title: Excitatory synaptic function and plasticity is persistently altered in ventral tegmental area dopamine neurons after prenatal ethanol exposure.
abstract: Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction propensity (risk). However, the neuronal mechanisms underlying this effect remain unknown. We examined whether increased excitatory synaptic transmission in ventral tegmental area (VTA) dopamine (DA) neurons, which is associated with drug addiction, was impacted by PE. Pregnant rats were exposed to ethanol (0 or 6 g/kg/day) via intragastric intubation from gestational day 8-20. Amphetamine self-administration, whole-cell recordings, and electron microscopy were performed in male offspring between 2 and 12-week-old. The results showed enhanced amphetamine self-administration in PE animals. In PE animals, we observed a persistent augmentation in calcium-permeable AMPA receptor (CP-AMPAR) expression, indicated by increased rectification and reduced decay time of AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), enhanced depression of AMPAR-EPSCs by NASPM (a selective CP-AMPAR antagonist), and increased GluA3 subunits in VTA DA neuron dendrites. Increased CP-AMPAR expression in PE animals led to enhanced excitatory synaptic strength and the induction of CP-AMPAR-dependent long-term potentiation (LTP), an anti-Hebbian form of LTP. These observations suggest that, in PE animals, increased excitatory synaptic strength in VTA DA neurons might be susceptible to further strengthening even in the absence of impulse flow. The PE-induced persistent increase in CP-AMPAR expression, the resulting enhancement in excitatory synaptic strength, and CP-AMPAR-dependent LTP are similar to effects observed after repeated exposure to drugs of abuse, conditions known to increase addiction risk. Therefore, these mechanisms could be important neuronal substrates underlying PE-induced enhancement in amphetamine self-administration and increased addiction risk in individuals with fetal alcohol spectrum disorders.
authors.affiliation: Research Institute on Addictions, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hausknecht
authors.affiliation: Research Institute on Addictions, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Haj-Dahmane
authors.affiliation: Research Institute on Addictions, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: Ying-Ling
authors.initials: YL
authors.lastname: Shen
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, IL, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Vezina
authors.affiliation: Department of Pathology and Anatomical Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Dlugos
authors.affiliation: Research Institute on Addictions, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: Roh-Yu
authors.initials: RY
authors.lastname: Shen
mesh_terms: D018663:Adrenergic Agents / Q000008:administration & dosage; D000661:Amphetamine / Q000008:administration & dosage; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D002492:Central Nervous System Depressants / Q000633:toxicity*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D004558:Electric Stimulation; D000431:Ethanol / Q000633:toxicity*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D046529:Microscopy, Electron, Transmission; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D012646:Self Administration; D013569:Synapses / Q000648:ultrastructure; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000473:pathology*
chemical_list: D018663:Adrenergic Agents; D002492:Central Nervous System Depressants; D018091:Receptors, AMPA; D000431:Ethanol; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase