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Mediation of amphetamine-induced long-term depression of synaptic transmission by CB1 cannabinoid receptors in the rat amygdala.

ABSTRACT: The amygdala is thought to mediate memory consolidation of amphetamine-induced conditioned place preference, a behavioral paradigm that requires memory for an association between environmental cues and the affective state produced by the drug treatment. Here we show that amphetamine induces long-term synaptic depression (LTD) in the amygdala. Amphetamine LTD is not affected by dopamine, serotonin 1A, and norepinephrine alpha2 receptor antagonists but is blocked by the cannabinoid CB1 receptor antagonist AM251. It is mimicked by the CB1 agonist WIN55212-2 and facilitated and partially occluded by endocannabinoid uptake inhibitor AM404. Both amphetamine and WIN55212-2 LTDs are associated with an increase in the ratio of paired-pulse facilitation and a decrease in the frequency but not the amplitude of miniature EPSCs. They are also sensitive to block by P/Q type calcium channel blocker and occluded by each other, indicating that these two forms of synaptic plasticity share a common underlying mechanism. Loading postsynaptic neuron with calcium chelator blocked amphetamine LTD in some but not all neurons tested. However, in the presence of AM404, amphetamine LTD was present in all neurons recorded. These results suggest that amphetamine-induced endocannabinoid release depends on a rise in intracellular calcium and the incomplete block of LTD in some neurons may be attributable to the spillover of endocannabinoid from nearby cells. The finding that endocannabinoids underlie the synaptic actions of amphetamine may open a new avenue for the treatment of psychostimulants addiction.

SUBMITTER: Huang YC

PROVIDER: S-EPMC6741012 | biostudies-literature | 2003 Nov

REPOSITORIES: biostudies-literature

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Mediation of amphetamine-induced long-term depression of synaptic transmission by CB1 cannabinoid receptors in the rat amygdala.

Huang Ya-Chun YC Wang Su-Jane SJ Chiou Lih-Chu LC Gean Po-Wu PW

The Journal of neuroscience : the official journal of the Society for Neuroscience 20031101 32

The amygdala is thought to mediate memory consolidation of amphetamine-induced conditioned place preference, a behavioral paradigm that requires memory for an association between environmental cues and the affective state produced by the drug treatment. Here we show that amphetamine induces long-term synaptic depression (LTD) in the amygdala. Amphetamine LTD is not affected by dopamine, serotonin 1A, and norepinephrine alpha2 receptor antagonists but is blocked by the cannabinoid CB1 receptor an ...[more]

PMID: 14614090

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Project description:Saliva serves multiple important functions within the body that we typically take for granted, such as helping prepare food for swallowing and defense against oral pathogens. Dry mouth is a primary symptom of Sjӧgren’s syndrome and is a side effect of many drug treatments. Cannabis users frequently report dry mouth, but the basis for this is still unknown. If the effects occur via the endogenous cannabinoid signaling system, then this may represent a novel mechanism for the regulation of salivation. We examined expression of cannabinoid CB1 receptors in submandibular salivary gland using immunohistochemistry and tested regulation of salivation by THC and cannabinoid-related ligands. We now report that CB1 receptors are expressed in the axons of cholinergic neurons innervating the submandibular gland. No staining is seen in submandibular gland epithelial cells (acinar and ductal), or myoepithelial cells (MECs). Treatment with THC (4 mg/kg, IP) or the cannabinoid receptor agonist CP55940 (0.5 mg/kg) reduced salivation in both male and female mice 1 h after treatment. CBD had no effect on its own but reversed the effect of THC in a concentration-dependent manner. Neither the CB1 receptor antagonist SR141716 (4 mg/kg) nor the CB2-selective agonist JWH133 (4 mg/kg) had an effect on salivation. We also found that fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide and related lipids, regulates salivation. Salivation was reduced in FAAH knockout mice as well as mice treated with the FAAH blocker URB597 (4 mg/kg). URB597 had no effect in CB1 knockout mice. FAAH protein is detected intracellularly in acinar but not ductal epithelial cells. In lipidomics experiments, we found that FAAH knockout mice chiefly had elevated levels of acylethanolamines, including anandamide, and reduced levels of acyglycines. Our results are consistent with a model wherein endocannabinoids activate CB1 receptors on cholinergic axons innervating the submandibular gland. THC likely acts by plugging into this system, activating CB1 receptors to reduce salivation, thus offering a mechanism underlying the dry mouth reported by cannabis users.

Project description:Background and purposeBoth cannabinoid CB1 and adenosine A2A receptors (CB1 receptors and A2A receptors) control synaptic transmission at corticostriatal synapses, with great therapeutic importance for neurological and psychiatric disorders. A postsynaptic CB1 -A2A receptor interaction has already been elucidated, but the presynaptic A2A receptor-mediated control of presynaptic neuromodulation by CB1 receptors remains to be defined. Because the corticostriatal terminals provide the major input to the basal ganglia, understanding the interactive nature of converging neuromodulation on them will provide us with novel powerful tools to understand the physiology of corticostriatal synaptic transmission and interpret changes associated with pathological conditions.Experimental approachPharmacological manipulation of CB1 and A2A receptors was carried out in brain nerve terminals isolated from rats and mice, using flow synaptometry, immunoprecipitation, radioligand binding, ATP and glutamate release measurement. Whole-cell patch-clamp recordings were made in horizontal corticostriatal slices.Key resultsFlow synaptometry showed that A2A receptors were extensively co-localized with CB1 receptor-immunopositive corticostriatal terminals and A2A receptors co-immunoprecipitated CB1 receptors in these purified terminals. A2A receptor activation decreased CB1 receptor radioligand binding and decreased the CB1 receptor-mediated inhibition of high-K(+) -evoked glutamate release in corticostriatal terminals. Accordingly, A2A receptor activation prevented CB1 receptor-mediated paired-pulse facilitation and attenuated the CB1 receptor-mediated inhibition of synaptic transmission in glutamatergic synapses of corticostriatal slices.Conclusions and implicationsActivation of presynaptic A2A receptors dampened CB1 receptor-mediated inhibition of corticostriatal terminals. This constitutes a thus far unrecognized mechanism to modulate the potent CB1 receptor-mediated presynaptic inhibition, allowing frequency-dependent enhancement of synaptic efficacy at corticostriatal synapses.

Dataset Information

Mediation of amphetamine-induced long-term depression of synaptic transmission by CB1 cannabinoid receptors in the rat amygdala.

Publications

Mediation of amphetamine-induced long-term depression of synaptic transmission by CB1 cannabinoid receptors in the rat amygdala.

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