Neurophysiological Signals as Potential Translatable Biomarkers for Modulation of Metabotropic Glutamate 5 Receptors.

Neurophysiological signals as potential translatable biomarkers for modulation of metabotropic glutamate 5 receptors.

Neuropharmacology. 2013 Jul 4;
Harvey BD, Siok CJ, Kiss T, Volfson D, Grimwood S, Shaffer CL, Hajós M

The Group I metabotropic glutamate receptor subtype 5 (mGluR5) is widely distributed in the brain with dense expression in the cerebral cortex, hippocampus, and basal ganglia. These receptors have been implicated in psychiatric and neurological disorders such as schizophrenia, Fragile X syndrome, addiction, anxiety/depression, Parkinson’s disease and neuropathic pain. The present study evaluated the effects of the mGluR5 negative allosteric modulators (NAMs) 4-difluoromethoxy-3-(pyridine-2-ylethynyl)phenyl)5H-pyrrolo[3,4-b]pyridine-6(7H)-yl methanone (GRN-529) and methyl (3aR,4S,7aR)-4-hydroxy-4-[(3-methylphenyl)ethynyl]octahydro-1H-indole-1-carboxylate (AFQ056) on polysomnographic (PSG) and quantitative electroencephalographic (qEEG) measures in freely moving rats. Furthermore, the anxiolytic profile of GRN-529 was characterized in anesthetized rats by measuring stimulation-induced hippocampal theta oscillation. The present findings demonstrate that inhibition of mGluR5 via its allosteric site profoundly modulates high-level neuronal network activities as indicated by changes in sleep-wake activity and power distribution of qEEG. Both GRN-529 and AFQ056 reduced the total time spent in rapid-eye movement with AFQ056 producing a significant increase in wakefulness at the highest dose tested. Additionally, qEEG revealed significant compound-induced increases in delta power concomitant with more subtle decreases in theta and alpha band power. Receptor occupancy (RO) studies revealed that GRN-529 and AFQ056 at all doses resulted in over 45% mGluR5 occupancy. Furthermore, GRN-529 dose-dependently decreased elicited hippocampal theta frequency, consistent with previous findings using clinically active anxiolytic compounds. The described changes in neurophysiological signals identified in freely moving rats may be considered suitable translational biomarkers for the clinical evaluation of mGluR5 NAMs. HubMed – addiction


Role of amygdala in drug memory.

Neurobiol Learn Mem. 2013 Jul 2;
Luo YX, Xue YX, Shen HW, Lu L

Drug addiction is a chronic brain disorder with the hallmark of a high rate of relapse to compulsive drug seeking and drug taking even after long-term abstinence. Addiction has been considered as an aberrant memory that has been termed “addiction memory.” Drug-related memory plays a critical role in the maintenance of learned addictive behaviors and emergence of relapse. Disrupting these long-lasting memories by administering amnestic agents or other manipulations during specific phases of drug memory is a promising strategy for relapse prevention. Recent studies on the processes of drug addiction and relapse have demonstrated that the amygdala is involved in associative drug addiction learning processes. In this review, we focus on preclinical studies that used conditioned place preference and self-administration models to investigate the differential roles of the amygdala in each phase of drug-related memory, including acquisition, consolidation, retrieval, reconsolidation, and extinction. These studies indicate that the amygdala plays a critical role in both cue-associative learning and the expression of cue-induced relapse to drug-seeking behavior. HubMed – addiction


Partial extinction of a conditioned context enhances preference for elements previously associated with cocaine but not with chocolate.

Physiol Behav. 2013 Jul 3;
Orsini C, Bonito-Oliva A, Montanari C, Conversi D, Cabib S

Drug-associated stimuli are crucial to reinstatement of drug-seeking after periods of abstinence, representing a central problem in treatment of addiction. The present study investigated the influence of partial extinction of the conditioned context on the expression of conditioned place preference (CPP). Mice of the inbred DBA/2J strain were conditioned with cocaine or chocolate in a context identified by multiple elements (A+B) and subsequently CPP expression was evaluated in a context containing only one element (A or B) or both (A+B). Cocaine- and chocolate-conditioned mice showed CPP in presence of the original compound stimulus. However, cocaine-conditioned mice did not show CPP when tested in A or B context, while chocolate-conditioned mice did show CPP to single elements context. After conditioning mice were exposed to extinction training of the context A or B and then tested for CPP 1 and 9days after the end of the extinction (days 9 and 18). Cocaine-conditioned mice showed CPP 9days after extinction while chocolate-conditioned mice were relatively insensitive to the extinction procedure on day 1 after extinction, but they did not show CPP for the partial or the original compound 9days after extinction. Cocaine-conditioned mice not submitted to the extinction training (simple passage of time) or submitted to a sham-extinction procedure (saline injections and confinement in a new environment) did not show CPP on day 9 or 18. Cocaine-conditioned mice exposed to extinction training showed increased c-fos expression in several brain areas in comparison to mice exposed to sham-extinction. The extinction procedure not specifically reduced behavioral sensitization. The results suggest that extinction training involving only elements of a drug-associated context can result in increased associative strength of those elements. HubMed – addiction


Ghrelin amplifies the nicotine-induced dopamine release in the rat striatum.

Neurochem Int. 2013 Jul 3;
Palotai M, Bagosi Z, Jászberényi M, Csabafi K, Dochnal R, Manczinger M, Telegdy G, Szabó G

The orexigenic peptide ghrelin plays a prominent role in the regulation of energy balance and in the mediation of reward mechanisms and reinforcement for addictive drugs, such as nicotine. Nicotine is the principal psychoactive component in tobacco, which is responsible for addiction and relapse of smokers. Nicotine activates the mesencephalic dopaminergic neurons via nicotinic acetylcholine receptors (nAchR). Ghrelin stimulates the dopaminergic neurons via growth hormone secretagogue receptors (GHS-R1A) in the ventral tegmental area and the substantia nigra pars compacta resulting in the release of dopamine in the ventral and dorsal striatum, respectively. In the present study an in vitro superfusion of rat striatal slices was performed, in order to investigate the direct action of ghrelin on the striatal dopamine release and the interaction of ghrelin with nicotine through this neurotransmitter release. Ghrelin increased significantly the dopamine release from the rat striatum following electrical stimulation. This stimulatory effect was reversed by both the selective nAchR antagonist mecamylamine and the selective GHS-R1A antagonist GHRP-6. Nicotine also increased significantly the dopamine release under the same conditions. This stimulatory effect was antagonized by mecamylamine, but not by GHRP-6. Ghrelin further stimulated the nicotine-induced dopamine release, as this effect was abolished by mecamylamine and was partially inhibited by GHRP-6. The present results demonstrate that ghrelin stimulates directly the dopamine release and amplifies nicotine-induced dopamine release in the rat striatum. We presume that striatal cholinergic interneurons also express GHS-R1A, through which ghrelin can amplify the nicotine-induced dopamine release in the striatum. This study provides further evidence of the impact of ghrelin on the mesolimbic and nigrostriatal dopaminergic pathways. It also suggests that ghrelin signaling may serve as a novel pharmacological target for treatment of addictive and neurodegenerative disorders. HubMed – addiction



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