Table 1.
Changes in 5-HTergic neuroplasticity following prenatal alcohol exposure
| Species | Model | Dose of ethanol | Route of administration | BEC | Duration of treatment | Results | Ref # |
| Sprague Dawley rats | Rhombencephalon neuronal culture | 25 to 100 nM | culture media | – | 4 days | Increased apoptosis of fetal rhonbencephalic neurons and reduced number of 5-HT neurons. That is prevented by cotreatment with ipsapirone 100nM | 38 |
| C57BL6 mice | foetal exposure | 20% (EDC) | liquid diet | 65 mg/dl on E14 | From E8 to E15 | 20–30% fewer 5-HT-immunoreactive neurons in the Raphe and retard of migration in E15 embryos | 37 |
| C57BL6 mice | foetal exposure | 20% (EDC) | liquid diet | – | From E8 to E16 | Reduced number of 5-HT-immunoreactive neurons inMR and DR. Decreased 5-HT-immunoreactive fibers in the medial forebrain bundle (MFB). Reduced 5-HT fiber diameter | 36 |
| C57BL6 mice | foetal exposure | 20 or 25% (EDC) | liquid diet | 44.3±11.6 (E8), 54.7±14.2 (E11), 142.7±49.5 (E14) and 72.8+19.1 (E17) mg/dl | From E7 or E8.5 | 60% of embryos at E13 and 20% at E15 showed perforation of the floor plate in the diencephalic vesicle. 70–80% of embryos failed to complete the formation of neural tissue at the roof. 60–80% of embryos showed delayed closure of the ventral canal | 32 |
| C57BL6 mice | foetal exposure | 25% (EDC) | liquid diet | – | From E7 to E11 or E13 | 20–30% fewer 5-HT-immunoreactive neurons in MR and DR and retard of migration in E11 and E13 embryos | 34 |
| C57BL6 mice | foetal exposure | 25% (EDC) | liquid diet | 142.7±49.5 (E14) and 72.8+19.1 (E17) mg/dl | From E7 to E18 | 20% reduction of 5-HT-immunoreactive neurons in the MR and DR at E18 and 30% at P45 | 42 |
| C57BL6 mice | foetal exposure | 25% (EDC) | liquid diet | 142.7±49.5 (E14) and 72.8+19.1 (E17) mg/dl | E7 to E15 or E18 | Fewer 5-HT-immunoreactive fibers in theMFB and along the projecting pathway through the hypothalamus, septal nucleus, frontal and parietal cortices, and HIP. Underdevelopment of the brain regions along 5-HT fiber projections. Underdevelopment of somatosensory thalamocortical projections, which are known to transiently express 5-HT transporters and to be regulated by 5-HT | 54 |
| C57BL6 mice | foetal exposure | 25% (EDC) | liquid diet | – | From E7 to E13 | Reduced whole brain concentration of 5-HT in E13 animals | 48 |
| Wistar rats | foetal exposure | 2×2.9 g/kg (4 hr interval) | IP injection | 446 mg/dl | Only at E8 | Increased 5-HT1 function at P45: increased forepaw treading and hind limb abduction induced by 5-MeODMT (2.5 mg/kg, i.p.). Increased 5-HT2A function at P45: increased head twitch response to 5-HTP (150 mg/kg, s.c.) | 65 |
| Sprague Dawley rats | foetal exposure | 6.6% v/v, about 35% (EDC) | liquid diet | – | For 4 to 6 weeks prior to breeding and during gestation (alcohol removed at postnatal day 3) | Brain stem: reduction of 40–60% of 5-HT (E15, E19 and P5) and 24 to 60% of 5-HIAA (E19 and P5). Cortex: reduction of 40% of 5-HT (P5) and 25% of 5-HIAA (E19 and P5). 5-HT1A binding: increased in the brainstem, decreased in the cortex. No difference in 5-HT1B binding | 35 |
| Sprague Dawley rats | foetal exposure | 6.6% v/v, about 35% (EDC) | liquid diet | – | 6 weeks prior to breeding and during gestation | 28 to 40% reduction of 5-HT-immunoreactive neurons in the MR and DR | 43 |
| Sprague Dawley rats | foetal exposure | 6.6% v/v, about 35% (EDC) | liquid diet | 80–120 mg/dl | 7 weeks prior to breeding and during gestation | P5: Decreased 5-HT-immunoreactive neurons of 32% in DR and 24% in MR at P5 and 32% in DR and 27% in MR at P19. Maternal treatment with ipsapirone (3 mg/kg/day, from E13 to E20) prevents these deficits | 44 |
| Sprague Dawley rats | foetal exposure | 6.6% v/v, about 35% (EDC) | liquid diet | 110 mg/dl | 8 weeks prior to breeding and during gestation | Decreased levels of 5-HT and 5-HIAA in the cortex, brainstem and cerebellum of P19 and P35 rats | 47 |
