Table 2.
Changes in 5-HTergic neuroplasticity following acute and chronic ethanol exposure
| Species | Model | Dose of ethanol | Route of administration | BEC | Duration oftreatment | Results | Ref # |
| Wistar rats | Acute injection or reverse microdialyse | 0.5, 1 or 2 g/kg (injection) or 25, 50 or 100 mM (dialyse) | IP or local infusion in the NAC | – | Acute | IP injection: 2.0 g/kg markedly increases 5-HT levels in the NAC within 15 min. Reverse microdialysis: 100 mM ethanol increases 5-HT levels for 1 hr in the NAC | 116 |
| Wistar rats | Acute injection or reverse microdialyse | 0.5, 1 or 2 g/kg (injection) or 25, 50 or 100 mM (dialyse) | IP or local infusion in the CeA | – | Acute | IP injection: 1.0 and 2.0 g/kg markedly increases 5-HT levels in the AMG within 20 min. Reverse microdialysis: ethanol dose-dependently increases 5-HT levels for 2 hr in the AMG | 117 |
| Lewis and Fisher rats | Acute injection | 0.5, 1 or 2 g/kg | IP | – | Acute | Ethanol 1 g/kg and 2 g/kg increased 5-HT levels in the NAC (44%) (in Lewis but not Fisher rats) | 118 |
| Wistar BgVV and Wistar-Harlan rats | Acute injection | 1 g/kg | IP | 111–113 mg/dl | Acute | Microdialysis: Ethanol 1 g/kg (ip) or exposure in the elevated-plus maze increases 5-HT release in the mPFC of Wistar-BgVV rats | 119 |
| Sprague Dawley rats | Acute injection | 0.1, 1 and 10% (v/v) | Local infusion in the VTA | – | Acute | Microdialysis: 10% ethanol increases 5-HT levels in the VTA, which is not blocked by Ca2+ depletion or TTX (1uM) | 120 |
| Sprague Dawley rats | Acute injection | 16% (w/v) | IP | 50–80 mM | Acute | Microdialysis: increased levels of 5-HIAA in the striatum | 121 |
| Wistar rats | Acute injection | 0.1 and 1 g/kg | IP | – | Acute | Microdialysis: ethanol 0.1 and 1 g/kg (ip) increases 5-HIAA in the NAC | 122 |
| Sprague Dawley rats | Acute injection | 0.5, 1, and 2 g/kg | IP | – | Acute | Microdialysis: Ethanol 0.5, 1, and 2 g/kg increases 5-HT in the NAC | 125 |
| Sprague Dawley, F344 and Lewis rats | Acute injection | 20–160 mM | bath (Slices) | – | Acute | Electrophysiology: Ethanol dose-dependly increases VTA neuron firing rate. 5-HT potentiates the increasing effect of ethanol on VTA neuron firing rates, which is replicated by the 5-HT2 agonist DOI (50nM and 2uM) | 126 |
| C57Bl6 mice | Acute injection | 30 mM | bath (Slices) | – | Acute | Electrophysiology: Ethanol (30 mM) inhibits DR 5-HT neuron excitability via activation of extrasynaptic glycine receptors | 128 |
| ICR mice | Acute and repeated | 1.0, 2.0, 3.0 or 4.0 g/kg | IP | – | Acute or Repeated (1.0 or 2.0 g/kg once daily for 7 days) | Microdialysis: Acute, 5-HIAA concentrations were increased in the hypothalamus after injection of 3.0 and 4.0 g/kg of ethanol. Repeated, no change observed in 5-HIAA concentration | 123 |
| Wistar rats | Acute and repeated | 2.5 g/kg | IP | – | Acute or 1 repeated injections (24 h after) | Microdialysis: Acute ethanol increases 5-HT levels in the caudate putamen. Repeated: pretreatment with ethanol slightly decreases the elevation in 5-HT induced by ethanol, as compared to a single injection. Electrophysiology in awake animals: Ethanol reduces the firing frequency of 5-HT neurons | 124 |
| Sprague Dawley rats | Acute and repeated | acute: 0.25–1.0 g/kg. Chronic: 1–5 g/kg every 6hr for 6 days + challenge (0.25–1 g/kg, i.v.) | acute: intravenous. Chronic: intragastric + intravenous challenge | – | Acute or repeated (for 6 days) | Electrophysiology: Acutely, ethanol decreases the firing rate of 5-HT DR neurons. Reduction of basal electrical activity of 5-HT neurons, 12 h after withdrawal from chronic ethanol. No change in 5-HT1A agonist (8-OHDPAT, 1–16 μg/kg, i.v.) sensitivity to reduce the firing rate after withdrawal | 127 |
