Pharmacological NOS-1 Inhibition Within the Hippocampus Prevented Expression of Cocaine Sensitization: Correlation with Reduced Synaptic Transmission.

Behavioral sensitization to psychostimulants hyperlocomotor effect is a useful model of addiction and craving. Particularly, cocaine sensitization in rats enhanced synaptic plasticity within the hippocampus, an important brain region for the associative learning processes underlying drug addiction. Nitric oxide (NO) is a neurotransmitter involved in both, hippocampal synaptic plasticity and cocaine sensitization. It has been previously demonstrated a key role of NOS-1/NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic plasticity. The aim of the present investigation was to determine whether NOS-1 inhibition after development of cocaine sensitization was able to reverse it, and to characterize the involvement of the hippocampus in this phenomenon. Male Wistar rats were administered only with cocaine (15 mg/kg/day i.p.) for 5 days. Then, animals received 7-nitroindazole (NOS-1 inhibitor) either systemically for the next 5 days or a single intra-hippocampal administration. Development of sensitization and its expression after withdrawal were tested, as well as threshold for long-term potentiation in hippocampus, NOS-1, and CREB protein levels and gene expression. The results showed that NOS-1 protein levels and gene expression were increased only in sensitized animals as well as CREB gene expression. NOS-1 inhibition after sensitization reversed behavioral expression and the highest level of hippocampal synaptic plasticity. In conclusion, NO signaling within the hippocampus is critical for the development and expression of cocaine sensitization. Therefore, NOS-1 inhibition or NO signaling pathways interferences during short-term withdrawal after repeated cocaine administration may represent plausible pharmacological targets to prevent or reduce susceptibility to relapse.

Involvement of nNOS/NO/sGC/cGMP signaling pathway in cocaine sensitization and in the associated hippocampal alterations: does phosphodiesterase 5 inhibition help to drug vulnerability?

RATIONALE: Repeated cocaine administration induces behavioral sensitization in about 50 % of treated animals. Nitric oxide could be involved in the acquisition and maintenance of behavioral cocaine effects, probably by activation of neuronal nitric oxide synthase (nNOS)/NO/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling pathway, since inhibition of the nNOS enzyme attenuates development of sensitization in rats. On the other hand, increased cGMP availability by phosphodiesterase 5 inhibitors has been correlated to the misuse and recreational use of these agents and also to the concomitant use with illicit drugs in humans. Hippocampus is an important brain region for conditioning to general context previously associated to drug availability, influencing drug-seeking behavior and sensitization. Moreover, cocaine and other drugs of abuse can affect the strength of glutamate synapses in this structure, lastly modifying neuronal activity in main regions of the reward circuitry. OBJECTIVE: The objective of this study is to determine whether the pharmacological manipulation of nNOS/NO/sGC/cGMP signaling pathway altered changes induced by repeated cocaine exposure. RESULTS: The present investigation showed a relationship between behavioral cocaine sensitization, reduced threshold to generate long-term potentiation (LTP) in hippocampal dentate gyrus, and increased nNOS activity in this structure. However, when nNOS or sGC were inhibited, the number of sensitized animals was reduced, and the threshold to generate LTP was increased. The opposite occurred when cGMP availability was increased. CONCLUSION: We demonstrate a key role of the nNOS activity and NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic transmission.

Impact of contextual cues in the expression of the memory associated with diazepam withdrawal: involvement of hippocampal PKMζ in vivo, and Arc expression and LTP in vitro.

Hippocampal synaptic plasticity has been related to learning and adaptive processes developed during chronic drug administration, suggesting the existence of a common neurobiological mechanism mediating drug addiction and memory. Moreover, protein kinase M zeta (PKMζ) is critical for the maintenance of hippocampal long-term potentiation (LTP) and spatial conditioned long-term memories. Also, a link between activity-regulated cytoskeleton-associated protein (Arc), PKMζ and LTP has been proposed. Our previous results demonstrated that re-exposure to the withdrawal environment was able to evoke the memory acquired when the anxiety measured as a diazepam (DZ) withdrawal sign was experienced. In the present work we evaluated if the memory associated with DZ withdrawal could be affected by changes in the contextual cues presented during withdrawal and by intrahippocampal administration of a PKMζ inhibitor. We found that the context was relevant for the expression of withdrawal signs as changes in contextual cues prevented the expression of the anxiety-like behavior observed during plus-maze (PM) re-exposure, the associated enhanced synaptic plasticity and the increase in Arc expression. Furthermore, intrahippocampal administration of PKMζ inhibitor previous to re-exposure to the PM test also impaired expression of anxiety-like behavior and the facilitated LTP. These results support the relevance of the hippocampal synaptic plasticity in the maintenance of the memory trace during benzodiazepines withdrawal, adding new evidences for common mechanisms between memory and drug addiction that can be intervened for treatment or prevention of this pathology.