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ABSTRACT: Stress is an often-reported cause for alcohol consumption in humans. Acute intermittent footshock is a frequently used paradigm to produce stress in laboratory animals including mice. The effect produced by intermittent footshock stress on ethanol self-administration has been inconsistent: both increases and decreases in ethanol consumption have been reported. The current set of studies further investigates, in three commonly studied mouse strains, the effect of footshock stress on ethanol self-administration. Furthermore, the effect of footshock on plasma corticosterone levels was determined to investigate potential biochemical correlates. Adult male C57BL/6J, DBA/2J, and A/J mice were allowed to self-administer 10% (wt/vol) ethanol for 12 days in a standard 23-h two-bottle paradigm before receiving either 15 min of mild inescapable footshock or no footshock. Shock intensity was equal to the mean intensity at which each strain vocalized as previously determined. Following footshock, animals had the opportunity to self-administer ethanol for an additional 23 h. Separate animals were subjected to either footshock or no shock prior to collection of plasma for corticosterone. Mild footshock stress altered ethanol self-administration and increased plasma corticosterone levels in C57BL/6J mice. Footshock stress did not alter ethanol self-administration or plasma corticosterone levels in DBA/2J or A/J mice. These data demonstrate that mild footshock stress is a suboptimal method of modeling the stress-induced increases in ethanol consumption often reported by humans.
Alcohol 08/2008; 42(6):469-76. · 2.47 Impact Factor
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ABSTRACT: Chronic intermittent ethanol exposure (CIEE) in adolescent rats has been shown to produce long-lasting hypnotic, metabolic, and functional tolerance. Recently, it has been hypothesized that allopregnanolone mediates some effects of ethanol, including ethanol-induced impairments in the performance of the Morris Water Maze Task (MWMT). The current studies explore the relationship between cortical and hippocampal allopregnanolone levels and ethanol-induced impairments in the MWMT following CIEE treatment in adolescent rats. Adolescent rats were administered 5.0 g/kg ethanol or saline every 48 h for a 20-day period beginning on postnatal day (P) 30. Training in the spatial version of the MWMT occurred on nontreatment days. Following completion of CIEE treatment and training, MWMT performance was tested 30 min after ethanol (2.0 g/kg) or saline challenge on P 50 and P 62. A separate group of rats were CIEE treated and received an ethanol (2.0 g/kg) or saline challenge on P 50 or 62, and were used for hippocampal and cortical allopregnanolone determination. CIEE during adolescence produced tolerance to both ethanol-induced impairments in the MWMT and ethanol-induced allopregnanolone levels in the hippocampus on P 50. However, when animals were tested at P 62, the reduction in ethanol-induced MWMT impairments found in CIEE rats was reversed and allopregnanolone levels from both saline or ethanol challenge were increased above levels found in control animals. Taken together, these results suggest that CIEE during adolescence produces tolerance to ethanol-induced impairments in MWMT and corresponding changes in ethanol-induced allopregnanolone levels in the hippocampus. Furthermore, cognitive tolerance is reversible and time dependent, but the reversal of cognitive tolerance is not correlated with normalization of hippocampal allopregnanolone levels.
Alcohol 08/2006; 39(3):151-8. · 2.47 Impact Factor
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ABSTRACT: Systemic ethanol administration elevates plasma and brain levels of GABAergic neuroactive steroids, including 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) that contribute to specific behavioral actions of ethanol. The present study determined the effect of adrenalectomy and 5alpha-reductase type-1/type-2 enzyme inhibition, known to reduce neuroactive steroids, on ethanol-induced increases in cerebral cortical levels of 3alpha,5alpha-THP and hypnotic effects in male rats. Systemic ethanol administration to male rats increases plasma levels of progesterone and corticosterone similar to acute stress, indicating release of these steroids from adrenal glands. Adrenalectomy markedly reduced the elevation of cerebral cortical 3alpha,5alpha-THP and plasma progesterone levels and reduced the duration of ethanol-induced loss of righting reflex. Prior systemic administration of 5alpha-dihydroprogesterone (10 or 15 mg/kg, i.p.), an immediate precursor of 3alpha,5alpha-THP, to adrenalectomized rats not only restored the ethanol-induced increases in cerebral cortical 3alpha,5alpha-THP levels but also reversed the effect of adrenalectomy on ethanol-induced loss of righting reflex. Prior administration of the 5alpha-reductase inhibitor finasteride (2 x 25, 2 x 75 or 2 x 150 mg/kg, s.c.) and the 5alpha-reductase type-1 inhibitor SKF-105,111 (50 mg/kg, i.p.) did not reduce ethanol-induced increases in the cerebral cortical levels of 3alpha,5alpha-THP at hypnotic doses of ethanol. Furthermore, these drugs did not alter the duration of loss of righting reflex. However, significant correlations between cerebral cortical 3alpha,5alpha-THP levels and the duration of loss of righting reflex were obtained regardless of finasteride administration. These results demonstrate the contributory role of neuroactive steroids in the ethanol-induced loss of righting reflex and the source of ethanol-induced elevation of GABAergic neuroactive steroids. Ethanol-induced increases in neurosteroids could be pertinent to the etiology of sleep-related disorders associated with alcoholism.
Brain Research 09/2003; 980(2):255-65. · 2.73 Impact Factor
