Acute ethanol administration and acute allopregnanolone administration impair spatial memory in the Morris water task.
ABSTRACT Acute ethanol administration degrades performance on many learning and memory tasks, including tasks that are dependent on spatial information. One common test of spatial learning and memory is the Morris water task, a task that requires subjects to learn the spatial location of a submerged escape platform located in a pool of cloudy water. However, although some studies report that acute ethanol administration degrades spatial memory performance in the Morris task, other studies report no significant performance impairment. Acute ethanol administration also produces a dose- and time-dependent increase in the concentration of the endogenous neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) in rat brain. Given that ethanol and allopregnanolone are both gamma-aminobutyric acid type A receptor modulators, both drugs should produce similar degradations in spatial learning and memory.
Adult male rats were trained with either the spatial version or the nonspatial version of the Morris water task. After 4 days of training, the spatial or nonspatial memory performance of subjects was assessed after either an ethanol (1.0, 1.5, or 2.0 g/kg) or allopregnanolone (12.5, 17.0, or 20.0 mg/kg) challenge.
Acute ethanol administration and acute allopregnanolone administration impaired spatial memory performance in a dose-dependent manner in the Morris water task. In addition, the impairment was selective in that neither acute ethanol nor acute allopregnanolone administration impaired nonspatial memory performance in the Morris water task.
Acute ethanol administration and acute allopregnanolone administration impaired spatial memory performance but did not impair nonspatial memory performance in the Morris water task. These results demonstrate that both ethanol and allopregnanolone produce selective cognitive deficits that are not due to general sensory or motor deficits.
Article: Effect of 3α-anderostanediol and indomethacin on acquisition, consolidation and retrieval stage of spatial memory in adult male rats.[show abstract] [hide abstract]
ABSTRACT: Background: Testosterone and its metabolites have important roles in learning and memory. The current study has conducted to assess the effect of pre-training, post-training and pre-probe trial intrahippocampal CA1 administration of 3α-anderostanediol (one of the metabolites of testosterone) and indomethacin (as 3α-hydroxysteroid dehydrogenase enzyme blocker) on acquisition, consolidation and retrieval in Morris water maze (MWM) task. Methods: Adult male rats were bilaterally cannulated into CA1 region of hippocampus and then received 3α-diol (0.2, 1, 3 and 6 mug/0.5 mul/side), indomethacin (1.5, 3 and 6 mug/0.5 mul/side), indomethacin (3 mug/0.5 mul/side) + 3α-diol (1 mug/0.5 mul/side), 25-35 min before training, immediately after training and 25-35 min before probe trial in MWM task. Results: Our results showed that injection of 3α-diol and indomethacin significantly increased the escape latency and traveled distance to find hidden platform in acquisition and consolidation stage, but did not have any effect on retrieval of spatial learning as compared with the control group. Conclusion: It is concluded that intra-CA1 administration of 3α-diol and indomethacin could impair spatial learning and memory in acquisition and consolidation stage. Also, intrahippocampal injection of indomethacin + 3α-diol could not change spatial learning and memory impairment effect of indomethacin or 3α-diol in MWM task.Iranian biomedical journal 07/2012; 16(3):145-55.
Article: Low brain allopregnanolone levels mediate flattened circadian activity associated with memory impairments in aged rats.[show abstract] [hide abstract]
ABSTRACT: Sleep and cognitive impairments are two of the most prevalent neuropsychiatric disorders in the aged population. Age-related memory dysfunctions can result from alterations in sleep/wake circadian rhythm. However, the underlying mechanism of these alterations is unknown. Here, we demonstrate the role of alterations in brain steroid levels in age-related sleep-dependent memory impairment in rats. Sleep/wake circadian activity and spatial memory performance were evaluated in adult, middle-aged, and aged rats, and steroid levels were measured in brain structures involved in mediating sleep-dependent memory processes using gas chromatography/mass spectrometry. The causal relationship between circadian activity and allopregnanolone levels was assessed using an inhibitor of allopregnanolone synthesis (indomethacin). Similar to observations in humans, a subpopulation of middle-aged and aged rats show flattened amplitude of circadian activity associated with impaired spatial long-term memory performance. Sleep-dependent memory dysfunction was associated with a low level of allopregnanolone in the hypothalamus, pedunculopontine nucleus, and ventral striatum. Inhibition of allopregnanolone synthesis in young rats decreased allopregnanolone in the hypothalamus and produced flattened amplitude of circadian activity similar to aged rats. These findings identify brainstem and basal forebrain allopregnanolone as an essential endogenous substrate involved in mediating sleep-dependent memory function in young and aged rats. Allopregnanolone may play a critical role in preserving individuals from age-induced alterations in sleep and memory processes and may represent a novel target for attenuating age-related declines in sleep and memory.Biological psychiatry 11/2010; 68(10):956-63. · 8.93 Impact Factor
Article: Genetic analysis of the neurosteroid deoxycorticosterone and its relation to alcohol phenotypes: identification of QTLs and downstream gene regulation.[show abstract] [hide abstract]
ABSTRACT: Deoxycorticosterone (DOC) is an endogenous neurosteroid found in brain and serum, precursor of the GABAergic neuroactive steroid (3α,5α)-3,21-dihydroxypregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) and the glucocorticoid corticosterone. These steroids are elevated following stress or ethanol administration, contribute to ethanol sensitivity, and their elevation is blunted in ethanol dependence. To systematically define the genetic basis, regulation, and behavioral significance of DOC levels in plasma and cerebral cortex we examined such levels across 47 young adult males from C57BL/6J (B6)×DBA/2J (D2) (BXD) mouse strains for quantitative trait loci (QTL) and bioinformatics analyses of behavior and gene regulation. Mice were injected with saline or 0.075 mg/kg dexamethasone sodium salt at 8:00 am and were sacrificed 6 hours later. DOC levels were measured by radioimmunoassay. Basal cerebral cortical DOC levels ranged between 1.4 and 12.2 ng/g (8.7-fold variation, p<0.0001) with a heritability of ∼0.37. Basal plasma DOC levels ranged between 2.8 and 12.1 ng/ml (4.3-fold variation, p<0.0001) with heritability of ∼0.32. QTLs for basal DOC levels were identified on chromosomes 4 (cerebral cortex) and 14 (plasma). Dexamethasone-induced changes in DOC levels showed a 4.4-fold variation in cerebral cortex and a 4.1-fold variation in plasma, but no QTLs were identified. DOC levels across BXD strains were further shown to be co-regulated with networks of genes linked to neuronal, immune, and endocrine function. DOC levels and its responses to dexamethasone were associated with several behavioral measures of ethanol sensitivity previously determined across the BXD strains by multiple laboratories. Both basal and dexamethasone-suppressed DOC levels are positively correlated with ethanol sensitivity suggesting that the neurosteroid DOC may be a putative biomarker of alcohol phenotypes. DOC levels were also strongly correlated with networks of genes associated with neuronal function, innate immune pathways, and steroid metabolism, likely linked to behavioral phenotypes.PLoS ONE 01/2011; 6(4):e18405. · 4.09 Impact Factor