested on two successive sessions separated by a 5 h interval, experimental subjects exhibited a decreased ability to perform normally on the second test. Our data are interpreted as showing that long-term ethanol administration results in accelerated forgetting and increased vulnerability to proactive interference and, as such, they are compared to the memory dysfunctions observed in amnesic patients.

Using two inbred strains of mice which have similar rates of alcohol metabolism, we asked whether prenatal alcohol exposure would cause greater incidence and severity of defects in the development of two forebrain fiber tracts, the corpus callosum and the anterior commissure, in mice prone to these defects (BALB/c) than in mice not prone to these defects (C57BL/6). Pregnant animals were fed 0.6 kcal/g body weight of a Sustacal-based liquid diet containing 0, 15, 17.5, 20, or 25% ethanol-derived calories from day 7 to fetal assessment on day 18 of gestation. Most of alcohol's greatest effects and the greatest strain differences in alcohol's effects on fetal variables were produced by the 17.5% diet. This dose had inhibitory effects on fetal body, brain, and midsagittal corpus callosum and anterior commissure growth. All these effects, except that on brain weight, were significantly greater in C57s than in BALBs. When the results were compared with prenatal growth curves for normal untreated mice, the effect of alcohol on corpus callosum but not anterior commissure growth was largely explained by its effects on overall development. The 17.5% diet had a greater specific effect on size of the anterior commissure in C57s than BALBs but increased the incidence and severity of its permanent dysmorphology in BALBs more than in C57s. Anterior commissure size and morphology may be sensitive indicators of alcohol's effects on prenatal brain development. Hereditary differences in rate of maternal alcohol metabolism no doubt have important consequences for risks arising from prenatal alcohol exposure. However, this study clearly indicates that inherited factors, other than those that influence rate of alcohol metabolism, are important influences on the overall fetal response and the specific responses of the anterior commissure to prenatal alcohol exposure.