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Long-Evans and Sprague-Dawley rats show differential behavioral responses to cocaethylene, a metabolite derived from the simultaneous ingestion of ethanol and cocaine. Such differences may also be manifested when these outbred strains are exposed to ethanol and cocaine. To test this hypothesis, both strains were fed an ethanol-diet (8.7% v/v) in conjunction with cocaine (15 mg/kg) injections for 15 days. The following parameters were evaluated: (a) ethanol consumption, (b) cocaine-induced behavioral activity, (c) blood ethanol levels, (d) blood, liver, or brain cocaine and cocaethylene levels, and (e) liver catalase and esterase activity. We found that Long-Evans rats drank significantly more of the ethanol diet relative to the Sprague-Dawley line during the first few days of the test session. This rat phenotype also differed significantly from the Sprague-Dawley line in terms of behavioral activity after cocaine administration. Blood ethanol levels did not differ between strains. Similarly, we failed to detect strain-dependent differences in blood, liver, or brain cocaine levels as measured by gas chromatography/mass spectrometry. Cocaethylene levels, however, were higher in blood and brain of Long-Evans relative to Sprague-Dawley cohorts. Although the ethanol-cocaine regimen produced a marked suppression of catalase and esterase activity compared with control-fed rats, this suppression was roughly equivalent in both rat phenotypes. These data are discussed in the context of genotypic background and vulnerability to polysubstance abuse.

Ethanol exposure during fetal development can result in behavioral and neurological deficits, including reduced cognitive functions, retarded growth, and craniofacial abnormalities. Adenosine is an endogenous neuromodulator that fine-tunes the release and/or synaptic activities of several neurotransmitters, including glutamate, dopamine, and serotonin. Our aim was to determine whether ethanol exposure during early development affects adenosine receptors, particularly the A1 receptor subtype, in adult rats. Female rats were given water or 15% (vol/vol) ethanol in water prior to mating and throughout gestation and lactation. Sixty-day-old male rat offspring from these dams were randomly selected and assayed for adenosine A1 receptor expression in four brain areas: cortex, cerebellum, hippocampus, and striatum. Our results indicate that ethanol intake by dams decreased body and brain weights of offspring and reduced both A1 receptor mRNA and protein density in cortex and cerebellum. These preliminary findings indicate that ethanol intake by dams during pregnancy and lactation can affect adenosine A1 receptor signalling in the offspring. A pair-fed controlled study is warranted to explore these findings further.

Previous research from our laboratory has shown that exposure to chronic psychosocial stress increased voluntary ethanol consumption and preference as well as acquisition of ethanol-induced conditioned place preference (CPP) in mice. This study was done to determine whether an enriched environment could have "curative" effects on chronic psychosocial stress-induced ethanol intake and CPP. For this purpose, experimental mice "intruders" were exposed to the chronic subordinate colony (CSC) housing for 19 consecutive days in the presence of an aggressive "resident" mouse. At the end of that period, mice were tested for their anxiety-like behavior using the elevated plus maze (EPM) test then housed in a standard or enriched environment (SE or EE respectively). Anxiety and ethanol-related behaviors were investigated using the open field (OF) test, a standard two-bottle choice drinking paradigm, and the CPP procedure. As expected, CSC exposure increased anxiety-like behavior and reduced weight gain as compared to single housed colony (SHC) controls. In addition, CSC exposure increased voluntary ethanol intake and ethanol-CPP. Interestingly, we found that EE significantly and consistently reduced anxiety and ethanol consumption and preference. However, neither tastants' (saccharin and quinine) intake nor blood ethanol metabolism were affected by EE. Finally, and most importantly, EE reduced the acquisition of CPP induced by 1.5g/kg ethanol. Taken together, these results support the hypothesis that EE can reduce voluntary ethanol intake and ethanol-induced conditioned reward and seems to be one of the strategies to reduce the behavioral deficits and the risk of anxiety-induced alcohol abuse.

AbstractThe present study was undertaken to assess the influences of chronic maternal ethanol consumption, prior to and during gestation, on the development of synaptic plasma membranes (SPMs) and on the synthesis of SPM glycoproteins in offspring. Comparisons were made between animals whose mothers were pair‐fed a control or 6.6% (v/v) ethanol liquid diet in which protein accounted for either 18% (original) (C & E) or 21% (revised) (*C & *E) of the calories. In addition, groups of pups that were either cross‐fostered (*C & *E) with chow‐fed surrogate mothers or reverse cross‐fostered (offspring of chow‐fed mothers with *C & *E mothers) were examined. Ethanol and matched (same dietary group) control pups had comparable brain and body weights, brain protein content, and yield of SPM proteins during the 10–24 day age period examined. However, the yield of SPM proteins from ethanol and control offspring of and/or reared by the three groups of rat mothers that received the *E and *C liquid diets was greater than that of the offspring of rats that were fed the original diets. This suggests that the original diets were not nutritionally adequate for pregnant rats. Despite the fact that the content of SPM proteins was comparable in ethanol and matched control pups, the offspring of ethanol‐treated rats had an abnormal distribution of [3H]‐or [14C]‐fucose‐derived radioactivity among SPM glycoproteins. The SPM abnormalities were most severe in the non‐cross‐fostered offspring of E rats. No SPM glycoprotein abnormalities were found in the reverse cross‐fostered group. The results of the present study demonstrate that chronic maternal ethanol consumption prior to parturition has a severe effect on the synthesis of SPM glycoproteins in developing offspring without affecting the content of SPMs per se. It also demonstrates the importance of optimizing the composition of liquid diets used to feed pregnant rats.

