Regional differences in the effects of withdrawal from repeated cocaine upon Homer and glutamate receptor expression: A two-species comparison

Ary, Alexis W.; Szumlinski, Karen K.

doi:10.1016/j.brainres.2007.09.035

Cited by 63 publications

(85 citation statements)

References 90 publications

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“…Preclinical studies in laboratory animals reported cocaine-induced mGluR5 down-regulation in animals after self-administration (Ghasemzadeh et al 2009) and withdrawal (Ary and Szumlinski 2007). Similar data were obtained with cocaine in imaging studies in humans (Martinez et al 2014;Milella et al 2014).…”

Section: Brain Imaging Expression Studiesmentioning

confidence: 52%

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

2016

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RationaleMost habitual smokers find it difficult to quit smoking because they are dependent upon the nicotine present in tobacco smoke. Tobacco dependence is commonly treated pharmacologically using nicotine replacement therapy or drugs, such as varenicline, that target the nicotinic receptor.Relapse rates, however, remain high and there remains a need to develop novel non-nicotinic pharmacotherapies for the dependence that are more effective than existing treatments. ObjectiveThe purpose of this paper is to review the evidence from preclinical and clinical studies that drugs that antagonise the metabotropic glutamate receptor 5 (mGluR5) in the brain are likely to be efficacious as treatments for tobacco dependence. ResultsImaging studies reveal that chronic exposure to tobacco smoke reduces the density of mGluR5s in human brain. Preclinical results demonstrate that negative allosteric modulators (NAMs) at mGluR5 attenuate both nicotine self-administration and the reinstatement of responding evoked by exposure to conditioned cues paired with nicotine delivery. They also attenuate the effects of nicotine on brain dopamine pathways implicated in addiction. ConclusionsAlthough mGluR5 NAMs attenuate most of the key facets of nicotine dependence they potentiate the symptoms of nicotine withdrawal. This may limit their value as smoking cessation aids. The NAMs that have been employed most widely in preclinical studies of nicotine dependence have too many "off target" effects to be used clinically. However newer mGluR5 NAMs have been developed for clinical use in other indications. Future studies will determine if these agents can also be used effectively and safely to treat tobacco dependence.

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Section: Brain Imaging Expression Studiesmentioning

confidence: 52%

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

2016

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“…Finally, in agreement with our findings, preclinical studies demonstrated specific cocaine-induced alterations of mGluR5 expression primarily in the NAcc core rather than globally. [12][13][14][15][16][17] Some limitations of the present report merit comment: i) Due to limited spatial resolution of PET imaging, we cannot fully exclude the possibility that CU may have exhibited subtle differences especially in the NAcc core region in comparison to controls. ii) The present study cannot conclusively answer if the reduced mGluR5 availability in smokers represents a pre-existent condition or is indeed acquired.…”

Section: Discussionmentioning

confidence: 80%

“…Furthermore, we failed to find a significant association between smoking duration and mGluR5 availability. However, when 12 Akkus et al 35 took age into account the association was not significant either. A notable difference emerged with regard to smoking abstinence, where we found that briefer smoking abstinence was associated with lower mGluR5 availability.…”

Section: Discussionmentioning

confidence: 93%

“…Preclinical studies have shown that chronic self-administration of cocaine disrupts synaptic communication between the PFC and the striatum and results in decreased basal levels of non-synaptic, extracellular glutamate in the NAcc. 11,[62][63][64][65] Reduced extracellular glutamate tone in the NAcc core has in turn been associated with downregulation of mGluR5 expression and function in rats, [12][13][14][15][16][17] resulting in disrupted synaptic plasticity, which is assumed to contribute to the persisting nature of addiction. 9 It has been proposed, that the observed down-regulation of mGluR5s and Homer1b/c, post-synaptic scaffolding proteins influencing mGluR5 trafficking and signal transduction, after chronic cocaine administration may constitute a compensatory mechanism, as mGluR5 antagonists attenuate drug-seeking behaviors.…”

