Glutamatergic mechanisms underpinning stress-induced vulnerability to cocaine abuse in BDNF Met prodomain carriers

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Congreso; ISN (INTERNATIONAL SOCIETY OF NEUROCHEMISTRY) Meeting; 2023

ISN (INTERNATIONAL SOCIETY OF NEUROCHEMISTRY) Meeting

Brain-derived neurotrophic factor (BDNF) is a neurotrophin widely expressed in the brain and it has a primary role in the development, differentiation, maturation and plasticity of the developing nervous system. In the last decades, a single nucleotide polymorphism (SNP) in BDNF gene which results in the substitution of the amino acid Valine by Methionine at codon 66 (Val66Met) in the BDNF prodomain region, has been widely studied. The Met allele is associated with decreased BDNF secretion and altered stress response, with increased susceptibility to neuropsychiatric disorders and substance abuse disorders. In this study we will evaluate the involvement of Met prodomain BDNF (Met-pBDNF) in the impact of stress on vulnerability to cocaine addiction. For this purpose, we generated lentiviral (LV) particles carrying Met-pBDNF and Val-pBDNF variants of prodomain, and we microinjected them in the nucleus accumbens core (NAc). Our results reveal an enhancement of locomotor activity in stressed Met-pBDNF rats compared with stressed and non-stressed Val-pBDNF animals after cocaine. In animal models, stress-induced addictive behaviors have been associated with enduring neuroadaptive alterations in glutamatergic transmission in the reward circuitry. GLT-1 downregulation in the NAcore has been proposed as a pathogenic hallmark underlying stress induced vulnerability to developing addictive behaviors. In our laboratory we described an impairment of glutamate homeostasis attributed to GLT-1 downregulation. In correlation, here we demonstrate a lasting decrease in GLT-1 levels in NAc in Met-pBDNF animals. This evidence suggests a novel, crucial role for the Met-pBDNF in the neurobiological mechanisms underpinning the comorbidity between stress exposure and addiction disorders. Currently, we seek to elucidate changes in synaptic plasticity, studying the impaired glutamate homeostasis induced by microglia in our model, to get a clearer understanding of the comorbidity between stress and addiction