Comparison of the neurophysiological effects of allopregnanolone and ethanol in rats.

RATIONALE: The central nervous system actions of allopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one) and ethanol are at least partially mediated by modulation of gamma-aminobutyric acid (GABA)-A receptors. Although ethanol and allopregnanolone have similar behavioral effects, their macro-electrophysiological profiles have not been directly compared. OBJECTIVE: The purpose of this study was to compare the effects of allopregnanolone and ethanol on the electroencephalogram (EEG) and event-related potentials (ERPs). METHODS: Male Wistar rats were implanted with cortical and amygdalar electrodes. The rats were then administered allopregnanolone (0.0-10 mg/kg), ethanol (0.0-1.0 g/kg), or a combination of the two before recording. RESULTS: Allopregnanolone and ethanol had similar effects on ERPs. When administered alone, both decreased cortical P1-N1 ERP amplitude by 25-50% and N1 amplitude in the amygdala by 75-80%. Combined administration of ethanol (0.50 g/kg) and allopregnanolone (5.0 mg/kg), doses which were ineffective alone, decreased N1 amplitude in the amygdala by 60%. Allopregnanolone and ethanol had dissimilar EEG effects. Allopregnanolone increased high frequency power in the cortex and amygdala by 25-30%. Ethanol decreased cortical and amygdalar power in the same high frequency bands by 25-45%. Allopregnanolone, but not ethanol, also shifted cortical frequency in the 32- to 50-Hz band. Combined administration of allopregnanolone and ethanol had no effect on EEG power but enhanced allopregnanolone's effect on cortical frequency. CONCLUSIONS: These data suggest that allopregnanolone's macro-electrophysiological profile resembles barbiturates and benzodiazepines more than ethanol. Further, the interactions of allopregnanolone and ethanol appear complex, with multiple effects observed (enhancement or reversal) depending on the neurophysiological variable assessed.

Sex differences in development of morphine tolerance and dependence in the rat.

RATIONALE: Several investigators have shown that male rodents are more sensitive than females to morphine's antinociceptive effects. OBJECTIVE: The present study was conducted to determine whether this sex difference is stable after chronic morphine treatment. RESULTS: Acutely administered morphine produced significantly greater hotplate and tail withdrawal antinociception in males than in females. In contrast, there were no sex differences in morphine's hotplate or tail withdrawal effects under repeated (1-week interval) dosing conditions. In a separate group of rats, after 2 weeks of twice-daily morphine treatment (10-20 mg/kg per injection), the ED50 for morphine's antinociceptive effects increased approximately 6.9-fold in males versus only 3.7-fold in females; chronic morphine treatment also disrupted the estrous cycle of females. In a separate group of rats treated with 10 mg/kg morphine twice daily for 5 days, treatment with naloxone (1.0 mg/kg) on day 6 produced greater withdrawal scores in males than in females. CONCLUSIONS: These experiments demonstrate sex differences in development of tolerance to and dependence on morphine in the rat.

Increases in sucrose consumption, but not ethanol consumption, following ICV NPY administration.

Neuropeptide Y (NPY) is a centrally acting neuromodulator that influences both consummatory behaviors and anxiety. NPY's effects on feeding are primarily regulated through Y5 receptors in hypothalamic sites, whereas NPY-induced anxiolysis appears to be mediated by Y1 receptors in the amygdala. Recently, NPY has been postulated to play a role in the regulation of ethanol consumption. The present study assessed the influence of intracerebroventricular (ICV) administration of NPY on the consumption of 10% ethanol or 2% sucrose in rats. Male Wistar rats were trained to self-administer 10% ethanol using the sucrose-substitution procedure and then implanted with an intracerebroventricular (ICV) cannula. The effects of NPY (0-15 microg) on ethanol consumption and sucrose consumption were then examined. ICV NPY infusion had no significant effects on the consumption of 10% ethanol, however, NPY significantly increased the consumption of 2% sucrose, [F(1, 11) = 6.18, p = 0.03]. These data suggest that ethanol intake and sucrose intake are differentially regulated by NPY. It is hypothesized that ICV infusion of NPY may be affecting both Y1 and Y5 receptors producing increased consummatory drive and anxiolysis, two factors that have opposing effects on subsequent ethanol consumption. Therefore, additional studies including site specific injection of NPY will be necessary to provide further insight into the role of NPY on ethanol consumption.

Differences in neurophysiological indices of associative learning in alcohol-preferring and nonpreferring rats.

Alcohol-preferring (P) and -nonpreferring (NP) rats differ in baseline neurophysiological measures as well as in their neurophysiological responses to ethanol. In the present study, these lines of rats were assessed to determine whether they also differ in their neurophysiological responses during an associative learning paradigm. Male P and NP rats were implanted with electrodes in the frontal cortex, parietal cortex, and amygdala. Both groups were then exposed to an associative learning paradigm. During the first five sessions (conditioning phase), an infrequently presented tone was paired with the delivery of a food pellet. A second tone was also presented during these sessions, but this tone was never paired with food pellet presentation. During the second five sessions (extinction phase), neither of the tones were paired with food pellet presentation. Event-related potentials (ERPs) in response to the tones were recorded during both phases of the experiment. During the first session, the latency of the N1 and P3 waves from the cortical lead in response to the food-paired tone was significantly longer in the NP rats than in P rats. In addition, P rats displayed significant increases in the latency of the P2 wave component in the cortex and the P3A wave component in the amygdala in response to changes in the association between food pellet and tone presentation. These data indicate that the P rats were more responsive to changes in the association between food pellet delivery and tone presentation. They also suggest more enhanced associative learning in P rats than in NP rats. This enhanced learning could be an innate trait of P rats or the result of altered learning due to differences in anxiety between P and NP rats.

Effects of allopregnanolone on the EEG of alcohol-preferring and alcohol-nonpreferring rats.

BACKGROUND: Alcohol preferring (P) and alcohol-nonpreferring (NP) rats have been shown to have differing behavioral and electrophysiological responses to drugs that are positive modulators of the gamma-aminobutyric acid type A (GABA-A) receptor complex, such as ethanol and benzodiazepines. The neuroactive steroid allopregnanolone is also a positive modulator of GABA-A receptors; therefore, we hypothesized that P and NP rats would respond differently to intraperitoneally administered allopregnanolone. METHODS: Male P and NP rats were implanted with screw electrodes that overlay the frontal and parietal cortices and with a depth electrode aimed at the amygdala. Allopregnanolone (0.0-10.0 mg/kg ip) was administered 10 min before recording the EEG. RESULTS: Allopregnanolone increased high-frequency power (8-32 Hz) in the cortex and amygdala of both P rats and NP rats. In addition, allopregnanolone increased the predominant frequency of the cortical EEG in the 8 to 16 Hz bandwidth, decreased the predominant frequency in the 32 to 50 Hz bandwidth, and increased EEG variability (16-50 Hz). The effects of allopregnanolone were qualitatively similar in P and NP rats. However, P rats were more sensitive to low doses of allopregnanolone in cortex, whereas NP rats responded to lower doses of allopregnanolone in the amygdala. CONCLUSIONS: These data indicate that P and NP rats differ in their sensitivity to the EEG effects of allopregnanolone in the cortex and amygdala, which suggests that differences in GABAergic systems between P and NP rats may contribute to some of the differences observed in their behavioral repertoire.