Section: Discussionmentioning

confidence: 99%

“…[8][9][10] In particular, glutamatergic projections from the prefrontal cortex (PFC) to the nucleus accumbens (NAcc) appear to be relevant for drug reinstatement and drugseeking behavior in animals and may also play an important role in craving and relapse-related behaviors in psychostimulant-addicted humans. 9,11 Chronic self-administration in rats resulted in lower basal extracellular, non-synaptic glutamate levels in the NAcc, which in turn has been associated with down-regulation of group I and II metabotropic glutamate receptor (mGluR) expression and function in rats, [12][13][14][15][16][17] resulting in altered synaptic plasticity. Impaired plasticity has been suggested to contribute to the relative inability to form adaptive behaviors that help inhibiting relapse in drug users.…”

Section: Introductionmentioning

confidence: 99%

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Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans

et al. 2013

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Long-lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we investigated if human cocaine users (CU) exhibit altered mGluR5 availability compared with drug-naïve control subjects. Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with 11C-ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology. CU and controls did not significantly differ in regional mGluR5 availability. In contrast, smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20%) compared with non-smokers (n=11). In terms of effect sizes, lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50, 21%), insula (d=1.47, 20%), and putamen (d=1.46, 18%). Duration of smoking abstinence was positively associated with mGluR5 density in all brain regions of interest, indicating that lower mGluR5 availability was particularly pronounced in individuals who had smoked very recently. Specifically tobacco smoking was associated with lower mGluR5 availability in both CU and controls, while cocaine use was not linked to detectable mGluR5 alterations. These findings have important implications regarding the development of novel pharmacotherapies aimed at facilitating smoking cessation. AbstractLong-lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we investigated if human cocaine users exhibit altered mGluR5 availability compared to drug-naïve control subjects.Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with 11 C-ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology.Cocaine users and controls did not significantly differ in regional mGluR5 availability. In contrast, smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20%) compared to non-smokers (n=11). In terms of effect sizes, lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50, 21%), insula (d=1.47, 20%), and putamen ...

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No association of alcohol dependence with HOMER 1 and 2 genetic variants

Preuss

Rujescu

Fehr

et al. 2010

American J of Med Genetics Pt B

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Several lines of evidence indicate that alterations of the central cortico-accumbens glutamate pathway are involved in the development and maintenance of alcohol- and substance-use disorders. The HOMER protein family is encoded by 3 genes HOMER (1-3) which are components of the excitatory postsynaptic density complex and function to modulate synaptic activity by the regulation of glutamate signaling. HOMER 1 and 2 have been reported to contribute to chronic alcohol-induced long-term neurochemical changes in the endogenous reward system. Data from animal models suggest a potential role of the Homer protein family in the development of alcohol and substance use. The aim of this study is to assess potential associations between HOMER 1 and 2 genetic variants in a larger sample of alcohol-dependent individuals and unrelated controls. Five genetic variants of HOMER 1 and 3 of HOMER 2 were genotyped in a multi-site sample of 1,923 German healthy controls and 2,039 alcohol-dependent subjects. Neither single SNP nor haplotype analysis could detect significant associations with alcohol dependence (AD) and related phenotypes. While most of the HOMER 1 and 2 SNPs are in low-to-moderate linkage disequilibrium, three major haplotypes of HOMER 1 and 4 haplotypes of HOMER 2 are present in the majority of alcohol-dependent and control subjects. In conclusion, our results suggest that single SNPs, respectively, haplotypes of the HOMER 1 and 2 genes are unlikely to play a major role in the pathophysiology of AD.

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Regional differences in the effects of withdrawal from repeated cocaine upon Homer and glutamate receptor expression: A two-species comparison

Cited by 63 publications

References 90 publications

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans

No association of alcohol dependence with HOMER 1 and 2 genetic variants

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