COCAINE-INDUCED HIPPOCAMPAL NEUROADAPTATIONS: UNMASKING PHOSPHODIESTERASE 5 ROLE IN THE VULNERABILITY TO SUBSTANCE USE DISORDERS

Mar del Plata

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2023; 2023

Behavioral sensitization to psychostimulants hyperlocomotor effect is a useful model to study addiction, the severe type of substance use disorders (SUD). Hippocampus (HP) and medial prefrontal cortex (mPFC) have been implicated in the neuropathological mechanisms underlying addiction. Nitric oxide (NO) is a neurotransmitter involved in neuronal excitability, synaptic plasticity and in psychostimulants sensitization. Furthermore, phosphodiesterase 5 inhibitors (PDE5i) enhance NO activated signaling pathways. The aim of our work is to characterize the role of NO in the development and expression of cocaine (COC) sensitization, analyzing the contribution of NO signaling in different brain areas and repursuing the angiotensin-1 receptors (AT1) antagonists, such as candesartan, as a potential pharmacological alternative to treat SUD. We have demonstrated that COC sensitization in rats (induced by repeated COC administration - 15 mg/kg/day i.p. for 5 days) enhanced synaptic plasticity, increased NO synthase type 1 (NOS1) protein levels and activity within the HP. The proportion of sensitized rats was reduced by inactivation of NOS1/NO/sGC/cGMP pathway (administering NOS1 or sGC selective inhibitors systemically), as well as HP synaptic plasticity and NOS1 activity. Oppositely, its activation with the PDE5i, sildenafil (administered systemically), significantly increased proportion of sensitized animals and HP synaptic plasticity. On the other hand, Angiotensin II modulates different central neurotransmitter systems, and modifies HP activity via NO-dependent mechanisms. Also, AT1 antagonists prevented several neuroadaptive changes related to amphetamine sensitization. In our work, systemic candesartan administration after expression of COC sensitization seems to reverse sensitization. When the mPFC was analyzed, activity of the pyramidal neurons was increased after COC sensitization, and systemic NOS1 inhibition during sensitization development prevented the observed increments. These results support the possible involvement of NOS1/NO/sGC/cGMP pathway in the vulnerability to develop COC sensitization by its activation in HP and mPFC. Then, to characterize the contribution of NO signaling within HP or mPFC to the expression of COC sensitization, we infused a selective NOS1 inhibitor intra HP or mPFC in animals expressing COC sensitization. Intra HP inhibition reversed COC sensitization, while inhibition within mPFC did not affect expression of this behavior. Considering the results presented, we can speculate that upregulation of the NOS1/NO/sGC/cGMP signaling pathway in different brain areas could initiate, contribute, or exacerbate SUD in humans. Here, the participation of PDE5i in these actions were unmasked showing that they may increase vulnerability to drug abuse. Interestingly, AT1 receptors antagonists may be useful to treat SUD and more studies need to be performed to understand their role in down regulation of NO-activated pathways.