| Wistar rats | Acute and repeated | 2×2.5 g/kg | IP | 237–256 mg/dl | Acute (2 injections in 2 days) | A single ip injection of ethanol 2.5 g/kg increases 5-HT levels in the ventral HIP. A second ip injection of ethanol 2.5 g/kg 24 hrs after does not elevate 5-HT levels | 113 |
| Rat (not precised) | Early postnatal gavage | 5 g/kg/day | intragastric | 325.7 mg/dl | Chronic (P4 to 10) | Early postnatal ethanol exposure increases 5-HT and 5-HIAA concentrations in the HIP of females but not males | 129 |
| Rat (not precised) | Early postnatal gavage | 6 g/kg/day | intragastric | 327.8 to 347.6 mg/dl | Chronic (P4 to 10) | A single ip injection of ethanol 2.5 g/kg increases 5-HT levels in the ventral HIP. A second ip injection of ethanol 2.5 g/kg 24 hrs after does not elevate 5-HT levels | 130 |
| Fischer 344 rats | Chronic diet | 6.6% v/v | liquid diet | 60 to 100 mg/dl | 6 weeks | Ethanol reduces 5-HT tissue content in the VTA of 14-month old animal but increases 5-HIAA concentration in the striatum, globus pallidus, NAC, frontal cortex, VTA and ventral pallidum of 24-month old animals | 132 |
| Fischer 344 rats | Chronic diet | 6.6% v/v | liquid diet | 60 to 100 mg/dl | 6 weeks | Increased 5-HT2A binding in the NAC of 5-month old ethanol fed rats | 146 |
| C57Bl6 mice | SHAC | 5% v/v | drinking solution | 109 mg/dl | 1 or 6 days | Increased extracellular concentration of 5-HT in the NAC of ethanol -inexperienced animals (SHAC1) but the 5-HT levels are no longer elevated in ethanol-experienced animals (SHAC6) | 115 |
| Wistar rats | Sucrose fading | gradually from SUC 10% / ETH 5% to SUC 5% /ETH 10% | drinking solution | 15.7 mg/dl | 50 days | History of ethanol/sucrose drinking reduces 5-HT content in the medial thalamus and medial hypothalamus and the 5-HIAA/5-HT ratio in the PFC pyriform, motor, auditory, visual and somatosensory cortices and medial thalamus | 133 |
| C57Bl6 mice | Chronic free choice drinking (3 water/1 ethanol bottles) | 0 to 10% v/v | drinking solution | – | 21 days | No change in 5-HTP, 5-HT or 5-HIAA levels in the striatum. Increased 5-HT1A sensitivity to ipsapirone (2 or 3 mg/kg, i.p.)-mediated reduction of 5-HTP accumulation and 5-HT neuron firing rate. Increased 5-HT1A-mediated GTPgammaS coupling in the DR. No difference in 8-OHDPAT-induced hypothermia | 142 |
| Wistar rats | Chronic diet + withdrawal + re-exposure | 7.2% v/v | liquid diet | 288 mg/dl | 10 or 21 days | Ethanol reduces 5-HT tissue content in the the cortex and striatum and increases 5-HIAA contents in the HIP after 10 days of exposure | 134 |
| Wistar rats | Withdrawal from chronic diet | 7.2% v/v | liquid diet | 289 mg/dl | 21 days + 2, 4 or 6 h of withdrawal | Decreased 5-HT tissue content in the cortex 4 h after withdrawal but Increased levels after audiogenic seizures (>6 hrs). Increased 5-HIAA in the cortex after 2 h of withdrawal. Decreased 5-HT in the striatum after 2, 4 and 6 hrs of withdrawal and after audiogenic seizures. No changes in 5-HT levels in the HIP but decreased 5-HIAA contents after 2 h of withdrawal and after audiogenic seizures | 135 |
| Sprague Dawley rats | Withdrawal from chronic diet | 9% v/v | liquid diet | 255 mg/dl | 14 days | Increase in 5-HT1A binding in the DR (+30%) but decrease in the HIP (–20%) and the cortex (–30%). Increase in 5-HT1B in the globus pallidus | 143 |
| Sprague Dawley rats | Withdrawal from chronic diet | 9% v/v | liquid diet | – | 14 days | Effect of 5-HT1A agonist (8-OHDPAT, 2.5 mg/kg ip) is sensitized on lower lip retraction but desensitized on flat body posture after 18 h of withdrawal | 144 |
