Gestational ethanol exposure impairs motor skills in female mice through dysregulated striatal dopamine and acetylcholine function

Abstract

Fetal alcohol exposure has deleterious consequences on the motor skills of patients affected by Fetal Alcohol Spectrum Disorder (FASD) and in pre-clinical models of gestational ethanol exposure (GEE). Deficits in striatal cholinergic interneurons (CINs) and dopamine function impair action learning and execution, yet the effects of GEE on acetylcholine (ACh) and striatal dopamine release remain unexplored. Here, we report that alcohol exposure during the first ten postnatal days (GEEP0-P10), which mimics ethanol consumption during the last gestational trimester in humans, induces sex-specific anatomical and motor skill deficits in female mice during adulthood. Consistent with these behavioral impairments, we observed increased stimulus evoked-dopamine levels in the dorsolateral striatum (DLS) of GEEP0-P10 female, but not male, mice. Further experiments revealed sex-specific deficits in β2-containing nicotinic ACh receptor (nAChR)-modulation of electrically evoked dopamine release. Moreover, we found a reduced decay of ACh transients and a decreased excitability of striatal CINs in DLS of GEEP0-P10 females, indicating striatal CIN dysfunctions. Finally, the administration of varenicline, a β2-containing nAChR partial agonist, and chemogenetic-mediated increase in CIN activity improved motor performance in adult GEEP0-P10 females. Altogether, these data shed new light on GEE-induced striatal deficits and establish potential pharmacological and circuit-specific interventions to ameliorate motor symptoms of FASD.

The Fetal Alcohol Spectrum Disorders—An Overview of Experimental Models, Therapeutic Strategies, and Future Research Directions

“…The administration of Varenicline in ethanol-exposed female mice helped to improve motor skills deficits in rotarod training. Based on these results, it is suggested that nAChR agonists could be a potential treatment for FASD [134].…”

Cholinergic interneurons in the shell region of the nucleus accumbens regulate binge alcohol consumption: A chemogenetic and genetic lesion study

“…Numerous studies have suggested that CINs play a crucial role in regulating the activity of MSNs and dopamine transmission in the NAcSh, which is a key brain region involved in alcohol consumption (Kolpakova et al, 2022). Conversely, alcohol and other addictive substances have been shown to interact with cholinergic neurons in different brain regions, including NAc, to cause impairment in behaviors, such as learning and cognition (Bariselli et al, 2023;Gangal et al, 2023;Ma et al, 2022;Smiley et al, 2021;Yorgason et al, 2022).…”

Social Interaction in Adolescent Rats with Neonatal Ethanol Exposure: Impact of Sex and CE-123, a Selective Dopamine Reuptake Inhibitor

“…Indeed, published data show that prenatal and neonatal alcohol exposure disrupts the dopamine system, including reducing spontaneous activity of dopamine neurons, enhancing the response to dopamine agonists, and decreasing levels of the dopamine metabolite, homovanillic acid (HVA), in dopamine neurons [28][29][30]. For example, hyperactivity during early development can be induced through chemical depletion of midbrain dopamine neurons in neonatal rats [31,32] or by administering alcohol prenatally [33,34] or neonatally [35].…”