Viral-mediated expression of extracellular signal-regulated kinase-2 in the ventral tegmental area modulates behavioral responses to cocaine

doi:10.1016/j.bbr.2010.05.040

Behavioural Brain Research

Volume 214, Issue 2, 25 December 2010, Pages 460-464

https://doi.org/10.1016/j.bbr.2010.05.040 Get rights and content

Abstract

Chronic exposure to cocaine increases the activity of extracellular signal-regulated kinase (ERK1/2) in the ventral tegmental area (VTA), a neural substrate for drugs of abuse. However, the functional significance of changes in ERK1/2 activity in this brain region is unknown. Using herpes simplex virus-mediated gene transfer to regulate ERK2 activity within the VTA in male rats, we show that overexpressing ERK2 increases preference for environments previously paired with low doses of cocaine and enhances cocaine-induced locomotion, whereas blocking ERK2 activity blocks cocaine-induced place conditioning and locomotor activity. These results demonstrate that ERK2-signaling within the VTA is a key modulator of functional responses to cocaine.

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Acknowledgements

This work was supported by grants from the National Institute on Drug Abuse (CABG and EJN) and the National Institute of Mental Health (EJN). SDI was supported by a McKnight Fellowship from the Florida Education Fund and a NRSA (F31DA027300) from NIDA. BLW was supported by a Neuroscience Fellowship from the Florida State University.

