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The objective of this study was to examine the effects of intraperitoneal injection of ethanol on the activity of the dorsal raphe nucleus (DRN) serotonin (5-hydroxytryptamine [5-HT]) system and its projections to the rostral caudate putamen (CPu) and determine whether rapid tolerance to the effects of ethanol develops in this system. Adult, male, Wistar rats were used in these experiments. In experiment 1, a microdialysis procedure was used to determine (a) the effects of acute intraperitoneal administration of ethanol (1.75 and 2.5 g/kg) on the extracellular levels of 5-HT in the rostral CPu and (b) whether rapid tolerance develops to these effects. In experiment 2, firing rates of 5-HT neurons were determined in the DRN after intraperitoneal administration of 2.5 g/kg of ethanol. The results of the microdialysis experiments indicated that the 2.5-g/kg dose significantly (P < .005) increased the extracellular levels of 5-HT to 150%-160% of baseline. Compared with findings for rats pretreated with saline 24 h earlier, prior treatment 24 h earlier with 2.5 g/kg of ethanol had no effect on the extracellular levels of 5-HT produced by a challenge dose of 2.5 g/kg of ethanol. Contrary to the effects in the CPu, intraperitoneal administration of 2.5 g/kg of ethanol significantly (P<.005) decreased the firing rates of 5-HT neurons in the DRN to approximately 50% of control. Overall, the results suggest to us that there is a dissociation between the effects of acute administration of ethanol on 5-HT cell body neuronal activity and 5-HT synaptic activity. The higher extracellular levels of 5-HT in the CPu may be due to increased release of 5-HT from a direct or an indirect action of ethanol, a result of inhibiting 5-HT reuptake, or related to both of these mechanisms. In addition, the findings suggest to us that rapid tolerance did not develop to the effects of ethanol on the 5-HT system within the CPu.

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BACKGROUND: Selectively-bred alcohol-preferring (P) rats have fewer serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) than do alcohol-nonpreferring (NP) rats. The present study was designed to test the hypothesis that the remaining 5-HT neurons in P rats compensated for their reduced number by increasing neuronal activity. METHODS: Spontaneous activity was recorded from single-spiking and bursting 5-HT neurons in the DRN of unanesthetized paralyzed, alcohol-naive P, NP, and Wistar rats. Firing frequencies, the percentages of action potentials in bursts, and the percentages of bursting neurons were evaluated. RESULTS: There were no significant differences among the three groups of rats in any of the parameters measured. Power analyses were performed on preliminary data to determine the sample sizes necessary for detection of significant differences. The mean firing frequencies of single-spiking 5-HT neurons averaged 1.8 (37 neurons), 1.7 (17 neurons), and 1.8 (41 neurons) spikes per second in P, NP, and Wistar rats, respectively. For bursting 5-HT neurons, the percentages of action potentials in bursts for P, NP, and Wistar rats were 55.0% (24 neurons), 49.7% (18 neurons), and 55.1% (21 neurons). The mean percentages of bursting 5-HT neurons encountered per electrode penetration were 44% for P rats (n = 28), 44% for NP rats (n = 14), and 34% for Wistar rats (n = 26). CONCLUSIONS: The results indicate that the sample of 5-HT neurons recorded in the DRN of P rats had not compensated for a reduced number by altering neuronal activity.

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The mesolimbic dopamine (DA) system is innately deficient in rats selectively bred for high alcohol drinking behavior compared with rats selectively bred for low alcohol drinking and unselected rats. In alcohol-preferring (P) rats, compared with alcohol-nonpreferring (NP) rats, this is evidenced by fewer DA neurons in the ventral tegmental area (VTA) projecting to the nucleus accumbens (ACB). Yet, despite this deficiency, DA release in the ACB is similar in P, NP, and Wistar rats. DA release is regulated by DA neuronal activity, and DA neurons fire tonically as well as in bursts. Burst firing has been shown to substantially enhance DA release compared with tonic firing. The present study was designed to test the hypothesis that the remaining VTA DA neurons in P rats have faster firing frequencies and/or burst fire more frequently than VTA DA neurons in Wistar rats. The spontaneous activity of VTA DA neurons was recorded in unanesthetized alcohol-naive P and Wistar rats. A conventional burst analysis on 500 consecutive action potentials revealed that P rats had a significantly (p < 0.05) greater percentage of action potentials in bursts when compared with Wistar rats (P: 50.9%, Wistar: 34.4%). Firing frequency and other burst parameters (burst interspike interval, burst length, interburst interval, and the number of action potentials per burst) did not distinguish the two groups of rats. The increased burst activity in P rats may represent a compensatory mechanism to maintain adequate basal levels of DA despite the deficiency in the mesolimbic DA system.

