Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study sought to assess whether the blockade of ionotropic glutamate receptors in the ventral tegmental area could modulate morphine withdrawal in morphine-dependent rats and the expression of stable DeltaFosB isoforms in the nucleus accumbens during morphine withdrawal. Rats were injected (i.p.) with increasing doses of morphine for 1 week to develop physical dependence, and withdrawal was then precipitated by one injection of naloxone (2 mg/kg, i.p.). Abstinence signs such as jumping, wet-dog shake, writhing posture, weight loss, and Gellert-Holtzman scale score were recorded to evaluate naloxone-induced morphine withdrawal. Two ionotropic glutamate receptor antagonists, dizocilpine (MK-801) and 6, 7-dinitroquinnoxaline-2, 3-dione (DNQX), were microinjected unilaterally into the ventral tegmental area 30 min before naloxone precipitation. A second injection of naloxone (2 mg/kg i.p.) was given 1 h after the first naloxone injection to sustain a maximal level of withdrawal so that the expression of stable DeltaFosB isoforms in the nucleus accumbens could be measured. This would enable determination of the correlation between the MK-801 or DNQX-induced decrease in somatic withdrawal signs and the change in neuronal activity in the nucleus accumbens. The results showed that both MK-801 and DNQX significantly alleviated all symptoms of morphine withdrawal except for weight loss and reduced the expression of stable DeltaFosB isoforms within the nucleus accumbens. These data suggest that ionotropic glutamatergic neurotransmission in the ventral tegmental area regulates the levels of stable DeltaFosB isoforms in the nucleus accumbens, which play a very important role in modulating opiate withdrawal.
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PMID:Ionotropic glutamatergic neurotransmission in the ventral tegmental area modulates DeltaFosB expression in the nucleus accumbens and abstinence syndrome in morphine withdrawal rats. 1630 24

Alcoholism is a heritable disease that afflicts about 8% of the adult population. Its development and symptoms, such as craving, loss of control, physical dependence, and tolerance, have been linked to changes in mesolimbic, mesocortical neurotransmitter systems utilizing biogenic amines, GABA, and glutamate. Identification of genes predisposing to alcoholism, or to alcohol-related behaviors in animal models, has been elusive because of variable interactions of multiple genes with relatively small individual effect size and sensitivity of the predisposing genotype to lifestyle and environmental factors. Here, using near-isogenic advanced animal models with reduced genetic background interactions, we integrate gene mapping and gene mRNA expression data in segregating and congenic mice and identify glutamate receptor metabotropic 7 (Grm7) as a cis-regulated gene for alcohol consumption. Traditionally, the mesoaccumbal dopamine reward hypothesis of addiction and the role of the ionotropic glutamate receptors have been emphasized. Our results lend support to an emerging direction of research on the role of metabotropic glutamate receptors in alcoholism and drug addiction. These data suggest for the first time that Grm7 is a risk factor for alcohol drinking and a new target in addiction therapy.
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PMID:Glutamate receptor metabotropic 7 is cis-regulated in the mouse brain and modulates alcohol drinking. 1793 74

Alcoholism is a serious public health concern that is characterized by the development of tolerance to alcohol's effects, increased consumption, loss of control over drinking and the development of physical dependence. This cycle is often times punctuated by periods of abstinence, craving and relapse. The development of tolerance and the expression of withdrawal effects, which manifest as dependence, have been to a great extent attributed to neuroadaptations within the mesocorticolimbic and extended amygdala systems. Alcohol affects various neurotransmitter systems in the brain including the adrenergic, cholinergic, dopaminergic, GABAergic, glutamatergic, peptidergic, and serotonergic systems. Due to the myriad of neurotransmitter and neuromodulator systems affected by alcohol, the efficacies of current pharmacotherapies targeting alcohol dependence are limited. Importantly, research findings of changes in glutamatergic neurotransmission induced by alcohol self- or experimenter-administration have resulted in a focus on therapies targeting glutamatergic receptors and normalization of glutamatergic neurotransmission. Glutamatergic receptors implicated in the effects of ethanol include the ionotropic glutamate receptors (AMPA, Kainate, and NMDA) and some metabotropic glutamate receptors. Regarding glutamatergic homeostasis, ceftriaxone, MS-153, and GPI-1046, which upregulate glutamate transporter 1 (GLT1) expression in mesocorticolimbic brain regions, reduce alcohol intake in genetic animal models of alcoholism. Given the hyperglutamatergic/hyperexcitable state of the central nervous system induced by chronic alcohol abuse and withdrawal, the evidence thus far indicates that a restoration of glutamatergic concentrations and activity within the mesocorticolimbic system and extended amygdala as well as multiple memory systems holds great promise for the treatment of alcohol dependence.
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PMID:Targeting glutamate uptake to treat alcohol use disorders. 2595 50