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Stress-induced vulnerability to develop cocaine addiction depends on cofilin modulation.

ABSTRACT: Actin dynamics in dendritic spines can be associated with the neurobiological mechanisms supporting the comorbidity between stress exposure and cocaine increase rewards. The actin cytoskeleton remodeling in the nucleus accumbens (NA) has been implicated in the expression of stress-induced cross-sensitization with cocaine. The present study evaluates the involvement of cofilin, a direct regulator of actin dynamics, in the impact of stress on vulnerability to cocaine addiction. We assess whether the neurobiological mechanisms that modulate repeated-cocaine administration also occur in a chronic restraint stress-induced cocaine self-administration model. We also determine if chronic stress induces alterations in dendritic spines through dysregulation of cofilin activity in the NA core. Here, we show that the inhibition of cofilin expression in the NA core using viral short-hairpin RNA is sufficient to prevent the cocaine sensitization induced by chronic stress. The reduced cofilin levels also impede a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor surface expression enhancement and promote the reduction of head diameter in animals pre-exposed to stress after a cocaine challenge in the NA core. Moreover, downregulation of cofilin expression prevents facilitation of the acquisition of cocaine self-administration (SA) in male rats pre-exposed to chronic stress without modifying performance in sucrose SA. These findings reveal a novel, crucial role for cofilin in the neurobiological mechanisms underpinning the comorbidity between stress exposure and addiction-related disorders.

SUBMITTER: Rigoni D

PROVIDER: S-EPMC8209265 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and purposeAlcohol exposure in utero may lead to a wide range of long-lasting morphological and behavioural deficiencies known as fetal alcohol spectrum disorders (FASD), associated with a higher risk of later developing neuropsychiatric disorders. However, little is known about the long-term consequences of cocaine use and abuse in individuals with FASD. This study aimed to investigate the effects of maternal binge alcohol drinking during prenatal and postnatal periods on cocaine reward-related behaviours in adult offspring.Experimental approachPregnant C57BL/6 female mice were exposed to an experimental protocol of binge alcohol consumption (drinking-in-the-dark test) from gestation to weaning. Male offspring were subsequently left undisturbed until reaching adulthood and were tested for cocaine-induced motivational responses (conditioned place preference, behavioural sensitization and operant self-administration). Protein expression of dopamine- and glutamate-related molecules was assessed following cocaine-induced reinstatement.Key resultsThe results show that prenatal and postnatal alcohol exposure enhanced the preference for the cocaine-paired chamber in the conditioned place preference test. Furthermore, early alcohol-exposed mice displayed attenuated cocaine-induced behavioural sensitization but also higher cocaine self-administration. Furthermore, alterations in glutamatergic excitability (GluA1/GluA2 ratio) and ?FosB expression were found in the prefrontal cortex and the striatum of alcohol-exposed mice after cocaine-primed reinstatement.Conclusion and implicationsOur findings demonstrate that maternal binge-like alcohol consumption during gestation and lactation alters sensitivity to the reinforcing effects of cocaine in adult offspring mice. Together, such data suggest that prenatal and postnatal alcohol exposure may underlie an enhanced susceptibility of alcohol-exposed offspring to develop drug addiction later in adulthood.

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Stress-induced vulnerability to develop cocaine addiction depends on cofilin modulation.

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