| Sprague Dawley rats | foetal exposure | 6.6% v/v, about 35% (EDC) | liquid diet | 110 mg/dl | 6 weeks prior to breeding and during gestation | Buspirone 4.5 mg/kg/day subcutaneously from E13 to E20 prevents the 50% reduction of 5-HT content in the cortex at P5 and the 30% reduction at P19. | 53 |
| Sprague Dawley rats | foetal exposure | 6.6% v/v, about 35% (EDC) | liquid diet | 120–130 mg/dl | 4–6 weeks prior to breeding and during pregnancy | Reduced 5-HT uptake sites in synaptosomes from motor cortex with 30% decrease of Km for 5-HT in P35 animals | 58 |
| Sprague Dawley rats | foetal exposure | 6.6% v/v, about 35% (EDC) | liquid diet | 75 to 120 mg/dl | 6 weeks prior to breeding and during gestation | Reduced SERT binding in the frontal cortex and parietal cortices, lateral hypothalamus, substantia nigra, medial septum and striatum of P19 and P35 animals. Most of these effects are prevented by maternal treatment with buspirone (4.5 mg/kg/day from E13 to E20, s.c.) | 59 |
| Sprague Dawley rats | foetal exposure | 6.6% v/v, about 35% (EDC) | liquid diet | 75 to 120 mg/dl | 6 weeks prior to breeding and during gestation | Increased 5-HT1A binding in the dentate gyrus but decreased in the parietal cortex and lateral septum in P35 animals. Maternal treatment with buspirone (E13 to E20, 4.5 mg/kg/day, s.c.) prevents most of these alterations. No change in 5-HT2A binding | 62 |
| Sprague Dawley rats | foetal exposure | 6.6% v/v, about 35% (EDC) | liquid diet | 130 mg/dl | 4–6 weeks prior to breeding and during pregnancy | Decreased of 5-HT1 binding sites: 20% in whole cortex, 38% in motor cortex and 10–30% in somatosensory cortex of both P19 and P37 animals | 61 |
| Sprague Dawley rats | foetal exposure | 6.6% v/v, about 35% (EDC) | liquid diet | – | During whole pregnancy | Increased response to the hypothermic effect of 5-HT1A agonist (8OHDPAT, 0.125 and 0.5 mg/kg, s.c.) in 70–90 day-old animals. Increased head-twitch response to 5-HT2A agonist in 70–90 day-old females | 63 |
| Sprague Dawley rats | foetal exposure | 6.6% v/v, about 35% (EDC) | liquid diet | – | During whole pregnancy | Increased novelty-induced anxiety-like behaviour and anxiolytic effects of 5-HT1A agonist (8OHDPAT, 0.06 mg/kg, s.c.) in females (P22) | 64 |
| Sprague Dawley rats | foetal exposure | 0.5, 1 and 2 g/kg ethanol once a day | subcutaneously injection | 3.32, 40.73 and 106.56 mg/dl in the 0.5, 1 and 2 g/kg groups, respectively | From E15 until birth | 5–15% reduction of 5-HT- and TPH-immunoreactive neurons at 3 and 5 weeks after birth, in a dose dependent manner | 45 |
| Sprague Dawley rats | foetal exposure | 36% (EDC) | liquid diet | – | From E1 to E22 | Decreased 5-HT-immunoreactive neurons in the DR (but not MR), rescued by oestrogen treatment (0.05 mg in pellet) in ovariectomized female | 46 |
| Sprague Dawley rats | foetal exposure | 36% (EDC) | liquid diet | 127 mg/100 ml | From E8 to birth | SERT binding in the cortex = decreased (P21, P40 and P60), in HIP = increased (P21, P40 and P60), in the BLA = increased (P21, P40 and P60), LA = increased (P40 and P60)VMH = decreased (P21) | 56 |
| Sprague Dawley rats | foetal exposure | 36% (EDC) | liquid diet | – | From gestational day 1 to E21 or birth | Reduced SERT mRNA in the brain of E21 foetus. Higher methylation of SERT in the hypothalamus of females at P55 | 57 |
| Wistar rats | foetal exposure | 8–16% w/v as sole drinking fluid | forced drinking | – | 3.5 months of 8% and 1 month of 16% before birth | Decreased 5-HTP levels in the whole brain without cerebellum of 5 month-old females | 49 |
| Rhesus monkeys | sweetened alcohol | 0.6 g/kg/day | liquid diet | 20–50 mg/dl | Early gestation (days 0 to 50), middle to late gestation (days 50 to 135) or continuous (days 0 to 135) | Early- and middle-to-late gestation-alcohol exposed monkeys carrying the short allele of the SERT had lower concentrations of 5-HIAA in the CSF | 50 |
| Human FAE/FAS children | maternal alcohol consumption | – | voluntary drinking | – | – | Reduced SERT binding in the mPFC of 7–14 year-old FAE/FAS children (SPECT) | 60 |
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.