Cocaine modulates both glutaminase gene expression and glutaminase activity in the brain of cocaine-sensitized mice

Blanco, Eduardo; Campos-Sandoval, José A.; Palomino, A.; Rojas, María Jesús Luque; Bilbao, Ainhoa; Suárez, Juan; Márquez, Javier; Fonseca, Fernando Rodrı́guez de

doi:10.1007/s00213-011-2418-x

Cited by 18 publications

(24 citation statements)

References 48 publications

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“…This offers unique opportunities for glutamine metabolism-based therapies in the brain. One possibility derives from work by Blanco et al ., who showed that cocaine-sensitized mice exhibited a decrease in glutaminase activity in the brain, with GLS1 being altered to a much greater extent than GLS2 [58]. Although the exact patterns of changes in expression and activity varied depending upon the region of the brain examined, this still suggests that glutaminase function is affected through the use of cocaine.…”

Section: Introductionmentioning

confidence: 99%

Glutaminase regulation in cancer cells: a druggable chain of events

Katt

Cerione

2014

Drug Discovery Today

103

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Metabolism is the process by which cells convert relatively simple extracellular nutrients into energy and building blocks necessary for their growth and survival. In cancer cells, metabolism is dramatically altered compared with normal cells. These alterations are known as the Warburg effect. One consequence of these changes is cellular addiction to glutamine. Because of this, in recent years the enzyme glutaminase has become a key target for small molecule therapeutic intervention. Like many oncotargets, however, glutaminase has a number of upstream partners that might offer additional druggable targets. This review summarizes the work from the current decade surrounding glutaminase and its regulation, and suggests strategies for therapeutic intervention in relevant cases.

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Section: Introductionmentioning

confidence: 99%

Glutaminase regulation in cancer cells: a druggable chain of events

Katt

Cerione

2014

Drug Discovery Today

103

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“…Thus, the action of cocaine in noradrenergic target circuits could also contribute to the behavioral response. Elevated catecholamine transmission is a primary mediator of cocaine addiction, and repeated exposure to cocaine is associated with the recruitment of glutaminase expression and glutamatergic transmission (Glowinski and Axelrod, 1965; Cornish and Kalivas, 2000; Malenka and Bear, 2004; Lopez-Moreno et al, 2008; Ruiz et al, 2010; Blanco et al, 2012). Regarding the cerebellum, the potentiating effects of cocaine on the GABA-mediated inhibition of Purkinje neurons were not observed after the selective depletion of noradrenergic neurons (Waterhouse et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Effects of acute versus repeated cocaine exposure on the expression of endocannabinoid signaling-related proteins in the mouse cerebellum

Palomino¹,

Pavón²,

Calvo³

et al. 2014

Front. Integr. Neurosci.

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Growing awareness of cerebellar involvement in addiction is based on the cerebellum’s intermediary position between motor and reward, potentially acting as an interface between motivational and cognitive functions. Here, we examined the impact of acute and repeated cocaine exposure on the two main signaling systems in the mouse cerebellum: the endocannabinoid (eCB) and glutamate systems. To this end, we investigated whether eCB signaling-related gene and protein expression {cannabinoid receptor type 1 receptors and enzymes that produce [diacylglycerol lipase alpha/beta (DAGLα/β) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD)] and degrade [monoacylglycerol lipase (MAGL) and fatty acid amino hydrolase (FAAH)] eCB} were altered. In addition, we analyzed the gene expression of relevant components of the glutamate signaling system [glutamate synthesizing enzymes liver-type glutaminase isoform (LGA) and kidney-type glutaminase isoform (KGA), metabotropic glutamatergic receptor (mGluR3/5), NMDA-ionotropic glutamatergic receptor (NR1/2A/2B/2C) and AMPA-ionotropic receptor subunits (GluR1/2/3/4)] and the gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, because noradrenergic terminals innervate the cerebellar cortex. Results indicated that acute cocaine exposure decreased DAGLα expression, suggesting a down-regulation of 2-arachidonylglycerol (2-AG) production, as well as gene expression of TH, KGA, mGluR3 and all ionotropic receptor subunits analyzed in the cerebellum. The acquisition of conditioned locomotion and sensitization after repeated cocaine exposure were associated with an increased NAPE-PLD/FAAH ratio, suggesting enhanced anandamide production, and a decreased DAGLβ/MAGL ratio, suggesting decreased 2-AG generation. Repeated cocaine also increased LGA gene expression but had no effect on glutamate receptors. These findings indicate that acute cocaine modulates the expression of the eCB and glutamate systems. Repeated cocaine results in normalization of glutamate receptor expression, although sustained changes in eCB is observed. We suggest that cocaine-induced alterations to cerebellar eCB should be considered when analyzing the adaptations imposed by psychostimulants that lead to addiction.

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“…This phenomenon, known as behavioral sensitization, is thought to underlie drug craving and relapse, and therefore it is one of the possible mechanisms implicated in cocaine abuse and dependence (Robinson and Berridge, ; Steketee, ). In rodents, behavioral sensitization is frequently studied using a challenge injection of cocaine in animals withdrawn from repeated cocaine administration (Blanco et al, ,b). This challenge injection elicits a higher locomotor activity than that observed in animals injected with an acute dose of cocaine, indicating a sensitized response to the drug (Kalivas and Stewart, ).…”

Section: Introductionmentioning

confidence: 99%

Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats

Galeano

Romero

Rojas

et al. 2013

Synapse

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Perinatal asphyxia (PA) increases the likelihood of suffering from dopamine-related disorders, such as ADHD and schizophrenia. Since dopaminergic transmission plays a major role in cocaine sensitization, the purpose of this study was to determine whether PA could be associated with altered behavioral sensitization to cocaine. To this end, adult rats born vaginally (CTL), by caesarean section (C+), or by C+ with 15 min (PA15, moderate PA) or 19 min (PA19, severe PA) of global anoxia were repeatedly administered with cocaine (i.p., 15 mg/kg) and then challenged with cocaine (i.p., 15 mg/kg) after a 5-day withdrawal period. In addition, c-Fos, FosB/ΔFosB, DAT, and TH expression were assessed in dorsal (CPu) and ventral (NAcc) striatum. Results indicated that PA15 rats exhibited an increased locomotor sensitization to cocaine, while PA19 rats displayed an abnormal acquisition of locomotor sensitization and did not express a sensitized response to cocaine. c-Fos expression in NAcc, but not in CPu, was associated with these alterations in cocaine sensitization. FosB/ΔFosB expression was increased in all groups and regions after repeated cocaine administration, although it reached lower expression levels in PA19 rats. In CTL, C+, and PA15, but not in PA19 rats, the expression of TH in NAcc was reduced in groups repeatedly treated with cocaine, independently of the challenge test. Furthermore, this reduction was more pronounced in PA15 rats. DAT expression remained unaltered in all groups and regions studied. These results suggest that moderate PA may increase the vulnerability to drug abuse and in particular to cocaine addiction.

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Cocaine modulates both glutaminase gene expression and glutaminase activity in the brain of cocaine-sensitized mice

Abstract: The present results indicate that glutaminase enzymes (mainly KGA) are modulated by cocaine in both the prefrontal cortex and the dorsal striatum, as part of the neuroadaptions associated with behavioural sensitization to this drug of abuse.

Cited by 18 publications

References 48 publications

Glutaminase regulation in cancer cells: a druggable chain of events

Glutaminase regulation in cancer cells: a druggable chain of events

Effects of acute versus repeated cocaine exposure on the expression of endocannabinoid signaling-related proteins in the mouse cerebellum

Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats

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