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We recently conducted a study of the behavioral effects of combined cocaine and ethanol in genetically defined mice. Male and female C57BL/6 (B6) and DBA/2 (D2) were tested in an automated activity monitor on 2 consecutive days. On day 1, all animals received an IP injection of sterile saline and were placed into the activity monitor for 30 min. Behaviors measured were total distance traveled, stereotypy, nosepokes, and wall-seeking. On day 2, all animals were tested again for 15 min following injection of one of the following: saline, 10% v/v ethanol at 2.0 g kg(-1) or 2.0 g kg(-1) ethanol plus 5, 15, or 30 mg kg(-1) cocaine. Cocaine alone at the same doses was injected into separate groups of animals. For the B6 strain, the overall effect of ethanol was to reduce cocaine-induced locomotor stimulation; no consistent effect of ethanol on cocaine-induced locomotion was observed in D2 mice. Cocaine-induced inhibition of nosepokes in both strains and sexes was partially reversed by ethanol. Ethanol also partially reversed cocaine-elevated stereotypy in both strains and both sexes. In B6 mice, cocaine-increased wall seeking tended to be reversed by coadministration of ethanol, whereas no consistent pattern was observed in the D2s. Results from this study suggest that the several measures affected by cocaine (locomotor activity, stereotypy, exploration, thigmotaxis) were, in turn, differentially affected by concurrent treatment with ethanol. Furthermore, our results point to genetic-based differences in ethanol's effects on cocaine-related behaviors. We address the implications for combined ethanol and cocaine use in humans. more...

Objective: We recently investigated the effects of EtOH on the mesolimbic dopamine and serotonin systems in male and female C57BL/6 (B6) and DBA/2J (D2) mice., Method: Male and female rodents from the B6 and D2 mouse strains (n = 11 per strain, sex and dose) were used in this study. Doses of EtOH (vs saline) administered were 1.0, 2.0 or 3.0 g/kg., Results: Treatment with saline or EtOH produced both strain- and sex-dependent differences in patterns of monoamine response. For example, D2s exhibited significantly higher overall dopamine (DA) levels than did B6s in the frontal cortex (FC), nucleus accumbens (NA) and caudate-putamen (CP). In the FC, female D2 evinced elevated 5HIAA at 1.0 g/kg. In the NA, D2 females showed dose related increases in levels of DA up to 3.0 g/kg, whereas in the D2 males and in B6 males and females we observed no response. Also in the NA, B6 males showed increases in dihydroxyphenyacetic acid (DOPAC) at 1.0 and 3.0 g/kg. In the CP, B6 males showed higher DA levels than B6 females at the saline, and all EtOH doses. For serotoninergic activity in the CP as well as the NA, EtOH produced a distinctive triphasic response, with the 1.0 and 3.0 g/kg doses of EtOH producing higher levels than saline and 2.0 g/kg of 5HIAA in B6 males than in B6 females., Conclusions: Our findings indicate strain and sex differences in monoamine response to acute doses of ethanol, and further implicate (via changes in DOPAC) presynaptic mechanisms in the effects of ethanol on dopamine. more...

Carbon monoxide (CO) is considered to be a novel neuronal messenger in the brain, similar to nitric oxide. The ontogeny of CO formation in transverse hippocampal slices of the guinea pig was elucidated at selected prenatal and postnatal ages, and the effect of in vitro ethanol exposure on hippocampal CO formation was determined. There was a higher rate of hippocampal CO formation in the fetus at gestational day (GD) 50 and GD 62 (term, about GD 68) compared with the adult. In vitro ethanol exposure (50 and 100 mM) decreased hippocampal CO formation in the GD 62 fetus, which was prevented by incubation with 500 microM L-glutamate. more...

Heme oxygenase (HO) catalyzes the oxidation of heme to produce carbon monoxide, which is considered to be a novel neuronal messenger in the brain and may play a role in neuronal development. The objective of this study was to determine the effects of in vitro, acute in vivo, and chronic in vivo ethanol exposure on HO activity in the hippocampus, frontal cerebral cortex, and cerebellum of the near-term fetal guinea pig. HO activity was determined using a gas chromatographic method to quantitate CO formation in the microsomal fraction of the homogenate of each selected brain region, incubated with saturating concentrations of heme, NADPH, and O2. Fetal body, brain, hippocampal, and cerebellar weights were recorded. In vitro ethanol exposure (25-100 mM) did not affect hippocampal, cerebral cortical, or cerebellar HO activity of the fetal guinea pig at gestational day (GD) 62 (term, about GD 68). Acute maternal oral administration of 4 g ethanol/kg maternal body weight at GD 62 did not affect HO activity in these three fetal brain areas compared with control fetuses (maternal administration of isocaloric sucrose or water). For chronic daily maternal oral administration of 4 g ethanol/kg maternal body weight throughout gestation, fetal body, brain, hippocampal, and cerebellar weights were decreased at GD 62 compared with isocaloric-sucrose/pair-fed and water treatment control groups. Furthermore, isocaloric-sucrose/pair-feeding treatment decreased fetal body and brain weights compared with water treatment. Chronic in vivo ethanol exposure did not alter HO activity in the near-term fetal hippocampus, frontal cerebral cortex, or cerebellum. This is the first study of the effect of ethanol exposure on HO activity in the developing brain of any species. The data demonstrate, for ethanol CNS teratogenesis in the guinea pig manifesting as fetal brain growth restriction, there is no associated change in HO activity in the hippocampus, frontal cerebral cortex, or cerebellum. more...