Acute and Chronic Cocaine-Induced Potentiation of Synaptic Strength in the Ventral Tegmental Area: Electrophysiological and Behavioral Correlates in Individual Rats

Borgland, Stephanie L.; Malenka, Robert C.; Bonci, Antonello

doi:10.1523/jneurosci.1312-04.2004

Cited by 270 publications

(291 citation statements)

References 38 publications

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“…In vivo administration of drugs of abuse with different molecular mechanisms of action as well as acute stress do, in fact, elicit LTP at excitatory synapses on VTA dopamine neurons (Bonci and Malenka, 1999;Ungless et al, 2001;Saal et al, 2003). The response to cocaine and stress have also been shown to require NMDAR activation (Shors and Servatius, 1995;Li et al, 1999;Thomas et al, 2001;Borgland et al, 2004). Our results suggest that extracellular field potential recording represents a viable alternative to studying these key questions using a technically straightforward approach.…”

Section: Nmdar-dependent Ltp Of Field Potentials Presents a Simpler Mmentioning

confidence: 70%

High-Frequency Afferent Stimulation Induces Long-Term Potentiation of Field Potentials in the Ventral Tegmental Area

Nugent

Hwong

Udaka

et al. 2007

Neuropsychopharmacol

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Excitatory synapses on dopamine neurons in the VTA can undergo both long-term potentiation and depression. Additionally, druginduced plasticity has been found at VTA synapses, and is proposed to play a role in reward-related learning and addiction by modifying dopamine cell firing. LTP at these synapses is difficult to generate experimentally in that it requires an undisturbed intracellular milieu and is often small in magnitude. Here, we demonstrate the induction of LTP as a property of evoked field potentials within the VTA. Excitatory field potentials were recorded extracellularly from VTA neurons in acute horizontal midbrain slices. Using extracellular and intracellular recording techniques, we found that evoked field potentials originate within the VTA itself and are largely composed of AMPA receptor-mediated EPSPs and action potentials triggered by activation of glutamatergic synapses on both dopamine and GABA neurons. High-frequency afferent stimulation (HFS) induced LTP of the field potential. The induction of this LTP was blocked by application of the NMDAR antagonist, d-APV, prior to HFS. As reported previously, glutamatergic synapses on GABA neurons did not express LTP while those on dopamine neurons did. We conclude that the potentiation of glutamatergic synapses on dopamine neurons is a major contributor to NMDA receptor-dependent LTP of the field potential. Field potential recordings may provide a convenient approach to explore the basic electrophysiological properties of VTA neurons and the development of addiction-related processes in this brain region.

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Section: Nmdar-dependent Ltp Of Field Potentials Presents a Simpler Mmentioning

confidence: 70%

High-Frequency Afferent Stimulation Induces Long-Term Potentiation of Field Potentials in the Ventral Tegmental Area

Nugent

Hwong

Udaka

et al. 2007

Neuropsychopharmacol

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“…In addition to behavioral plasticity, repeated cocaine treatment produces neurochemical (Di Chiara and Imperato, 1988), structural (Robinson and Kolb, 2004) and electrophysiological (Thomas et al, 2001;Borgland et al, 2004) alterations in mesocorticolimbic brain regions. These other forms of neural plasticity are all regulated by the Rascontrolled Raf-MEK-ERK protein kinase signaling cascade Sweatt, 1996, 1997;see Impey et al, 1999;Wu et al, 2001;Mazzucchelli et al, 2002;Goldin and Segal, 2003;Thomas and Huganir, 2004 for review).…”

Section: Discussionmentioning

confidence: 99%

Knockout of ERK1 Enhances Cocaine-Evoked Immediate Early Gene Expression and Behavioral Plasticity

Ferguson

Fasano

Yang

et al. 2006

Neuropsychopharmacol

110

100

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The ability of cocaine to produce lasting neural adaptations in mesocorticolimbic brain regions is thought to promote drug seeking and facilitate addiction in humans. The Ras-controlled Raf-MEK-ERK protein kinase signaling cascade has been implicated in the behavioral and neurobiological actions of cocaine in animals. However, these pharmacological studies have not been able to determine the specific role of the two predominant isoforms of ERK (ERK1 and ERK2) in these processes. We report here that deletion of the ERK1 isoform, which leads to increased ERK2 stimulus-dependent signaling, facilitates the development of cocaine-induced psychomotor sensitization and the acquisition of a cocaine conditioned place preference. Conversely, pharmacological blockade of ERK signaling attenuates the development of psychomotor sensitization to cocaine. Finally, cocaine-evoked gene expression in mesocorticolimbic brain regions is potentiated in ERK1-deficient mice. Thus, alterations in ERK signaling influence both the neurobiological impact of cocaine and its ability to produce enduring forms of drug experience-dependent behavioral plasticity. Our results suggest that enhanced ERK2 signaling following repeated drug exposure may facilitate the development of forms of cocaine-induced plasticity that contribute to addiction.

