Methamphetamine Blocks Adenosine A2A Receptor Activation via Sigma 1 and Cannabinoid CB1 Receptors (original) (raw)
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British Journal of Pharmacology, 2010
Adenosine and endocannabinoids are very ubiquitous non-classical neurotransmitters that exert a modulatory role on the transmission of other more ‘classical’ neurotransmitters. In this review we will focus on their common role as modulators of dopamine and glutamate neurotransmission in the striatum, the main input structure of the basal ganglia. We will pay particular attention to the role of adenosine A2A receptors and cannabinoid CB1 receptors. Experimental results suggest that presynaptic CB1 receptors interacting with A2A receptors in cortico-striatal glutamatergic terminals that make synaptic contact with dynorphinergic medium-sized spiny neurons (MSNs) are involved in the motor-depressant and addictive effects of cannabinoids. On the other hand, postsynaptic CB1 receptors interacting with A2A and D2 receptors in the dendritic spines of enkephalinergic MSNs and postsynaptic CB1 receptors in the dendritic spines of dynorphinergic MSN are probably involved in the cataleptogenic effects of cannabinoids. These receptor interactions most probably depend on the existence of a variety of heteromers of A2A, CB1 and D2 receptors in different elements of striatal spine modules. Drugs selective for the different striatal A2A and CB1 receptor heteromers could be used for the treatment of neuropsychiatric disorders and drug addiction and they could provide effective drugs with fewer side effects than currently used drugs.This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x
Striatal adenosine-cannabinoid receptor interactions in rats over-expressing adenosine A2Areceptors
Journal of Neurochemistry, 2015
Adenosine A 2A receptors (A 2A Rs) and cannabinoid CB 1 receptors (CB 1 Rs) are highly expressed in the striatum, where they functionally interact and form A 2A /CB 1 heteroreceptor complexes. We investigated the effects of CB 1 R stimulation in a transgenic rat strain over-expressing A 2A Rs under the control of the neural-specific enolase promoter (NSEA 2A rats) and in age-matched wild-type (WT) animals. The effects of the CB 1 R agonist WIN 55,212-2 (WIN) were significantly lower in NSEA 2A rats than in WT animals, as demonstrated by i) electrophysiological recordings of synaptic transmission in corticostriatal slices; ii) the measurement of glutamate outflow from striatal synaptosomes and iii) in vivo experiments on locomotor activity. Moreover, while the effects of WIN were modulated by both A 2A R agonist (CGS 21680) and antagonists (ZM 241385, KW-6002 and SCH-442416) in WT animals, the A 2A R antagonists failed to influence WIN-mediated effects in NSEA 2A rats. The present results demonstrate that in rats with genetic neuronal overexpression of A 2A Rs, the effects mediated by CB 1 R activation in the striatum are significantly reduced, suggesting a change in the stoichiometry of A 2A and CB 1 receptors and providing a strategy to dissect the involvement of A 2A R forming or not forming heteromers in the modulation of striatal functions. These findings add additional evidence for the existence of an interaction between striatal A 2A Rs and CB 1 Rs, playing a fundamental role in the regulation of striatal functions.
