Cocaine sensitization is correlated to increases in hippocampal synaptic plasticity and to a ?sensitization? of nitric oxide synthase activity.

MARIELA F. PÉREZ, LAURA GABACH, VALERIA CARLINI, LAURA MAGLIO, SUSANA RUBIALES AND OSCAR RAMÍREZ.

Chicago-Illinois, USA

Congreso; Society for Neuroscience; 2009

Society for Neuroscience

Hippocampus (HP) is a limbic structure that participates in learning and memory formation. Changes in HP synaptic transmission constitute some of the neuroadaptations occurred after exposure of drugs of abuse. Repeated cocaine (COC) administration induces sensitization to its effects on locomotion and nitric oxide (NO) could be involved in the acquisition and maintenance of the behavioral effects of COC, because inhibition of the enzyme NO synthase (NOS) attenuates the development of sensitization. Moreover, the role of NO in the mechanisms involved in COC sensitization has not been described. In the present work we combined behavioral experiments together with electrophysilogical and neurochemical experiments in order to: 1- determine if COC sensitization is associated to increases in synaptic plasticity, 2- establish a correlation between sensitization and NO production, measured by the conversion of citruline H3 to arginine H3, 3- to determine if the observed changes were consequence of sensitization or due to withdrawal from COC and 4- examine the dependence on NO of these events. Male Wistar rats were administered with COC (15 mg/kg/day, i.p.), NOS inhibitor (7-NI 50 mg/kg/day. i.p.) + COC or saline (SAL) for 5 days and locomotor activity was evaluated on days 1 and 5. Sensitized (S) rats were separated from non-sensitized rats (NS). The electrophysiologycal and neurochemical studies were performed on day 5 (non-W) or after 3 days of withdrawal (W). Rats from the S non-W group showed a reduction in threshold to generate LTP (SAL 102 ± 8 vs. S non-W 27 ± 4 Hz). The same results were observed in the S W group. The increase in synaptic plasticity was correlated to the increase on the NOS activity in the S non-W group (SAL 0.4 ± 0.1 vs. S non-W 2.83 ± 0.6 pmol/mg protein). The NOS activity showed a ?sensitized? pattern of activity in animals from S W group compared to animals that received acute COC (S W 775 ± 158 vs. acute COC 308 ± 51 %). Administration of 7-NI before COC not only prevented sensitization, but also increased the threshold to generate LTP and prevented the increased NOS activity. These findings indicate that NO and the pathways activated by this neuromodulator may have an important role in the changes induced by COC in hippocampal synaptic transmission, contributing to the development of sensitization and withdrawal.