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Previous studies have demonstrated a higher mean peak frequency of the hippocampal (HPC) theta rhythm during REM sleep in alcohol-nonpreferring (NP) rats when compared with alcohol-preferring (P) rats. Burst firing neurons of the medial septal area (MS/VDB) are thought to pace the HPC theta rhythm during REM sleep and ambulation. Therefore, extracellular action potentials of MS/VDB burst firing neurons and HPC-CA1 field potentials were recorded simultaneously in ambulating P and NP rats. These recordings revealed that the mean peak frequency of the HPC theta rhythm during ambulation was higher in NP rats (7.62 +/- 0.12 Hz) as compared with P rats (7.21 +/- 0.14 Hz) (P < 0.05). Consistent with the difference in the HPC theta rhythm, the burst pattern of MS/VDB neurons exhibited a shorter inter-burst interval in the NP rats (NP 82.4 +/- 5.4 ms, P 97.4 +/- 8 1 ms P < 0.05). The difference in the inter-burst interval was confirmed by the distribution of inter-spike intervals in cumulative inter-spike interval histograms and the frequency of peaks in the mean cumulative autocorrelation histograms for P and NP rats. The mean cumulative autocorrelation histograms for P and NP rats also revealed that the regularity of the burst pattern in NP rats was sustained over a longer time period as determined by the decay constant. The cross-correlation of MS/VDB burst activity and the HPC theta rhythm showed a strong relationship between the two signals in P and NP rats. In both P and NP rats, two similar phase relationships were observed between MS/VDB bursting neurons and the HPC theta rhythm. These findings are in agreement with the hypothesis that MS/VDB burst firing neurons are responsible for the variation in the HPC theta rhythm between the two lines. Other mechanisms consistent with these findings are also discussed.

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Blockade of GABAA receptor function in the area of the anterior basolateral amygdala of rats elicits physiological (increases in heart rate and blood pressure) and behavioral changes similar to symptoms of human anxiety states. Repeated subthreshold blockade of GABAA receptors in this region appears to result in a long-term 'priming' of these anxiety-like responses. The present study was conducted to characterize the 'priming' of the heart rate and blood pressure responses and to test if these 'primed' animals would show increases in anxiety responses. Male Wistar rats with arterial catheters placed for physiological measurements were implanted with chronic microinjection cannulae in the anterior basolateral amygdaloid nucleus (BLA) under pentobarbital anesthesia. Repeated daily injections of a subthreshold dose of bicuculline methiodide (GABAA receptor antagonist; BMI) into the BLA elicited 'priming' of physiological responses after 3-5 injections and this response was maintained for at least 6 weeks. The primed animals also showed increased anxiogenic responses to GABAA blockade in the BLA. The 'priming' of anxiety responses were clearly elicited before kindling of seizures as measured by EEG. These results suggest that this 'priming' phenomenon may be similar to kindling and long-term potentiation. This could be one potential mechanism for developing pathological emotional responses, such as chronic, high levels of anxiety.

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The activity of alcohol dehydrogenase is higher in the livers of female rats than that in male rats. Stereotaxic lesions of the anterior periventricular hypothalamus of male rats increased the activity of alcohol dehydrogenase by about 50 percent; larger lesions which destroyed many of the major hypothalamic nuclei increased the enzyme activity 100 percent and abolished the sexual difference in alcohol dehydrogenase activity. The changes in enzyme activity were independent of changes in plasma thyroxine, testosterone and estradiol levels. Hypothalamic lesions in female rats had no effect on the enzyme activity. The sexual difference in alcohol dehydrogenase activity in rats is under hypothalamic control and does not appear to be mediated directly by the plasma level of androgens or estrogens.

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L-aspartate and L-glutamate were microiontophoretically applied onto Purkinje cells and unidentified cerebellar neurons of urethane-anesthetized rats. Both amino acids produced a dose-dependent increase in the spontaneous firing rate of all cells tested. Fifty-three percent (8 of 15 cells) of the dose-response relationships for L-aspartate as compared to those for L-glutamate on Purkinje cells were not parallel, implying different mechanisms of action (suggesting different receptors). On these 8 Purkinje cells, L-glutamate was three times more potent than L-aspartate. Only thirty-three percent of the dose-response relationships (8 of 24 cells) for the two agents on the unidentified cerebellar cells were not parallel. There was no statistical difference in the potency of L-aspartate as compared to L-glutamate on these particular cells. Tests for antagonism on Purkinje cells revealed L-glutamic acid diethyl ester (GDEE) to be a more effective blocker of L-aspartate than of L-glutamate while DL-alpha-aminoadipic acid (DL alpha AA)) was not selective in antagonizing the action of either amino acid. These data are discussed in terms for L-aspartate functioning as a neurotransmitter in the cerebellum of rat and possessing receptor sites distinct from those for L-glutamate.

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The microiontophoretic application of taurine and GABA was studied in the cerebellar cortex of the rat. Both taurine and GABA produced a dose-dependent depression of spike frequency of cerebellar neurons. GABA (2-42 nA, mean 27 nA) induced an inhibition of spike discharge on all 138 cells tested, including 29 Purkinje cells. Taurine (60-200 nA, mean 108 nA) induced an inhibition of spike discharge on 93 of the 106 cerebellar neurons tested, including inhibition on 22 of 25 Purkinje cells. Iontophoretic application of bicuculline and picrotoxin antagonized the inhibitory effects of both GABA and taurine on Purkinje cells as well as on cerebellar neurons in general. Strychnine did not antagonize the inhibition of either GABA or taurine. Simultaneous application of taurine and GABA produced a synergistic inhibitory effect on the firing rate of Purkinje cells. Taurine, in contrast to GABA, appeared to be more depressant when applied in the Purkinje cell dendritic zone than when applied near the soma. The data are discussed in terms of taurine functioning as a neurotransmitter in the cerebellum of the rat and having receptor sites distinct from those for GABA.

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