Baclofen attenuates conditioned locomotion to cues associated with cocaine administration and stabilizes extracellular glutamate levels in rat nucleus accumbens

Hotsenpiller, Gregory; Wolf, Marina E.

doi:10.1016/s0306-4522(02)00951-x

Cited by 59 publications

(31 citation statements)

References 75 publications

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“…In addition, the activity of VTA DA neurons is modulated by excitatory (glutamatergic) and inhibitory (GABAergic) afferents. Activation of GABA B receptors on glutamatergic afferents would reduce excitatory inputs into the VTA (Johnson and North, 1992;Wu et al, 1999;Hotsenpiller and Wolf, 2003). In support of a key role of GABA B receptors in the VTA in blocking cocaineinduced hyperlocomotion, baclofen pretreatment dose dependently reduced nicotine-, morphine-, and cocaineevoked DA release in the NAc (Fadda et al 2003).…”

Section: -37 -mentioning

confidence: 93%

“…In rodents, the GABA B receptor agonist baclofen blocks cocaine-induced hyperlocomotion (Kalivas and Stewart, 1991) and cocaine-conditioned hyperlocomotion (Hotsenpiller and Wolf, 2003). Furthermore, baclofen has shown efficacy in human clinical trials in reducing cocaine, opiate, and alcohol craving (Addolorato et al, 2002;Brebner et al, 2002;Shoptaw et al, 2003;Cousins et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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GABAB Receptor-Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

Lhuillier

Mombereau

Cryan

et al. 2006

Neuropsychopharmacol

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Exposure to cocaine induces selective behavioral and molecular adaptations. In rodents, acute cocaine induces increased locomotor activity, whereas prolonged drug exposure results in behavioral locomotor sensitization, which is thought to be a consequence of druginduced neuroadaptive changes. Recent attention has been given to compounds activating GABA B receptors as potential antiaddictive therapies. In particular, the principle of allosteric positive GABA B receptor modulators is very promising in this respect, as positive modulators lack the sedative and muscle relaxant properties of full GABA B receptor agonists such as baclofen. Here, we investigated the effects of systemic application of the GABA B receptor-positive modulator GS39783 (N,N 0 -dicyclopentyl-2-methylsulfanyl-5-nitropyrimidine-4, 6-diamine) in animals treated with acute and chronic cocaine administration. Both GS39783 and baclofen dose dependently attenuated acute cocaine-induced hyperlocomotion. Furthermore, both compounds also efficiently blocked cocaine-induced Fos induction in the striatal complex. In chronic studies, GS39783 induced a modest attenuation of cocaine-induced locomotor sensitization. Chronic cocaine induces the accumulation of the transcription factor DFosB and upregulates cAMP-response-element-binding protein (CREB) and dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). GS39783 blocked the induction/activation of DARPP-32 and CREB in the nucleus accumbens and dorsal striatum and partially inhibited DFosB accumulation in the dorsal striatum. In summary, our data provide evidence that GS39783 attenuates the acute behavioral effects of cocaine exposure in rodents and in addition prevents the induction of selective long-term adaptive changes in dopaminergic signaling pathways. Further investigation of GABA B receptor-positive modulation as a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse is therefore warranted.

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Section: -37 -mentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

GABAB Receptor-Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

Lhuillier

Mombereau

Cryan

et al. 2006

Neuropsychopharmacol

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“…Indeed, GABAergic stimulation attenuates Pavlovian conditioned responses 108 and impairs conditioned responses to drugs of abuse. 92,109,110 As we acquire basic knowledge of brain circuits involved in addiction and on how environmental variables affect them, we will be able to develop behavioral strategies to compensate for these deficits in a manner akin to what is being proposed to promote plasticity of dysfunctional brain circuits and improve reading ability in children with learning disabilities [111][112][113] or on rehabilitation after brain injury. 114 Dual approaches that pair behavioral strategies with medications to compensate or counteract the neurobiological changes induced by chronic drug exposure or by genetic vulnerabilities are likely to offer in general more robust and longer lasting responses in addiction than either treatment given in isolation.…”

