The neuronal nitric oxide synthase (nNOS) gene contributes to the regulation of tyrosine hydroxylase (TH) by cocaine

Abstract

Recently, we demonstrated that intact nitric oxide (NO) signaling is essential for the development of cocaine behavioral sensitization in adulthood [2]. Given the requirement of dopamine (DA) transmission in cocaine-induced behavioral sensitization and the interactions between NO and DA systems, the present study investigated the role of the neuronal nitric oxide synthase (nNOS) gene and the effect of cocaine on the expression of tyrosine hydroxylase (TH)-immunoreactive (-ir) neurons. Adult (postnatal day 80) wild type (WT) and nNOS knockout (KO) mice received saline or a sensitizing regimen of cocaine (20mg/kg) for 5 days. After 24h, TH immunoreactivity was assessed in the ventral tegmental area (VTA) and the dorsal striatum (dST) using stereology and western blotting, respectively. We report that a) nNOS KO mice express lower levels of TH-ir neurons in the VTA compared to WT counterparts, b) cocaine administration to WT mice significantly increased striatal TH expression, and c) the same cocaine administration to nNOS KO mice significantly decreased striatal TH expression. Thus, the nitrergic system may contribute to cocaine-induced behavioral sensitization by regulating dopaminergic neurotransmission.

Psychostimulant-Induced Testicular Toxicity in Mice: Evidence of Cocaine and Caffeine Effects on the Local Dopaminergic System

“…These results only indicate alterations at the transcriptional level and should then be interpreted with caution since protein levels may not follow the same trend. Still, our results on DRs gene expression alterations together with increases in TH levels, show a similar pattern to cocaine actions on DA pathways on the CNS [ 13 , 14 , 58 ].…”

“…In the nucleus accumbens and striatum, the reinforcing effect of cocaine is characterized by increased DA transmission that binds to DRs, which can induce DR downregulation [ 13 , 14 ]. Also, DAT blockade by cocaine leads to a reduction in DA intracellular concentrations and enhanced TH levels at the dopaminergic terminal [ 58 ]. As previously mentioned, increased DA transmission is an important component of the mechanisms that underlie psychostimulant neurotoxicity [ 16 ].…”

Ontogenetic Expression of Dopamine-Related Transcription Factors and Tyrosine Hydroxylase in Prenatally Stressed Rats

“…Alternatively, other effectors might be regulating TH expression such as the nitrergic system. In this regard, Balda et al (2009) show that neural nitric oxide synthase (nNOS) knockout mice express lower levels of TH-immunoreactive neurons in the VTA area. Since, nNOS is known to be downregulated by glucocorticoids (Lopez-Figueroa et al 1998;Schwarz et al 1998), corticosterone down-regulated nNOS might be inhibiting TH in the early perinatal period.…”

Effects of topiramate on ethanol‐cocaine interactions and DNA methyltransferase gene expression in the rat prefrontal cortex

“…Three of the four genes assessed, Drd2 , Th and Oprm1 , related to the reward system were up‐regulated in the group treated with topiramate and cocaine. Previous studies have demonstrated in animal models that cocaine increased the expression of these three genes (Balda et al ., ; Kreek et al ., ; Lawhorn et al ., ). Nevertheless, our results demonstrate, for the first time, that there is a clear effect with the co‐administration of topiramate, but the underlying mechanism of action is unknown.…”