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Women rapidly progress from recreational cocaine use to dependence, consume greater quantities of cocaine, experience more positive subjective effects of cocaine and have higher incidences of relapse during abstinence. These effects have been replicated in animal models of cocaine addiction and indicate an enhanced sensitivity and therefore, vulnerability of females to cocaine addiction. Furthermore, it has been demonstrated that estradiol (E2) is a key mediator of the aforementioned effects of cocaine in women and female animals. However, studies identifying the influence of E2 on cocaine-associated reward and its underlying neurobiological mechanisms are lacking. Here, we further explored the influence of E2 on cocaine conditioned place preference in female rats. We show that E2 mediates cocaine-conditioned reward by potentiating cocaine-context associations. In addition, the E2-mediated increases in cocaine-induced CPP are associated with increased activation of ERK1/2 and mTOR proteins in the nucleus accumbens, dorsal striatum, and ventral tegmental area. To assess the involvement of ERK1/2 and mTOR in E2-mediated enhanced cocaine-CPP, we inhibited ERK1/2 and/or mTOR activity during cocaine-conditioning and before CPP-test. Inhibition of ERK1/2 during conditioning blocked cocaine-CPP in females, inhibition mTOR was without effect, and inhibiting ERK1/2 and mTOR before CPP-test blocked cocaine-CPP. In conclusion, we have established that E2 enhances cocaine-conditioned reward by potentiating cocaine-context associations formed during conditioning. Additionally, activation of ERK1/2 during cocaine-conditioning is necessary for the potentiation of cocaine-conditioned reward by E2.
Studies characterizing the molecular substrates underlying the effects of E2 during the formation of cocaine-context associations are virtually unknown. In this study, we established the influence of E2 during the formation of cocaine-CPP and characterized the role of ERK1/2 and mTOR activity on this effect within significant nodes of the reward pathway. The elucidation of the role of E2 in cocaine-induced intracellular signaling fills a significant gap in our knowledge regarding the mechanisms by which E2 affects intracellular signaling pathways to indicate the motivational salience of a stimulus. These data are crucial to our understanding of how fluctuating hormone levels can render females increasing sensitive to the rewarding effects of cocaine.
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Two decades ago, the observation of a rapid and sustained antidepressant response after ketamine administration provided an exciting new avenue in the search for more effective therapeutics for the treatment of clinical depression. Research elucidating the mechanism(s) underlying ketamine’s antidepressant properties has led to the development of several hypotheses, including that of disinhibition of excitatory glutamate neurons via blockade of N-methyl-d-aspartate (NMDA) receptors. Although the prominent understanding has been that ketamine’s mode of action is mediated solely via the NMDA receptor, this view has been challenged by reports implicating other glutamate receptors such as AMPA, and other neurotransmitter systems such as serotonin and opioids in the antidepressant response. The recent approval of esketamine (Spravato™) for the treatment of depression has sparked a resurgence of interest for a deeper understanding of the mechanism(s) underlying ketamine’s actions and safe therapeutic use. This review aims to present our current knowledge on both NMDA and non-NMDA mechanisms implicated in ketamine’s response, and addresses the controversy surrounding the antidepressant role and potency of its stereoisomers and metabolites. There is much that remains to be known about our understanding of ketamine’s antidepressant properties; and although the arrival of esketamine has been received with great enthusiasm, it is now more important than ever that its mechanisms of action be fully delineated, and both the short- and long-term neurobiological/functional consequences of its treatment be thoroughly characterized.
Vicarious Social Defeat Stress Induces Depression-Related Outcomes in Female Mice
2018, Biological Psychiatry
Citation Excerpt :
Specifically, ES alters extracellular signal-regulated kinase (ERK)-signaling within these brain regions. ERK is a signaling molecule that has been highly implicated in regulating responses to both affect-related (42–44) and reward-related behaviors (45,46). For example, within the NAcc of male mice, ES increases ERK2 gene expression (27) while decreasing ERK-related signaling transcripts within the ventral tegmental area (21).
Stress is a prevailing risk factor for mood-related illnesses, wherein women represent the majority of those affected by major depression. Despite the growing literature suggesting that affective disorders can arise after a traumatic event is vicariously experienced, this relationship remains understudied in female subjects at the preclinical level. Thus, the objective of the current investigation was to examine whether exposure to emotional and/or psychological stress (ES) mediates depression-related outcomes in female mice.
Female C57BL/6 mice (8 weeks old, null parity) vicariously experienced the defeat bout of a male conspecific, by a male CD1 aggressor, for 10 consecutive days. Twenty-four hours after the last stress exposure, female mice were tested in the social interaction, sucrose preference, tail suspension, or elevated plus maze tests. Furthermore, we examined whether ketamine and chlordiazepoxide, pharmacological agents used to treat mood-related disorders in the clinical population, would reverse the ES-induced social dysfunction.
When compared with control mice, female mice exposed to ES displayed decreased social behavior and preference for sucrose, along with increased immobility in the tail suspension test. Also, they displayed higher levels of blood serum corticosterone, as well as decreased body weight. Lastly, the ES-induced avoidance-like phenotype was ameliorated by both ketamine and chlordiazepoxide.
Our data indicate that female mice exposed to ES display a behavioral and physiologic profile that mimics symptoms of depression in the clinical population. As such, this experimental model may be adopted to examine vicarious stress-induced mood-related disorders, as well as pharmacological antidepressant response, in a sex-specific manner.
Pharmacological modulation of protein kinases as a new approach to treat addiction to cocaine and opiates
2016, European Journal of Pharmacology
Citation Excerpt :
Moreover, concomitant stimulation of dopamine D1 and NMDA receptors induces the formation of a dopamine D1R/NR1 complex, with dopamine D1 receptor facilitating the influx of calcium into the NMDA receptor and the ERK activation (Cahill et al., 2014). ERK signalling has been involved in the locomotor-stimulant effects of cocaine (Iñiguez et al., 2010) and in the sensitization to these effects induced by repeated cocaine administration (Boudreau et al., 2009; Cahill et al., 2014; Kim et al., 2011; Pascoli et al., 2011a, 2011b; Schierberl et al., 2011). Moreover, enhanced the phosphorylation of ERK (p-ERK) in the nucleus accumbens accompanied context-specific sensitization (Marin et al., 2009) and re-exposure to a cocaine-paired environment or drug challenge following a drug-free period (Janes et al., 2009).
Drug addiction shares brain mechanisms and molecular substrates with learning and memory processes, such as the stimulation of glutamate receptors and their downstream signalling pathways. In the present work we provide an up-to-date review of studies that have demonstrated the implication of the main memory-related calcium-dependent protein kinases in opiate and cocaine addiction. The effects of these drugs of abuse in different animal models of drug reward, dependence and addiction are altered by manipulation of the mitogen-activated protein kinase (MAPK) family, particularly extracellular signal regulated kinase (ERK), calcium/calmodulin-dependent kinase II (CaMKII), the protein kinase C (PKC) family (including PKMζ), cAMP-dependent protein kinase A (PKA), cGMP-dependent protein kinase G (PKG), the phosphatidylinositol 3-kinase (PI3K) pathway and its downstream target mammalian target of Rapamycin (mTOR), cyclin-dependent kinase 5 (Cdk5), heat-shock proteins (Hsp) and other enzymes and proteins. Research suggests that drugs of abuse induce dependence and addiction by modifying the signalling pathways that involve these memory-related protein kinases, and supports the idea that drug addiction is an excessive aberrant learning disorder in which the maladaptive memory of drug-associated cues maintains compulsive drug use and contributes to relapse. Moreover, the studies we review offer new pharmacological strategies to treat opiate and cocaine dependence based on the manipulation of these protein kinases. In particular, disruption of reconsolidation of drug-related memories may have a high therapeutic value in the treatment of drug addiction.
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Citation Excerpt :
This suggests that ERK1 acts as an inhibitor on ERK2 activation and a heightened stimulus- or cocaine-induced ERK2 signaling after ERK1 KO.146 In addition, selective ERK2 OE in the VTA resulted in an increase of sensitivity of cocaine-CPP and the repeated cocaine-mediated behavioral sensitization.96 In contrast, inhibition of ERK2 activity in the VTA attenuated the cocaine-CPP and the development and expression of cocaine-induced locomotor sensitization.
Addiction to psychostimulants has been considered as a chronic psychiatric disorder characterized by craving and compulsive drug seeking and use. Over the past two decades, accumulating evidence has demonstrated that repeated drug exposure causes long-lasting neurochemical and cellular changes that result in enduring neuroadaptation in brain circuitry and underlie compulsive drug consumption and relapse. Through intercellular signaling cascades, drugs of abuse induce remodeling in the rewarding circuitry that contributes to the neuroplasticity of learning and memory associated with addiction. Here, we review the role of the extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase, and its related intracellular signaling pathways in drug-induced neuroadaptive changes that are associated with drug-mediated psychomotor activity, rewarding properties and relapse of drug seeking behaviors. We also discuss the neurobiological and behavioral effects of pharmacological and genetic interferences with ERK-associated molecular cascades in response to abused substances. Understanding the dynamic modulation of ERK signaling in response to drugs may provide novel molecular targets for therapeutic strategies to drug addiction.
Life-long consequences of juvenile exposure to psychotropic drugs on brain and behavior
2014, Progress in Brain Research
Psychostimulants such as methylphenidate (MPH) and antidepressants such as fluoxetine (FLX) are widely used in the treatment of various mental disorders or as cognitive enhancers. These medications are often combined, for example, to treat comorbid disorders. There is a considerable body of evidence from animal models indicating that individually these psychotropic medications can have detrimental effects on the brain and behavior, especially when given during sensitive periods of brain development. However, almost no studies investigate possible interactions between these drugs. This is surprising given that their combined neurochemical effects (enhanced dopamine and serotonin neurotransmission) mimic some effects of illicit drugs such as cocaine and amphetamine. Here, we summarize recent studies in juvenile rats on the molecular effects in the mid- and forebrain and associated behavioral changes, after such combination treatments. Our findings indicate that these combined MPH + FLX treatments can produce similar molecular changes as seen after cocaine exposure while inducing behavioral changes indicative of dysregulated mood and motivation, effects that often endure into adulthood.