Molecular Brain Research, 1996
Multiple injections of methamphetamine WETHI produce long-lasting neurotoxic effects on the nigrostriatal dopamine (DA) system. The drug also causes increases in AP-1 A-binding activity in mice. Im the present study. wc tested the idea that toxic doses of METH might cause long-term increases in AP-I NA-binding. ice were giveq 10 mg/kg of METH 2. 3 or 4 times at a 2 h interval in 1 day. Striatal DA levels were markedly decreased at 3 h and 24 h in all injection groups. After 1 week, striatal DA level recovered to near control in the METH X2 group. but were still significantly decreased in the METH X3 and X4 groups. Similar drug administration schedules caused increases in AP-1 DNA-binding activity at the 3 h time point in all groups. The AP-1-binding activitj almost returned back to control level in the X 2 and X 3 injection groups at the 23. h and 1 week time point, but there were still increased levels of AP-l-binding activity in the METH X4 group. These findings raise the possibility that METH-induced neurotoxicity might involve prolonged activation of AP-I transcription factor. This might be related to the report that c-jijs or c-jm acti\.ation n-q be important in some models of neurodegeneration. Although methamphetamine (METH) is a well known toxicant, the cellular and molecular mechanisms involved in causing damage to monoaminergic systems are not fully clear. We have shown that oxygen-based radicals are probably involved in METH-induced neurotoxicity to DA systems [f-3,5,6]. Studies from this laboratory have also shown that the AP-1 DNA binding activity can be induced by methamphetamine administration in a dose-dependent fashion [ 121. In that study, non-toxic doses of the drug were used. AP-1 (.Tun/Fos) is constitutivefy expressed at low fevels in usual situations but can be rapidly induced in situations such as brain injury, seizure activity, stress and drug treatment [2,7,9.17]. In addition, Jun (AP-1) is also activated by carcinogenic agents, UV, gamma irradiation, NO, and DNA damage [S, 10,l I, 151. Because oxygen-based radicals are known activators of AP-1 [ 12,151 and because ??
…, 2007
The mechanism of action responsible for the motor depressant effects of cannabinoids, which operate through centrally expressed cannabinoid CB 1 receptors, is still a matter of debate. In the present study, we report that CB 1 and adenosine A 2A receptors form heteromeric complexes in co-transfected HEK-293T cells and rat striatum, where they colocalize in fibrilar structures. In a human neuroblastoma cell line, CB 1 receptor signaling was found to be completely dependent on A 2A receptor activation. Accordingly, blockade of A 2A receptors counteracted the motor depressant effects produced by the intrastriatal administration of a cannabinoid CB 1 receptor agonist. These biochemical and behavioral findings demonstrate that the profound motor effects of cannabinoids depend on physical and functional interactions between striatal A 2A and CB 1 receptors.
Adenosine–cannabinoid receptor interactions. Implications for striatal function
British journal of …, 2010
Adenosine and endocannabinoids are very ubiquitous non-classical neurotransmitters that exert a modulatory role on the transmission of other more 'classical' neurotransmitters. In this review we will focus on their common role as modulators of dopamine and glutamate neurotransmission in the striatum, the main input structure of the basal ganglia. We will pay particular attention to the role of adenosine A2A receptors and cannabinoid CB1 receptors. Experimental results suggest that presynaptic CB1 receptors interacting with A2A receptors in cortico-striatal glutamatergic terminals that make synaptic contact with dynorphinergic medium-sized spiny neurons (MSNs) are involved in the motor-depressant and addictive effects of cannabinoids. On the other hand, postsynaptic CB1 receptors interacting with A2A and D2 receptors in the dendritic spines of enkephalinergic MSNs and postsynaptic CB1 receptors in the dendritic spines of dynorphinergic MSN are probably involved in the cataleptogenic effects of cannabinoids. These receptor interactions most probably depend on the existence of a variety of heteromers of A2A, CB1 and D2 receptors in different elements of striatal spine modules. Drugs selective for the different striatal A2A and CB1 receptor heteromers could be used for the treatment of neuropsychiatric disorders and drug addiction and they could provide effective drugs with fewer side effects than currently used drugs.
Neuropharmacology, 2014
Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. D 9 -tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB 1 and CB 2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB 2 , but not of CB 1 , blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of methamphetamine considerably reduces the neurotoxicity of the drug through CB 2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain.
