Withdrawal from chronic ethanol increases the sensitivity of presynaptic 5-HT1A receptors modulating serotonin and dopamine synthesis in rat brain in vivo (original) (raw)
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Behavioral effects induced by 8-hydroxy-2-(din -propylamino)tetralin (8-OH-DPAT; i.e., lower lip retraction, flat body posture, and forepaw treading) were examined in rats during ethanol withdrawal following a 2-week period of access to a liquid diet containing 9% (v/v) ethanol. After an 18 h withdrawal period, tolerance to 8-OH-DPAT-induced fiat body posture and, conversely, sensitization to the effects of 8-OH-DPAT on lower lip retraction were observed in the 9% ethanol group as compared to control rats fed an isocaloric diet. In contrast, 8-OH-DPAT-induced forepaw treading in the 9% ethanol group was not significantly different in comparison to control rats. Plasma corticosterone levels were significantly higher in the ethanol-exposed group than in control animals, an effect which was not additive with the increase in corticosterone levels normally observed after the administration of low doses of 8-OH-DPAT. Altered flat body posture and lower lip retraction responses to a submaximal dose of 8-OH-DPAT (2.5 mg/kg i.p.) were still observed as late as 3 days after withdrawal of the 9% ethanol liquid diet, but were no longer apparent at 7 days. Interestingly, prominent ethanol withdrawal signs such as tremor and rigidity, while occurring on the first day, were completely absent on the third day. Taken together, these results indicate that chronic ethanol exposure differentially alters sensitivity to several pharmacological effects of the 5-HTaA receptor ligand 8-OH-DPAT. They further support the involvement of 5-HT (5-hydroxytryptamine, serotonin) systems in alcohol abuse and therapeutic interventions using 5-HTlA ligands.
Acute and chronic actions of ethanol on CA1 hippocampal responses to serotonin
Brain Research, 1996
The effects of acute or chronic ethanol on serotonin (5-HT)-induced membrane hyperpolarization and inhibition of the slow Ca2+-dependent after hyperpolarization (sAHP) were recorded in rat CA1 pyramidal neurons in hippocampal slices using sharp intracellular electrodes. 5-HT (1-100 txM) caused concentration-dependent hyperpolarization of the membrane that was not altered by simultaneous 30 mM ethanol treatment, but blunted by 10 ixM buspirone, a weak 5-HT1A agonist. 5-HT (1-30 I-~M) also partially inhibited (~ 40%) the sAHP following a burst of five or more action potentials. Initially ethanol (30 raM) alone did not alter the sAHP, but over a period of 38 min, a slow increase in amplitude (~ 40%) was observed. 5-HT-mediated inhibition of the sAHP was significantly greater with ethanol present, regardless of the length of exposure. Pyramidal neurons in hippocampal slices prepared from ethanol-dependent animals showed no obvious signs of withdrawal related hyperexcitability and neither concentration-dependent membrane hyperpolarization nor sAHP inhibition caused by 5-HT were significantly changed from responses in controls. These results suggest that hyperpolarizing responses to 5-HT in hippocampal CA1 pyramidal neurons are functionally resistant to acute or chronic ethanol treatment. 5-HT-mediated inhibition of the sAHP is enhanced by ethanol acutely, but does not show an adaptive change as a result of ethanol dependence.
Chronic Ethanol Administration Decreases 5-HT and Increases 5-HIAA Concentration in Rat Brain
Acta Pharmacologica et Toxicologica, 1980
The effect of acute and chronic ethanol administration on cerebral 5-hydroxytryptamine (5-HT) and 5hydroxyindoleacetic acid (5-HIAA) concentrations of male Sprague-Dawley and Wistar rats was studied. Acute ethanol administration caused a slight fall (by 13%) in 5-HT concentration and a slight increase (by 10%) in 5-HIAA concentration one hour after administration. In chronically treated rats the whole brain 5-HT concentration was decreased by 9% during ethanol intoxication. This fall was significant in the part of brain containing diencephalon, mesencephalon and telencephalon except cortex (by 23%; P<O.Ol) and in that containing pons and medulla oblongata (by 37%; P<O.OOI) but not in cerebral cortex. The cerebral 5-HIAA concentrations of chronically treated Wistar and Sprague-Dawley rats were increased during intoxication (4-6 hrs after last ethanol administration) and even more during withdrawal (16-18 hrs after last ethanol administration, by 24-58%; P<O.O5-0.01). The increase was observed in all three parts into which the brain of Wistar rats were dissected. Because ethanol did not further increase the probenecid induced elevation of cerebral 5-HIAA concentration, our results suggest that ethanol increases the cerebral 5-HIAA concentration by attenuating its removal from the brain.
Psychopharmacology, 2006
Rationale-Anxiety-like behavior resulting from repeated withdrawals from chronic ethanol diets is counteracted by systemic administration of a 5-HT 2C receptor antagonist or a 5-HT 1A receptor partial agonist. Objectives-This study investigated whether prior treatment with these agents into the amygdala, dorsal raphe nucleus, nucleus accumbens, or paraventricular nucleus during early withdrawals would ameliorate the social interaction deficits observed after a subsequent withdrawal. Methods-Sprague-Dawley rats were exposed to three cycles of 5 days of forced ethanol diet (4.5%, w/v), with 2 days of control diet after the first and second cycles. Drugs were administered into one of four brain sites 4 h after removal of ethanol on the first and 2nd cycles but not the third.