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Short communicationViral-mediated expression of extracellular signal-regulated kinase-2 in the ventral tegmental area modulates behavioral responses to cocaine

Abstract

Section snippets

Acknowledgements

Biochimie

Neuroscience

Brain Res

Neurosci Biobehav Rev

Curr Opin Pharmacol

Brain Res Rev

Cell

Trends Neurosci

Neuron

Neuroscience

Brain Res Brain Res Rev

Brain Res Brain Res Rev

Conditioned place preference: what does it add to our preclinical understanding of drug reward?

Psychopharmacology (Berl)

5-HT(1B) receptors in nucleus accumbens efferents enhance both rewarding and aversive effects of cocaine

Eur J Neurosci

Non-psychostimulant drugs of abuse and anxiogenic drugs activate with differential selectivity dopamine transmission in the nucleus accumbens and in the medial prefrontal cortex of the rat

Psychopharmacology (Berl)

Regulation of ERK (extracellular signal regulated kinase), part of the neurotrophin signal transduction cascade, in the rat mesolimbic dopamine system by chronic exposure to morphine or cocaine

J Neurosci

Neurotrophic mechanisms in drug addiction

Neuromol Med

C gamma in distinct regions of the ventral tegmental area differentially regulates morphine-induced locomotor activity

Synapse

Phospholipase Cgamma in distinct regions of the ventral tegmental area differentially modulates mood-related behaviors

J Neurosci

Sensitization to morphine induced by viral-mediated gene transfer

Science

Distinct sites of opiate reward and aversion within the midbrain identified using a herpes simplex virus vector expressing GluR1

J Neurosci

Short communication
Viral-mediated expression of extracellular signal-regulated kinase-2 in the ventral tegmental area modulates behavioral responses to cocaine