Séminaire du Pr Lucia Caffino - Cocaine withdrawal: from cognitive and emotional deficits to molecular mechanisms.

Cocaine withdrawal: from cognitive and emotional deficits to molecular mechanisms

Lucia Caffino

Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università Degli Studi di Milano, Via Giuseppe Balzaretti 9, 20133 Milan, Italy.

Cocaine is a highly addictive psychostimulant whose abuse induces long-lasting alterations in brain function. These effects are particularly profound when cocaine exposure occurs during adolescence, a developmental window marked by ongoing brain maturation and heightened sensitivity to environmental influences, with potentially enduring consequences that contribute to a substantial social and economic burden. Beyond active drug exposure, withdrawal is a highly dynamic phase, characterized by specific neurobiological adaptations driven by the interplay between drug exposure and abstinence. Over the years, we have investigated the consequences of adolescent cocaine exposure and subsequent withdrawal on different memory domains, which are critical processes during brain maturation, using animal models. We found that adolescent cocaine exposure disrupts multiple cognitive domains while concomitantly altering the neuroplastic properties of excitatory synapses across brain regions within the reward neurocircuitry.

More recently, we have focused our attention on investigating how an acute stress challenge, a key factor contributing to vulnerability to relapse, affects stress-coping responses in adolescent male rats with a history of cocaine exposure and withdrawal. At molecular level, increasing attention has been recently devoted to neuroimmune interactions involving brain-resident neural and immune cells in the regulation of synaptic remodeling and maintaining circuit homeostasis.

In this seminar, I will focus on our more recent findings demonstrating that prolonged withdrawal from adolescent cocaine exposure impairs emotional adaptation to acute stress, accompanied by persistent maladaptive microglia-neuron communication and their influence in the regulation of glutamatergic and GABAergic signaling pathways, particularly in the hippocampus.

Together, these data support the existence of a latent neuroplastic vulnerability induced by cocaine withdrawal that becomes apparent under challenging conditions potentially driving maladaptive processing and increasing susceptibility to relapse during abstinence