HIPPOCAMPAL NOS-1 INHIBITION INTERFERS WITH COCAINE SENSITIZATION EXPRESSION AND SYNAPTIC TRANSMISION.

ARTUR DE LA VILLARMOIS, E; GABACH, LAURA; OCCHIEPPO, ME; SCHIÖTH HB; CARLINI, VALERIA; PÉREZ, MARIELA

Pecs

Congreso; FEDERATION OF EUROPEAN NEUROSCIENCE SOCIETIES (FENS). ANNUAL MEETING 2017; 2017

FENS

Repeated administration of psychostimulants such as cocaine (COC) causes progressive increases in locomotor activity, called ?behavioural sensitization? that underlies drug-seeking behaviour and relapse. The hippocampus (HP) is a brain region implicated in associative learning processes that occur during addiction. A major form of synaptic plasticity in HP is long-term potentiation (LTP) characterized by an enduring increase in the efficacy of glutamatergic synaptic transmission. Nitric Oxide (NO) is a neurotransmitter that participates in HP synaptic plasticity and in behavioural effects of COC. Results from our group showed a key role of the NOS-1/NO/sGC/cGMP pathway in the development of COC sensitization and in the associated enhanced HP synaptic plasticity, because inhibition of NOS-1 during COC administration prevented sensitization. The aim of this work is to evaluate if NOS-1 inhibition after development of COC sensitization was able to reverse its expression, and to characterize the HP participation in this phenomenon. To this purpose, male Wistar rats were administrated with COC (i.p. 15 mg/kg/day) or saline (SAL) for 5 days, one group was sacrificed 60 min. after last administration; a second group received the NOS-1 inhibitor 7-nitroindazole (7-NI, 50 mg/kg/day) or vehicle (VEH) for the following 5 days; and a third group received a single intra-HP 7-NI (16.31 μg/μl) or VEH infusion. The last two groups received a COC or SAL challenge 24 hs. after the last 7-NI or VEH administration. To evaluate sensitization expression, locomotor activity was measured on days 1, 5 and in the challenge day. To measure HP synaptic transmission, the threshold to generate LTP was assessed by multi-unitary extracellular recordings on day 5 and in the challenge day. In addition we quantified NOS-1 protein levels by western blot, and NOS-1 and the cAMP response element-binding (CREB) gene expression by RT-PCR. Our results show that COC sensitized animals expressed increased NOS-1 protein and gene expression, CREB levels, and enhanced HP synaptic transmission on day 5. Furthermore, systemic or intra-HP NOS-1 inhibition reversed sensitization expression and the associated enhanced HP synaptic plasticity. We conclude that HP has a fundamental role in COC sensitization expression, emphasizing the NO participation in this phenomenon, and the interference of NO signaling pathways could be considered as pharmacological target to treat drug addiction and/or relapse.