Section: Treatment Implicationsmentioning

confidence: 99%

Dopamine in drug abuse and addiction: results from imaging studies and treatment implications

et al. 2004

Mol Psychiatry

1,026

793

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The involvement of dopamine in drug reinforcement is well recognized but its role in drug addiction is much less clear. Imaging studies have shown that the reinforcing effects of drugs of abuse in humans are contingent upon large and fast increases in dopamine that mimic but exceed in the intensity and duration those induced by dopamine cell firing to environmental events. In addition, imaging studies have also documented a role of dopamine in motivation, which appears to be encoded both by fast as well as smooth DA increases. Since dopamine cells fire in response to salient stimuli, the supraphysiological activation by drugs is likely to be experienced as highly salient (driving attention, arousal conditioned learning and motivation) and may also reset the thresholds required for environmental events to activate dopamine cells. Indeed, imaging studies have shown that in drug-addicted subjects, dopamine function is markedly disrupted (decreases in dopamine release and in dopamine D2 receptors in striatum) and this is associated with reduced activity of the orbitofrontal cortex (neuroanatomical region involved with salience attribution and motivation and implicated in compulsive behaviors) and the cingulate gyrus (neuroanatomical region involved with inhibitory control and attention and implicated in impulsivity). However, when addicted subjects are exposed to drug-related stimuli, these hypoactive regions become hyperactive in proportion to the expressed desire for the drug. We postulate that decreased dopamine function in addicted subjects results in decreased sensitivity to nondrug-related stimuli (including natural reinforcers) and disrupts frontal inhibition, both of which contribute to compulsive drug intake and impaired inhibitory control. These findings suggest new strategies for pharmacological and behavioral treatments, which focus on enhancing DA function and restoring brain circuits disrupted by chronic drug use to help motivate the addicted subject in activities that provide alternative sources of reinforcement, counteract conditioned responses, enhance their ability to control their drive to take drugs and interfere with their compulsive administration.

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“…Furthermore, while AM251 by itself increases glutamate release in the NAc, systemically administered AM251 prevents the cocaine-priming induced increase in NAc glutamate, providing a mechanism for the prevention of reinstatement behavior (Xi et al, 2006). Finally, there is some evidence that the GABAB receptor agonist baclofen can prevent conditioned locomotion to stimuli previously paired with cocaine, and can prevent predatory odor-induced increases in glutamate in the NAc (Hotsenpiller and Wolf, 2003). This is an indication that baclofen may be able to prevent NAc responses to salient stimuli, which may be important for inhibiting drug-seeking behavior in response to conditioned cues.…”

Section: Glutamatementioning

confidence: 99%

Microdialysis and the neurochemistry of addiction

Torregrossa

Kalivas

2008

Pharmacology Biochemistry and Behavior

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Drug addiction is a process beginning with the initial exposure to a drug of abuse, and leading, in some individuals, to chronic habitual use, and high rates of relapse. Microdialysis allows researchers to monitor the neurochemical changes that occur in the brain after the initial exposure to a drug, and the neurochemical changes that occur with repeated exposure. These changes in the brain are often referred to as drug-induced neuroplasticity, and the aim of this article is to review studies that have utilized microdialysis to increase our understanding of the neuroplasticity that occurs in the process of addiction. We will review how several neurotransmitter systems, including glutamate, GABA, the monoamines, and others, are altered after chronic drug exposure, and how microdialysis can be used to determine if putative treatments for addiction can reverse the drug-induced neuroplasticity in these systems. We will also briefly discuss our recent research using a known change in GABA neurotransmission that occurs during reinstatement of drug-seeking to screen for possible novel treatments to prevent relapse. Overall, microdialysis in combination with other behavioral and pharmacological techniques has greatly increased our understanding of addiction related neuroplasticity, and provides a means for discovering new ways to prevent these changes and treat addiction.

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Baclofen attenuates conditioned locomotion to cues associated with cocaine administration and stabilizes extracellular glutamate levels in rat nucleus accumbens

Cited by 59 publications

References 75 publications

GABAB Receptor-Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

GABAB Receptor-Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

Dopamine in drug abuse and addiction: results from imaging studies and treatment implications

Microdialysis and the neurochemistry of addiction

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