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Prenatal alcohol exposure reduces posterior dorsomedial striatum excitability and motivation in a sex- and age-dependent fashion.

ABSTRACT: Prenatal alcohol exposure (PAE)-induced clinical symptoms have been widely reported but effective treatments are not yet available due to our limited knowledge of the neuronal mechanisms underlying behavioral outputs. Operant behaviors, including both goal-directed and habitual actions, are essential for everyday life. The dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) have been identified as mediating each type of instrumental behavior, respectively. The current studies were designed to evaluate the effects of PAE (i.e., 3 g/kg, twice a day on gestational days 17-20) on goal-directed vs. habitual behaviors in both females and males during their adolescent and adult stages. We found that PAE-treated adult, but not adolescent, males display similar habitual oral sucrose self-administration but reduced goal-directed sucrose self-administration, compared to those treated by prenatal control (water) exposure (PCE). There were no differences in either habitual or goal-directed sucrose taking between PCE- vs. PAE-treated adolescent and adult females. These results indicate sex- and age-specific effects of PAE on operant behaviors. Further, whole-cell patch clamp recordings showed that the excitability of medium-sized spiny neurons (MSNs) in the posterior DMS (pDMS), but not the anterior DMS (aDMS), was significantly decreased in PAE-treated adult male rats. Notably, chemogenetic enhancement of MSN excitability in the pDMS by the DREADD agonist, compound 21, rescued the motivation of PAE-treated male adult rats. These data suggest that the pDMS may be a key neuronal substrate mediating the PAE-induced low motivation in male adults.

SUBMITTER: Roselli V

PROVIDER: S-EPMC7773417 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Excessive alcohol intake leads to mesostriatal neuroadaptations, and to addiction phenotypes. We recently found in rodents that alcohol increases fibroblast growth factor 2 (FGF2) expression in the dorsomedial striatum (DMS), which promotes alcohol consumption. Here, we show that systemic or intra-DMS blockade of the FGF2 receptor, FGF receptor-1 (FGFR1), suppresses alcohol consumption, and that the effects of FGF2-FGFR1 on alcohol drinking are mediated via the phosphoinositide 3 kinase (PI3K) signaling pathway. Specifically, we found that sub-chronic alcohol treatment (7 d × 2.5 g/kg, i.p.) increased Fgfr1 mRNA expression in the dorsal hippocampus and dorsal striatum. However, prolonged and excessive voluntary alcohol consumption in a two-bottle choice procedure increased Fgfr1 expression selectively in DMS. Importantly, systemic administration of the FGFR1 inhibitor PD173074 to mice, as well as its infusion into the DMS of rats, decreased alcohol consumption and preference, with no effects on natural reward consumption. Finally, inhibition of the PI3K, but not of the mitogen-activated protein kinase (MAPK) signaling pathway, blocked the effects of FGF2 on alcohol intake and preference. Our results suggest that activation of FGFR1 by FGF2 in the DMS leads to activation of the PI3K signaling pathway, which promotes excessive alcohol consumption, and that inhibition of FGFR1 may provide a novel therapeutic target for alcohol use disorder.SIGNIFICANCE STATEMENT Long-term alcohol consumption causes neuroadaptations in the mesostriatal reward system, leading to addiction-related behaviors. We recently showed that alcohol upregulates the expression of fibroblast growth factor 2 (FGF2) in dorsomedial striatum (DMS) or rats and mice, and in turn, FGF2 increases alcohol consumption. Here, we show that long-term alcohol intake also increases the expression of the FGF2 receptor, FGFR1 in the DMS. Importantly, inhibition of FGFR1 activity by a selective receptor antagonist reduces alcohol drinking, when given systemically or directly into the DMS. We further show that the effects of FGF2-FGFR1 on alcohol drinking are mediated via activation of the PI3K intracellular signaling pathway, providing an insight on the mechanism for this effect.

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Prenatal alcohol exposure reduces posterior dorsomedial striatum excitability and motivation in a sex- and age-dependent fashion.

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