| DBA2 mice | Chronic intermittent vapour | – | Vapour | 150–200 mg/dl | 5 days, 16 h/day | 5-HT2C antagonist (SB242,084, 3 mg/kg, ip) normalizes ethanol-induced anxiety and reduces ethanol-induced fos immunoreactivity in the ventral BNST. Ethanol increases 5-HT2C signalling in the ventral BNST | 149 |
| DBA2 mice | Chronic intermittent vapour | – | Vapour | 150–200 mg/dl | 5 days of 16 h/day followed by 24 h or 7 day withdrawal | Chronic ethanol exposure enhances the net activity of 5-HT neurons by reducing inhibitory transmission during early withdrawal and increasing excitatory transmission during late withdrawal. Chronic ethanol exposure also sensitizes the inhibitory effect of subsequent acute ethanol exposure | 162 |
| C57BL/6J, C3H/HeJ and DBA/2J inbred mice | Chronic intermittent vapour followed by 2 bottle choice | 22–27 mg/l (vapour) and 10% v/v (drinking) | vapour and drinking solution | 50 mg/dl after vapour session | 20 days, 3–6 h/d, followed by 5 h withdrawal and 4 h drinking | Alterations in 5-HT2C RNA editing in the NAC and the DR in C57bl6 mice following chronic ethanol exposure | 147 |
| C57Bl6 mice | 180–200 mg/dl | 20 days, 4–8 h/day | Decreased 5-HT and 5-HT/5-HIAA ratio in the DR and HIP. Increased mRNA expression of 5-HT2A, 2C and 7 in the DR, striatum and HIP following 20 days of alcohol vapour exposure. Increased alcohol-induced 5-HT release in the NAC of ethanol vapour-experienced animals. | 148 | |||
| Rhesus monkeys | Chronic 2 bottle choice | 4% v/v | drinking solution | – | 13 months | Increase 5-HT1A binding (PETSCAN) in cortex, AMG and HIP | 145 |
| Macaques | operant self- administration | 0.5, 1.0, and 1.5 g/kg | drinking solution | 90 mg/dl | 12 months | Increased expression and G protein-coupling of 5-HT1A receptors in the HIP | 150 |
| Macaques | operant self- administration | 0.5, 1.0, and 1.5 g/kg | drinking solution | 90 mg/dl | 13 months | Decreased SERT binding in the HIP | 154 |
| Human | Alcoholics | – | – | – | 15 years of drinking | Increased 5-HT1B binding in the pallidum/NAC of alcohol dependent subjects | 151 |
| Human | Alcoholics | – | – | – | 27 years of drinking | Decreased 5-HT1A-induced prolactin and cortisone release following a challenge of the 5-HT1A agonist Flevinoxan (1 mg/70 kg of body weight, iv) | 152 |
| Human | Alcoholics | – | – | – | - (post mortem) | 30% reduction of 5-HT1A binding in the anterior cingulate cortex of type 1 alcoholics | 153 |
| Human | Alcoholics | – | – | 95 g/day (90 kg) | 1 to 30 years | The longer duration of excessive alcohol consumption the lower PRL response to D-fenfluramine | 155 |
| Human | Alcoholics | – | – | – | 3–5 weeks of abstinence | 30% reduction of SERT binding in the brainstem | 156 |
| Human | Alcoholics | – | – | – | - (post mortem) | 30% reduction of SERT binding in the AMG | 157 |
| Human | Alcoholics | – | – | – | - (post mortem) | 26% reduction of SERT binding in the dorsal striatum | 158 |
| Human | Alcoholics | – | – | – | - (post mortem) | 35% increase of SERT binding in the NAC | 159 |
| Human | Alcoholics | – | – | – | - (post mortem) | 25% reduction of SERT binding in the cingulate cortex | 161 |
| Human | Alcoholics | – | – | – | - (post mortem) | 35% reduction of SERT binding in the cingulate cortex | 162 |
| Human | Alcoholics | – | – | 128 mg/dl at admission | 19 years | Plasma 5-HT concentration decreases during 14 days after withdrawal | 160, 163 |
Abbreviations: NAC, nucleus accumbens; VTA, ventral tegmental area; AMG, amygdala; BLA, basolateral amygdala; LA, lateral amygdala; HIP, hippocampus; PFC, prefrontal cortex; mPFC, medial prefrontal cortex; DR, dorsal raphe; MR, median raphe; TPH, tryptophan hydroxylase; EDC, ethanol derived calories.