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 selfadministration 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 (AMPAREPSCs), 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 selfadministration and increased addiction risk in individuals with fetal alcohol spectrum disorders.

Prenatal and postnatal alcohol exposure increases vulnerability to cocaine addiction in adult mice

“…Likewise, increased sensitivity in the CPP, induced by a psychostimulant drug such as amphetamine, was observed in PAE rats upon reaching adulthood (Wang et al, ). Moreover, rats receiving alcohol during gestation self‐administered more amphetamine and exerted greater effort to obtain the drug under a PR schedule (Hausknecht et al, ; Wang et al, ). In contrast to our findings, increased locomotor sensitization to psychostimulants, such as cocaine and amphetamine, was described in adult PLAE offspring rats (Barbier et al, ).…”

“…Also, GluA2-lacking AMPARs in the NAc regulate the incubation of cocaine craving after prolonged withdrawal (Conrad et al, 2008). In an FASD rat model, Hausknecht et al (2015) reported a persistent augmentation of calcium-permeable AMPAR expression in VTA DA neurons, which could lead to an enhanced excitatory synaptic strength. Also, binge alcohol exposure during the third trimester-equivalent period to human pregnancy increased the frequency of spontaneous excitatory glutamatergic postsynaptic currents in the basolateral amygdala of offspring rats (Baculis, Diaz, & Fernando Valenzuela, 2015).…”

Persistent effects of obesity: a neuroplasticity hypothesis

“…Dopaminergic circuits encode or incentivize reward or reward-learning, 90 and a rich body of literature has shown that substance abuse alters dopaminergic neurotransmission. [91][92][93][94] Exposure to drugs of abuse, including morphine, ethanol, cocaine, or methamphetamine induces morphological, [95][96][97][98] electrophysiological, 38,99 biomolecular, 100,101 and plasticity 98,[102][103][104] changes in midbrain VTA dopaminergic neurons and their projections to the ventral striatum.…”

Pre‐ and postnatal alcohol exposure delays, in female but not in male rats, the extinction of an auditory fear conditioned memory and increases alcohol consumption

“…However, patients exhibiting comorbidity between PTSD and alcohol use disorder also feature dysregulations of mesolimbic dopaminergic transmission (for review see Gilpin & Weiner, ). PAE also results in a dysregulated DA system (Converse et al, ; Schneider, Moore, & Adkins, ; Shen, Choong, & Thompson, ) due to abnormally increased excitatory synaptic strength in VTA DA neurons, which increases behavioral sensibility to drug abuse and increased addiction risk in PAE animals (Hausknecht et al, ).…”