Rats exposed to unexpected reward loss increase voluntary oral consumption of ethanol. Such consumption has been assumed to attenuate loss-induced negative affect (called emotional self-medication). To test this assumption, food-deprived male Wistar rats were exposed to 10 sessions of access to 32% sucrose followed by 5 sessions of access to 4% sucrose (reward downshift). A two-bottle preference test was initiated immediately after each consummatory session to assess ethanol intake. The experimental group received access to 2% ethanol and water, whereas the control group received access to two water bottles. On sessions 11, 12, and 15, immediately after the preference test, animals were tested in the elevated plus maze (EPM) for signs of anxiety. Sucrose consumption was reduced after the 32-to-4% sucrose downshift on sessions 11 and 12, but behavior recovered by session 15. Consummatory suppression was followed by increased ethanol intake in the preference test after sessions 11 and 12, but intake was reduced to preshift levels by session 15; no changes were observed in water controls. Finally, general activity (closed-arm entries and total arm entries) in the EPM increased in the ethanol group on session 12, but not on session 15, relative to water controls. The increase in ethanol consumption induced by reward downshift had measurable effects on activity as assessed in the EPM. These results show that voluntary oral 2% ethanol consumption after reward downshift can affect subsequent behavior, but fall short of providing unambiguous evidence that such ethanol consumption reduces negative affect.

This study was conducted to determine the temporal and regional vulnerability of the brain as a function of exposure to alcohol during brain development. Our goal was to manipulate the timing of alcohol exposure and assess the relative risk of cell loss in two different brain regions. Groups of timed pregnant Sprague‐Dawley rats received binge‐like alcohol exposure during either the first 10 days (first‐trimester equivalent) or second 10 days of gestation (second‐trimester equivalent), or the combination of first‐ and second‐trimester equivalents for prenatal treatments. Offspring from some of the animals exposed to alcohol during the combined first‐ and second‐trimester equivalent were reared artificially from postnatal days (P) 4 through 9 (part of the third‐trimester equivalent) and also received binge‐like alcohol during this period, producing animals that were exposed to alcohol during all three trimesters equivalent. Offspring from untreated dams were also reared artificially and received alcohol from only P4‐9, thus creating animals that were exposed to alcohol only during part of the third‐trimester equivalent. All pups were perfused on P10. Appropriate controls (nutritional and normally reared) were matched to every alcohol treatment combination. Peak blood alcohol concentrations were not different among the treatment groups for a given sampling time. Total cell numbers in the cerebellum (Purkinje and granule cells) and the olfactory bulb (mitral and granule cells) were estimated by the unbiased stereological technique, the optical disector. In terms of temporal vulnerability, alcohol exposure during the equivalent of all three trimesters resulted in a greater reduction in cerebellar Purkinje cell numbers compared with exposure to alcohol during the third‐trimester equivalent, whereas both groups had a significant reduction in cell number compared with all other timing groups. Cerebellar granule cell number was reduced after alcohol exposure during all three trimesters equivalent, compared with all other timing groups. Alcohol exposure during the third‐trimester equivalent resulted in a decrement in the number of olfactory bulb mitral cell numbers compared with all other groups, but there were no differences among the timing groups in numbers of olfactory bulb granule cells. When the cell loss in the two regions was compared within each alcohol treatment group to determine the relative regional vulnerability, the primary salient finding was that cerebellar Purkinje cells were more vulnerable to alcohol‐induced loss subsequent to exposure during all three trimesters equivalent. No other regional differences were detected. These results extend earlier findings by showing that alcohol exposure during different periods of brain development results in regional differences in cell loss as a function of the timing of alcohol exposure during brain development and illustrate the variability of alcohol‐induced neuronal loss.

Obesity is a significant risk factor in the pathogenesis of obstructive sleep apnoea (OSA) altering airway anatomy and collapsibility, and respiratory control. The association between obesity and OSA has led to an increasing focus on the role of weight loss as a potential treatment for OSA. To date, most discussion of obesity and OSA assumes a one-way cause and effect relationship, with obesity contributing to the pathogenesis of OSA. However, OSA itself may contribute to the development of obesity. OSA has a potential role in the development and reinforcement of obesity via changes to energy expenditure during sleep and wake periods, dietary habits, the neurohormonal mechanisms that control satiety and hunger, and sleep duration arising from fragmented sleep. Thus, there is emerging evidence that OSA itself feeds back into a complex mechanism that leads either to the development or reinforcement of the obese state. Whilst current evidence does not confirm that treatment of OSA directly influences weight loss, it does suggest that the potential role OSA plays in obesity and weight loss deserves further research.

Prenatal ethanol exposure can cause a number of physiological deficits known as fetal alcohol syndrome (FAS). Because protein kinase C (PKC) regulates the cell cycle and has been linked to growth, we examined the effect of ethanol on PKC isoform expression in a developing chick brain. Ethanol exposure causes decreased head weight in chickens at day 5 in a dose-dependent manner and a decreased brain weight at days 7 and 10 at an ethanol concentration of 1.0 g/kg. Antibodies specific for PKC-alpha, beta, gamma, delta, epsilon, iota, lambda, mu and zeta were used to examine ethanol's effect on PKC expression in the growth-suppressed brain at days 5, 7 and 10 of development. Only four of the PKC isoforms tested are expressed in the chick brain prior to day 10: alpha, gamma, epsilon, and iota. PKC-alpha, gamma, and epsilon are developmentally increased during the time period studied. Ethanol causes a decreased expression of PKC-alpha on days 5, 7 and 10 and a decreased expression of PKC-gamma on days 7 and 10. Ethanol causes a decreased expression of PKC-epsilon only on day 7. PKC-iota expression is unchanged over the developmental times studied and ethanol exposure has no effect on PKC-iota expression. These data suggest that only specific PKC isoforms are developmentally expressed in the embryonic chick brain and that ethanol may inhibit the expression of those PKC isoforms that are developmentally regulated.