Role of 5-hydroxytryptamine 1B (5-HT1B) receptors in the regulation of ethanol intake in rodents
Journal of Psychopharmacology, 2012
Evidence indicates that the serotonergic system is important in mediating dependence on and craving for alcohol. Among serotonin receptors, 5-hydroxytryptamine 1B (5-HT1B) receptors have been associated with drug abuse including alcohol. In this review, the neurocircuitry involving 5-HT1B receptors in central reward brain regions related to alcohol intake are discussed in detail. Emphasis has been placed on the pharmacological manipulations of 5-HT1B receptor-mediated alcohol intake. Furthermore, 5-HT1B auto- and hetero-receptors regulate alcohol intake through the regulatory mechanism involving release of 5-HT, gamma-aminobutyric acid (GABA), dopamine, and glutamate is evaluated. Thus, interactions between 5-HT1B receptors and these neurotransmitter systems are suggested to modulate alcohol-drinking behavior. This review on the role of 5-HT1B receptors in neurotransmitter release and consequent alcohol intake provides important information about the potential therapeutic role of 5-...
The effects of chronic ethanol self-administration on hippocampal 5-HT1A receptors in monkeys
Drug and Alcohol Dependence, 2014
Background: Chronic alcohol consumption reduces brain serotonin and alters the synaptic mechanisms involved in memory formation. Hippocampal 5-HT 1A receptors modulate these mechanisms, but the neuroadaptive response of 5HT 1A receptors to chronic alcohol self-administration is not well understood. Methods: Hippocampal tissue from monkeys that voluntarily self-administered ethanol for 12 months (n = 9) and accompanying controls (n = 8) were prepared for in vitro receptor autoradiography and laser capture microdissection. The 5-HT 1A receptor antagonist, [ 3 H]MPPF, and the agonist, [ 3 H]8-OH-DPAT, were used to measure total and G-protein coupled 5-HT 1A receptors respectively. The expression of the genes encoding the 5-HT 1A receptor and its trafficking protein Yif1B was measured in microdissected dentate gyrus (DG) granule cells and CA1 pyramidal neurons. Results: An increase in G-protein coupled, but not total, receptors was observed in the posterior pyramidal cell layer of CA1 in ethanol drinkers compared to controls. Chronic ethanol self-administration was also associated with an up-regulation of total and G-protein coupled 5-HT 1A receptors in the posterior DG polymorphic layer. Changes in receptor binding were not associated with concomitant changes in 5-HT 1A receptor mRNA expression. Chronic ethanol self-administration was associated with a significant increase in Yif1B gene expression in posterior CA1 pyramidal neurons. Conclusions: Chronic, ethanol self-administration up-regulates hippocampal 5-HT 1A receptor density in a region-specific manner that does not appear to be due to alterations at the level of transcription but instead may be due to increased receptor trafficking. Further exploration of the mechanisms mediating chronic ethanol-induced 5-HT 1A receptor up-regulation and how hippocampal neurotransmission is altered is warranted.
Scientific Reports, 2018
Repeated episodes of binge-like alcohol consumption produce anxiety, depression and various deleterious effects including alterations in neurogenesis. While the involvement of the serotonin receptor 1 A (5-HT1A) in the regulation of anxiety-like behavior and neurogenesis is well documented, its contribution to alcohol withdrawal-induced anxiety and alcohol-induced deficits in neurogenesis is less documented. Using the Drinking-In-the-Dark (DID) paradigm to model chronic long-term (12 weeks) binge-like voluntary alcohol consumption in mice, we show that the selective partial activation of 5-HT1A receptors by tandospirone (3 mg/kg) prevents alcohol withdrawal-induced anxiety in a battery of behavioral tests (marble burying, elevated-plus-maze, open-field), which is accompanied by a robust decrease in binge-like ethanol intake (1 and 3 mg/kg). Furthermore, using triple immunolabelling of proliferation and neuronal differentiation markers, we show that long-term DID elicits profound def...
Chronic alcoholization alters the expression of 5-HTIA and 5-HTIB receptor subtypes in rat brain
The expression of central 5-HTIA and 5-HTIB receptors was studied in several brain areas of rats subjected to a 2-week period of chronic alcoholization, followed by 18 h withdrawal. Quantitative autoradiography indicated that the ethanol treatment provoked an increase (~ +30%) in the labeling by [3H]8-hydroxy-2-(din -propylamino)tetralin ([3H]8-OH°DPAT) and [3H]N-[2-[4-(2-methoxyphenyl)-l-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide ([3H]WAY-100635) of 5-HTIA autoreceptors in the dorsal raphe nucleus, accompanied by a concomitant decrease in the labeling of postsynaptic 5-HT1A receptors in the hippocampus (~-20%), anterior (~-30%) and posterior (~-32%) cortices. These changes were associated with a tendency toward an increase and decrease in 5-HT1A mRNA levels in the anterior raphe area and hippocampus, respectively, suggesting that the changes observed are due to modifications in 5-HT1A receptor protein synthesis. The autoradiographic labeling of 5-HTiB receptors by serotonin-O-carboxymethylglycyl[lZSI]iodotyrosinamide ([125I]GTI) was found to increase (+55%) in the globus pallidus of alcoholized rats. Interestingly, a significant increase (+ 57%) in 5-HTaB receptor mRNA levels was observed in the striatum, which contains cell bodies of neurons projecting into the globus pallidus. These data suggest that altered sensitivity of chronically alcoholized rats to 5-HTIA and 5-HTiB receptor ligands may result from alcohol-induced changes in the transcription of the genes encoding these receptors.