Metabolic Brain Disease, 2013
There is an abundance of evidence showing that repeated use of 3,4-methlylenedioxymethamphetamine (MDMA; ecstasy) is associated with brain dysfunction, memory disturbance, locomotor hyperactivity, and hyperthermia. MDMA is toxic to both the serotonergic neurons and dopaminergic system. Adenosine is an endogenous purine nucleoside with a neuromodulatory function in the central nervous system. Nuclear factor kappa-B (NF-kB) plays a pivotal role in the initiation and perpetuation of an immune response by triggering the expression of major inflammatory mediators such as cytokines, chemokines, and adhesion molecules. Here, we investigated the effects of the A2a adenosine receptor (A2a-R) agonist (CGS) and antagonist (SCH) on NF-kB expression after MDMA administration. Male Sprague-Dawley rats were injected to MDMA (10 mg/kg) followed by intraperitoneal injection of either CGS or SCH (0.03 mg/kg each) to animals. The hippocampi were then removed for western blot and RT-PCR analyses. MDMA significantly elevated NF-kB expression. Our results show that administration of CGS following MDMA significantly elevated the NF-kB expression both at mRNA and protein levels. By contrast, administration of the A2a-R antagonist SCH resulted in a decrease in the NF-kB levels. Taken together, these results indicate that, co-administration of A2a agonist (CGS) can protect against MDMA neurotoxic effects by increasing NF-kB expression levels; suggesting a potential application for protection against the neurotoxic effects observed in MDMA users.
Proceedings of the National Academy of Sciences, 2003
The mesolimbic dopamine system and cAMP-dependent͞protein kinase A (PKA) pathways are strongly implicated in addictive behaviors. Here we determine the role of dopamine D2 receptors (D2) in PKA signaling responses to ␦-opioid (DOR) and cannabinoid (CB1) receptors. We find in NG108-15͞D2 cells and in cultured primary neurons that a brief exposure to saturating concentrations of DOR and CB1 agonists increases cAMP, promotes PKA C␣ translocation and increases cAMP-dependent gene expression. Activation of PKA signaling is mediated by Gi-␥ dimers. Importantly, subthreshold concentrations of DOR or CB1 agonists with D2 agonists, which are without effect when added separately, together activate cAMP͞PKA signaling synergistically. There is also synergy between DOR or CB1 with ethanol, another addicting agent. In all instances, synergy requires adenosine activation of adenosine A2 receptors and is mediated by ␥ dimers. Synergy by this molecular mechanism appears to confer hypersensitivity to opioids and cannabinoids while simultaneously increasing the sensitivity of D2 signaling when receptors are expressed on the same cells. This mechanism may account, in part, for drug-induced activation of medium spiny neurons in the nucleus accumbens.
Addiction Biology, 2011
Several recent studies suggest functional and molecular interactions between striatal adenosine A 2A and cannabinoid CB 1 receptors. Here we demonstrate that A 2A receptors selectively modulate reinforcing effects of cannabinoids. We studied effects of A 2A receptor blockade on the reinforcing effects of delta-9-tetrahydrocannabinol (THC) and the endogenous CB 1 receptor ligand anandamide under a fixed-ratio (FR) schedule of intravenous drug injection in squirrel monkeys. A low dose of the selective adenosine A 2A receptor antagonist MSX-3 (1 mg/kg) caused downward shifts of THC and anandamide dose-response curves. In contrast, a higher dose of MSX-3 (3 mg/kg) shifted THC and anandamide dose-response curves to the left. MSX-3 did not modify cocaine or food-pellet self-administration. Also, MSX-3 neither promoted reinstatement of extinguished drug-seeking behavior nor altered reinstatement of drug-seeking behavior by noncontingent priming injections of THC. Finally, using in-vivo microdialysis in freely-moving rats, a behaviorally active dose of MSX-3 significantly counteracted THC-induced, but not cocaineinduced, increases in extracellular dopamine levels in the nucleus accumbens shell. The significant and selective results obtained with the lower dose of MSX-3 suggest that adenosine A 2A antagonists acting preferentially at presynaptic A 2A receptors might selectively reduce reinforcing effects of cannabinoids that lead to their abuse. However, the appearance of potentiating rather than suppressing effects on cannabinoid reinforcement at the higher dose of MSX-3 would likely preclude the use of such a compound as a medication for cannabis abuse. Adenosine A 2A antagonists with more selectivity for presynaptic versus postsynaptic receptors could be potential medications for treatment of cannabis abuse.