The effects of chronic ethanol self-administration on hippocampal 5-HT1A receptors in monkeys (original) (raw)
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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 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.
Neuroscience Letters, 2002
The in vivo sensitivity of presynaptic 5-HT 1A receptors (autoreceptors and heteroreceptors) modulating the synthesis of 5-hydroxytryptophan/serotonin (5-HTP/5-HT) and 3,4-dihydroxyphenylalanine/dopamine (DOPA/DA) in rat brain was investigated after ethanol treatment and withdrawal. In saline-treated rats as well as in acute ethanol (2 g/kg, intraperitoneally (i.p.), 2 h)-and chronic ethanol (2 g/kg for 7 days)-treated rats, a low dose of the 5-HT 1A receptor agonist 8hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT; 0.1 mg/kg, i.p., 1 h) did not decrease the synthesis of 5-HTP in brain (except modestly in striatum; 20% after the chronic treatment) or that of DOPA in striatum. In contrast, in chronic ethanolwithdrawn rats (24 h), 8-OH-DPAT significantly decreased the synthesis of 5-HTP in the hippocampus (29%), cerebral cortex (41%) and striatum (33%) and that of DOPA in the striatum (28%). Similar effects were induced by the mixed 5-HT 1A agonist/D 2 antagonist buspirone (1 mg/kg, i.p., 1 h) which also decreased 5-HTP synthesis in the hippocampus (24%), cerebral cortex (36%) and striatum (35%) of chronic ethanol-withdrawn rats. These results indicate that chronic ethanol and more clearly the spontaneous withdrawal from chronic ethanol induce supersensitivity of 5-HT 1A -auto/heteroreceptors modulating the synthesis of 5-HT and DA in rat brain. q
Chronic voluntary ethanol intake hypersensitizes 5-HT 1A autoreceptors in C57BL/6J mice
Journal of Neurochemistry, 2008
Alcoholism is a complex disorder involving, among others, the serotoninergic (5-HT) system, mainly regulated by 5-HT 1A autoreceptors in the dorsal raphe nucleus. 5-HT 1A autoreceptor desensitization induced by chronic 5-HT reuptake inactivation has been associated with a decrease in ethanol intake in mice. We investigated here whether, conversely, chronic ethanol intake could induce 5-HT 1A autoreceptor supersensitivity, thereby contributing to the maintenance of high ethanol consumption. C57BL/6J mice were subjected to a progressive ethanol intake procedure in a free-choice paradigm (3-10% ethanol versus tap water; 21 days) and 5-HT 1A autoreceptor functional state was assessed using different approaches. Acute administration of the 5-HT 1A receptor agonist ipsapirone decreased the rate of tryptophan hydroxylation in striatum, and this effect was significantly larger (+75%) in mice that drank ethanol than in those drinking water. Furthermore, ethanol intake produced both an increased potency (+45%) of ipsapirone to inhibit the firing of 5-HT neurons, and a raise (+35%) in 5-HT 1A autoreceptormediated stimulation of [ 35 S]GTP-c-S binding in the dorsal raphe nucleus. These data showed that chronic voluntary ethanol intake in C57BL/6J mice induced 5-HT 1A autoreceptor supersensitivity, at the origin of a 5-HT neurotransmission deficit, which might be causally related to the addictive effects of ethanol intake.
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...
Pharmacological Reports, 2023
Background Serotonin (5-HT) 5-HT 2C receptor mRNA editing (at five sites, A-E), implicated in neuropsychiatric disorders, including clinical depression, remains unexplored during alcohol abstinence-often accompanied by depressive symptoms. Methods We used deep sequencing to investigate 5-HT 2C receptor editing in mice during early ethanol deprivation following prolonged alcohol exposure and mice lacking tryptophan hydroxylase (TPH)2, a key enzyme in central 5-HT production. We also examined Tph2 expression in ethanol-deprived animals using quantitative real-time PCR (qPCR). Results Cessation from chronic 10% ethanol exposure in a two-bottle choice paradigm enhanced immobility time and decreased latency in the forced swim test (FST), indicating a depression-like phenotype. In the hippocampus, ethanoldeprived "high ethanol-drinking" mice displayed reduced Tph2 expression, elevated 5-HT 2C receptor editing efficiency, and decreased frequency of the D mRNA variant, encoding the less-edited INV protein isoform. Tph2-/mice showed attenuated receptor editing in the hippocampus and elevated frequency of non-edited None and D variants. In the prefrontal cortex, Tph2 deficiency increased receptor mRNA editing at site D and reduced the frequency of AB transcript, predicting a reduction in the corresponding partially edited VNI isoform. Conclusions Our findings reveal differential effects of 5-HT depletion and ethanol cessation on 5-HT 2C receptor editing. Central 5-HT depletion attenuated editing in the prefrontal cortex and the hippocampus, whereas ethanol deprivation, coinciding with reduced Tph2 expression in the hippocampus, enhanced receptor editing efficiency specifically in this brain region. This study highlights the interplay between 5-HT synthesis, ethanol cessation, and 5-HT 2C receptor editing, providing potential mechanism underlying increased ethanol consumption and deprivation.
