Nitric Oxide (NO) Signaling as a Potential Therapeutic Modality Against Psychostimulants

Abstract

Abuse of psychostimulants presents a significant health and social problem worldwide. Traditionally, the dopaminergic system has received much attention for its role in the development and manifestation of addictive behavior. The identification of the close interaction between the dopaminergic and glutamatergic pathway and by extension the nitric oxide (NO) signaling pathway (the nitrergic system) have provided a broader scope on the mechanisms underlying the development of addictive behavior following exposure to cocaine and methamphetamine. NO signaling is associated with the acquisition and maintenance of several behavioral phenotypes induced by cocaine and methamphetamine (METH), as well as in METH-induced dopaminergic depletion. Because it appears that NO signaling influences response to reward, memory formation, and free radical-induced neurotoxicity, pharmacotherapies targeting NO signaling pathway may prove beneficial in the treatment of psychostimulants abuse.

Nitric oxide in the medial prefrontal cortex contributes to the acquisition of cocaine place preference and synaptic plasticity in the laterodorsal tegmental nucleus

“…The main findings of the present study were that: (1) intra-mPFC injection of the non-selective NOS inhibitor L-NAME or the selective nNOS inhibitor L-NPA inhibits cocaine CPP acquisition; and (2) intra-mPFC injection of L-NPA inhibits the induction of presynaptic plasticity in LDT cholinergic neurons induced by repeated cocaine administration. To the best of our knowledge, this is the first direct evidence showing that NO generated by nNOS in the mPFC plays a crucial role in both the acquisition of cocaine CPP and the induction of neuroplasticity in the LDT.…”

“…Nitric oxide (NO) is a gaseous neurotransmitter associated with a variety of physiological functions and with neuroplasticity related to learning and memory [1]. Additionally, NO has been reported to play an important role in addictive behaviors induced by cocaine [2]. A previous study revealed that systemic injection of an NO synthase (NOS) inhibitor attenuates cocaine-induced conditioned place preference (CPP) and that knockout of neuronal NOS (nNOS) abolishes development of cocaine CPP [3].…”

Neuroplasticity in cholinergic neurons of the laterodorsal tegmental nucleus contributes to the development of cocaine addiction

“…NO has also been reported to play a crucial role in the development of cocaine addiction, although the brain region(s) in which NO acts and its precise contribution remain unclear (Itzhak et al, 1998;Liddie et al, 2013). As NOS inhibition in the mPFC blocks the induction of presynaptic plasticity in LDT cholinergic neurons , subsequent studies have examined whether this inhibition of LDT synaptic plasticity is associated with cocaine CPP.…”

Signaling Mechanisms in the Nitric Oxide Donor- and Amphetamine-Induced Dopamine Release in Mesencephalic Primary Cultured Neurons

“…Several studies have shown that nitric oxide (NO), a free radical gas recognized as an atypical neurotransmitter, is involved in the pathways that underlie the neurotoxic effects of Amph (Itzhak and Ali 2006;Liddie et al 2013). In fact, the neurotoxicity caused by Amph and the neurodegenerative process observed in Parkinson's disease seem to involve similar sources of oxidative stress, characterized by a redox imbalance between free radicals or other ROS and antioxidant defenses, where NO has an important role (Perfeito et al 2013).…”

“…These species trigger toxic pathways in the CNS (Antunes et al 2005) and may contribute to the neurodegenerative and neurotoxic cellular processes implicated in many mental and neurologic diseases, such as schizophrenia and drug addiction (Liddie et al 2013;Minutolo et al 2012). High levels of NO metabolites were found in the plasma of schizophrenic patients under treatment (Minutolo et al 2012), but also increased serum NO levels of pre-treated patients (Taneli et al 2004).…”