Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D05731 (Rimonabant)
 326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reinforcing effects mediated by accumbal CB(1) receptors (CB(1)R) are controversial, as well as their role in the rewarding effects of cocaine. Accumbal glutamate and glutamate receptors have been proposed to be involved in CB(1)R-mediated effects on cocaine reward. Rewarding effects of cocaine can be evaluated with the conditioned place preference or CPP test. Rimonabant, a cannabinoid CB(1)R ligand, lentiviruses aimed at silencing CB(1)R, and selective glutamatergic ligands are good tools for studying the function of accumbal CB(1) and glutamate receptors. The objectives of the present study were (i) to discern the CPP effects of in vivo gene silencing of accumbal CB(1) receptors by means of lentiviruses containing siRNAs; (ii) to discern the CPP effects of intra-accumbens infusions of the cannabinoid CB(1)R ligand rimonabant, and to evaluate whether effects are due to receptor blockade or inverse agonism; (iii) to discern the role of CB(1)R located within the nucleus accumbens shell in the rewarding effects of cocaine, by means of local infusions of rimonabant, and (iv) to discern the role of glutamate receptors (AMPAR, NMDAR, mGluR2/3) in rimonabant-induced effects on CPP in cocaine-treated rats. The findings revealed that in vivo silencing of accumbal CB(1) receptors with Lenti-CB(1)R-siRNAs induced place aversion to cocaine, but intra-accumbal rimonabant induced place preference in its own right, indicating that this compound seems to act as inverse agonist on the CPP. Glutamate receptors participate in rimonabant-mediated place preference because it was abolished after blocking AMPA glutamate receptors, but not NMDAR or mGluR2/3. Finally, in cocaine-treated rats, local rimonabant induced place aversion to the drug (not place preference), and this effect was mediated by glutamate neurotransmission because it was abolished after blockade of AMPA, NMDA or mGlu2/3 receptors, even though only the blockade of mGlu2/3 autoreceptors restored the emergence of place preference to cocaine.
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PMID:Intra-accumbens rimonabant is rewarding but induces aversion to cocaine in cocaine-treated rats, as does in vivo accumbal cannabinoid CB1 receptor silencing: critical role for glutamate receptors. 2016 55

Chronic activation or inhibition of cannabinoid receptors (CB1) leads to continuous suppression of neuronal plasticity in hippocampus and other brain regions, suggesting that endocannabinoids may have a functional role in synaptic processes that produce state-dependent transient modulation of hippocampal cell activity. In support of this, it has previously been shown in vitro that cannabinoid CB1 receptors modulate second messenger systems in hippocampal neurons that can regulate operation of intracellular processes including receptors which release calcium from intracellular stores. Here we demonstrate in hippocampal slices a similar endocannabinoid action on excitatory glutamatergic synapses via modulation of NMDA-receptor mediated intracellular calcium levels in confocal imaged neurons. Calcium entry through glutamatergic NMDA-mediated ion channels increases intracellular calcium concentrations by modifying release from ryanodine-sensitive channels in endoplasmic reticulum. The studies reported here show that NMDA-elicited increases in Calcium Green fluorescence are enhanced by CB1 receptor antagonists (i.e., Rimonabant), and inhibited by CB1 agonists (i.e., WIN 55,212-2). Suppression of endocannabinoid breakdown by either reuptake inhibition (AM404) or fatty-acid amide hydrolase inhibition (URB597) produced suppression of NMDA-elicited calcium increases comparable to WIN 55,212-2, while enhancement of calcium release provoked by endocannabinoid receptor antagonists (Rimonabant) was shown to depend on the blockade of CB1receptor mediated de-phosphorylation of Ryanodine receptors. Such CB1 receptor modulation of NMDA elicited increases in intracellular calcium may account for the respective disruption and enhancement by CB1 agents of trial-specific hippocampal neuron ensemble firing patterns during performance of a short-term memory task, reported previously from this laboratory.
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PMID:Cannabinoid receptor activation modifies NMDA receptor mediated release of intracellular calcium: implications for endocannabinoid control of hippocampal neural plasticity. 2128 75