Alcohol, 2011
Serotonin 1B (5-HT 1B ) heteroreceptors on nucleus accumbens shell (NAcSh) projection neurons have been shown to enhance the voluntary consumption of alcohol by rats, presumably by modulating the activity of the mesolimbic reward pathway. The present study examined whether increasing 5-HT 1B receptors expressed on NAcSh projection neurons via viral mediated gene transfer enhances ethanol consumption during the initiation or maintenance phase of drinking and alters the temporal pattern of drinking behavior. Animals received stereotaxic injections of viral vectors expressing either 5-HT 1B receptor and green fluorescent protein or green fluorescent protein alone. Home cages equipped with a three-bottle (water, 6%, and 12% ethanol) lickometer system recorded animals' drinking behavior continuously, capturing either initiation or maintenance drinking behavior patterns. Overexpression of 5-HT 1B receptors during initiation increased consumption of 12% ethanol during both forced access and free choice consumption. There was a shift in drinking pattern for 6% ethanol with an increase in number of drinking bouts per day, although the total number of drinking bouts for 12% ethanol was not different. Finally, increased 5-HT 1B expression induced more bouts with very high frequency licking from the ethanol bottle sippers. During the maintenance phase of drinking, there were no differences between groups in total volume of ethanol consumed; however, there was a shift toward drinking bouts of longer duration, especially for 12% ethanol. This suggests that during maintenance drinking, increased 5-HT 1B receptors facilitate longer drinking bouts of more modest volumes. Taken together, these results indicate that 5-HT 1B receptors expressed on NAcSh projection neurons facilitate ethanol drinking, with different effects during initiation and maintenance of ethanol drinking behavior.
Chronic intermittent ethanol exposure alters CA1 synaptic transmission in rat hippocampal slices
Neuroscience, 1999
We investigated the neuroadaptive changes in synaptic transmission in the CA1 region of the hippocampus as a result of chronic intermittent ethanol exposure. Male Wistar rats were exposed daily (14 h) to ethanol vapors (blood alcohol levels 150-200 mg%) for 12-14 days, and synaptic field potentials elicited by Schaffer collateral stimulation were compared in hippocampal slices from control and chronic ethanol-treated rats. Excitatory postsynaptic responses of slices were recorded under three conditions: (i) normal physiological saline; (ii) continued presence of 33 mM (150 mg%) ethanol (chronic ethanol-treated rats only); (iii) acute exposure to 33 mM ethanol. When recorded in ethanol-free physiological saline, the mean amplitude of the dendritic synaptic potential and the somatic population spike were significantly smaller in slices from chronic ethanol-treated rats compared to slices from control rats. Under conditions of continuous ethanol exposure, somatic and dendritic synaptic responses of slices taken from chronic ethanol-treated rats were further depressed, suggesting that neural pathways in area CA1 remained sensitive to ethanol. Acute application of ethanol led to a more pronounced reduction of the mean somatic population spike amplitude in slices from chronic ethanol-treated rats than in slices from control rats. However, dendritic synaptic responses were unaffected by acute ethanol in slices from both control and chronic ethanol-treated rats. In addition, we examined the involvement of presynaptic mechanisms in the effects of chronic intermittent ethanol using paired-pulse protocols. When recorded in the continued presence of ethanol, slices from chronic ethanol-treated rats exhibited a significant reduction in paired-pulse facilitation of the dendritic synaptic response compared to slices from control rats, indicating a presynaptic component to the neuroadaptive effects of chronic intermittent ethanol exposure. Conversely, acute ethanol exposure resulted in an enhancement of paired-pulse facilitation of the dendritic synaptic response, an effect that was similar in slices from both control and chronic ethanol-treated rats. Paired-pulse facilitation of the somatic population spike amplitude was not altered by chronic ethanol treatment. However, acute ethanol exposure significantly enhanced paired-pulse facilitation of the somatic population spike in slices from chronic ethanol-treated rats. This effect of acute ethanol was not observed in slices from control rats. Paired-pulse inhibition was not significantly altered in slices from chronic ethanol-treated rats, suggesting that GABAergic inhibitory mechanisms were not involved in the neuroadaptive effects of chronic intermittent ethanol exposure. We suggest that chronic intermittent ethanol exposure can induce multiple neuroadaptive changes in synaptic transmission of CA1 pyramidal neurons that are detectable at both the pre-and postsynaptic levels. Alterations in paired-pulse facilitation indicate presynaptic changes involving the release of the excitatory neurotransmitter glutamate, whereas changes in dendritic synaptic responses suggest postsynaptic changes in the responsiveness of neurons to synaptic input. Moreover, differential effects of chronic ethanol treatment on synaptic responses recorded in the dendrites versus the somatic region implicate additional effects of ethanol on somatically located mechanisms of CA1 pyramidal neurons. Furthermore, we suggest that complete tolerance to ethanol does not occur in the CA1 region of the hippocampus following chronic intermittent ethanol exposure.
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.