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“…The hypocretin neurons heavily innervate and directly excite neurons in both the VTA and NAc, and hypocretin increases the excitability of VTA neurons by increasing their expression of glutamate receptors. [6][7][8] Most likely, hypocretin amplifies signaling in the mesolimbic pathway. The importance of hypocretin in reward processing is very clear from the observations that mice lacking hypocretin show little or no addiction to morphine, and hypocretin can reinstate drug-seeking behavior in rodents in which this behavior was previously extinguished.…”

Section: S C I E N T I F I C I N V E S T I G a T I O N Smentioning

confidence: 99%

Reward-Seeking Behavior in Human Narcolepsy

Dimitrova

Fronczek

Ploeg

et al. 2011

Journal of Clinical Sleep Medicine

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Study Objectives: The hypocretin system enhances signaling in the mesolimbic pathways regulating reward processing and addiction. Because individuals with narcolepsy with cataplexy have low hypocretin levels, we hypothesized that they may be less prone to risk-and reward-seeking behaviors, including substance abuse. Design: Endpoints were performance on an array of psychometric tests (including the Eysenck Impulsiveness Scale, the Zuckerman Sensation Seeking Scale, the Gormally Binge Eating Scale, and the Beck Depression and Anxiety Inventory) and on the Balloon Analogue Risk Task (BART). Setting: Tertiary narcolepsy referral centers in Leiden (The Netherlands) and Boston (USA). Patients: Subjects with narcolepsy with cataplexy (n = 30), narcolepsy without cataplexy (n = 15), and controls (n = 32) matched for age, sex, and smoking behavior. Interventions: None. Measurements and Results: There was no difference in risktaking behavior between narcolepsy with or without cataplexy and the control group, as measured using the BART and the array of questionnaires. However, subjects in the narcolepsy with cataplexy group had significantly higher scores on the Eysenck Impulsiveness Scale (p < 0.05), with 10.0% categorized as impulsive, compared to 6.7% of the narcolepsy without cataplexy group and none of the controls. Narcoleptics with cataplexy also scored significantly higher than controls on the Binge Eating Scale (p < 0.05), with moderate or severe binge eating in 23%. On the depression and anxiety scales, all narcolepsy patients, especially those with cataplexy, scored significantly higher than controls. Conclusions:We found that narcoleptics with or without cataplexy generally have normal risk-taking behavior, but narcoleptics with cataplexy were more impulsive and more prone to binge eating than patients without cataplexy and controls. Our findings shed new light on the relation between sleepiness and impulsiveness. Furthermore, rates of depression and anxiety were higher in all narcoleptic subjects. However, using the current methods, no evidence could be found to support the hypothesis that hypocretin deficiency would affect reward-processing in humans. Keywords: Narcolepsy, cataplexy, hypocretin, orexin, risktaking, addiction, reward-seeking, substance abuse, sleep, sleepiness Citation: Dimitrova A; Fronczek R; Van der Ploeg J; Scammell T; Gautam S; Pascual-Leone A; Lammers GJ. Rewardseeking behavior in human narcolepsy. S C I E N T I F I C I N V E S T I G A T I O N SN arcolepsy with cataplexy is caused by an extensive loss of the neurons producing the hypocretin (orexin) neuropeptides. 1,2 Loss of these essential signaling molecules results in chronic daytime sleepiness, cataplexy, and other REM sleep associated phenomena. 3 In addition, considerable research indicates that the hypocretin system enhances signaling in the mesolimbic pathways that regulate reward processing and addiction, and hypocretin is now considered a key factor in of the neural mechanisms of drug addiction. 4,5 In response to drugs of a...

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Acute and Chronic Cocaine-Induced Potentiation of Synaptic Strength in the Ventral Tegmental Area: Electrophysiological and Behavioral Correlates in Individual Rats

Cited by 270 publications

References 38 publications

High-Frequency Afferent Stimulation Induces Long-Term Potentiation of Field Potentials in the Ventral Tegmental Area

High-Frequency Afferent Stimulation Induces Long-Term Potentiation of Field Potentials in the Ventral Tegmental Area

Knockout of ERK1 Enhances Cocaine-Evoked Immediate Early Gene Expression and Behavioral Plasticity

Reward-Seeking Behavior in Human Narcolepsy

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