Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioral analysis

Marcellino, Daniel; Carriba, Paulina; Filip, Małgorzata; Borgkvist, Anders; Frankowska, Małgorzata; Bellido, I.; Tanganelli, Sergio; Müller, Christian; Fisone, Gilberto; Lluı́s, Carme; Agnati, Luigi F.; Franco, Rafael; Fuxé, Kjell

doi:10.1016/j.neuropharm.2007.12.011

Cited by 149 publications

(145 citation statements)

References 26 publications

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“…The doses of quinpirole and its pretreatment time are in agreement with the previously published studies (Marcellino et al, 2008), whereas doses of cocaine (0.625 mg/kg) and GBR 12783 (1.25 mg/kg) were based on our detailed dose-response curve investigations on locomotor activity. Namely, in combination behavioral experiments with quinpirole we have chosen the behaviorally inactive doses of GBR 12783 and cocaine, ie, subthreshold doses that have not altered the motor functions of the rats by themselves under equivalent locomotor conditions.…”

Section: Behavioral Experimentssupporting

confidence: 86%

A Novel Mechanism of Cocaine to Enhance Dopamine D2-Like Receptor Mediated Neurochemical and Behavioral Effects. An In Vivo and In Vitro Study

Ferraro

Frankowska

Marcellino

et al. 2012

Neuropsychopharmacol

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Recent in vitro results suggest that cocaine may exert direct and/or indirect allosteric enhancing actions at dopamine (DA) D 2 receptors (D 2 Rs). In the present paper we tested the hypothesis that cocaine in vivo can enhance the effects of the D 2 -likeR agonist quinpirole in rats by using microdialysis and pharmacological behavioral studies. Furthermore, in vitro D 2 -likeR binding characteristics and Ga i/o -protein coupling, in the absence and in the presence of cocaine, have been investigated in rat striatal membranes. Intra-nucleus accumbens perfusion of the D 2 -likeR agonist quinpirole (10 mM) reduced local dialysate glutamate levels, whereas cocaine (10 and 100 nM) was ineffective. At a low concentration (100 nM), cocaine significantly enhanced quinpirole-induced reduction of accumbal extracellular glutamate levels. The behavioral experiments showed that cocaine (0.625 mg/kg), but not the DA uptake blocker GBR 12783 (1.25 mg/ kg), enhanced quinpirole (1 mg/kg)-induced hyperlocomotion. Finally, cocaine (100 nM), but not GBR 12783 (200 nM), produced a small, but significant increase in the efficacy of DA to stimulate binding of GTPgS to striatal D 2 -likeRs, whereas the D 2 -likeR binding characteristics were unchanged in striatal membranes by cocaine in the nM range. The significant increase in the maximal response to DA-stimulated GTPgS binding to D 2 -likeRs by 100 nM cocaine remained in the presence of GBR 12783. The observed cocaine-induced enhancement of the Ga i/o -protein coupling of D 2 Rs may be in part because of allosteric direct and/or indirect enhancing effects of cocaine at these receptors. These novel actions of cocaine may have relevance for understanding the actions of cocaine upon accumbal DA, and/or glutamate transmission and thus its rewarding as well as relapsing effects.

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Section: Behavioral Experimentssupporting

confidence: 86%

A Novel Mechanism of Cocaine to Enhance Dopamine D2-Like Receptor Mediated Neurochemical and Behavioral Effects. An In Vivo and In Vitro Study

Ferraro

Frankowska

Marcellino

et al. 2012

Neuropsychopharmacol

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“…Both CB1 and D2 receptors couple to G i-o proteins and inhibit adenylyl-cyclase, whereas their costimulation results in G s protein-dependent activation of adenylylcyclase (44,45). Moreover, CB1 receptor agonists and antagonists counteract and potentiate, respectively, D2 receptor agonist effects (46)(47)(48)(49), although D2 and CB1 receptor interactions might differ between rodents and primates (50,51). It is therefore possible that in marijuana abusers, chronic CB1 receptor stimulation prevented the striatal D2/D3 receptor down-regulation observed with repeated drug use (reviewed in ref.…”

Section: Discussionmentioning

confidence: 99%

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

Volkow

Wang

Telang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

195

147

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Moves to legalize marijuana highlight the urgency to investigate effects of chronic marijuana in the human brain. Here, we challenged 48 participants (24 controls and 24 marijuana abusers) with methylphenidate (MP), a drug that elevates extracellular dopamine (DA) as a surrogate for probing the reactivity of the brain to DA stimulation. We compared the subjective, cardiovascular, and brain DA responses (measured with PET and [ 11 C]raclopride) to MP between controls and marijuana abusers. Although baseline (placebo) measures of striatal DA D2 receptor availability did not differ between groups, the marijuana abusers showed markedly blunted responses when challenged with MP. Specifically, compared with controls, marijuana abusers had significantly attenuated behavioral ("self-reports" for high, drug effects, anxiety, and restlessness), cardiovascular (pulse rate and diastolic blood pressure), and brain DA [reduced decreases in distribution volumes (DVs) of [ 11 C]raclopride, although normal reductions in striatal nondisplaceable binding potential (BP ND )] responses to MP. In ventral striatum (key brain reward region), MP-induced reductions in DVs and BP ND (reflecting DA increases) were inversely correlated with scores of negative emotionality, which were significantly higher for marijuana abusers than controls. In marijuana abusers, DA responses in ventral striatum were also inversely correlated with addiction severity and craving. The attenuated responses to MP, including reduced decreases in striatal DVs, are consistent with decreased brain reactivity to the DA stimulation in marijuana abusers that might contribute to their negative emotionality (increased stress reactivity and irritability) and addictive behaviors.nucleus accumbens | amotivation | cannabinoid 1 receptors | brain imaging | midbrain D espite the high prevalence of marijuana consumption, the effects of marijuana abuse in the human brain are not well understood. Marijuana, like other drugs of abuse, stimulates brain dopamine (DA) signaling in the nucleus accumbens (1, 2), which is a mechanism believed to underlie the rewarding effects of drugs (3-5) and to trigger the neuroadaptations that result in addiction (reviewed in ref. 6). Indeed, in humans, imaging studies have shown that drugs of abuse increase DA release in striatum (including the nucleus accumbens), and these increases have been associated with the subjective experience of reward (7-9). However, for marijuana, the results have been inconsistent: One study reported striatal DA increases during intoxication (10); two studies showed no effects (11, 12); and one study reported DA increases in individuals with a psychotic disorder and in their relatives, but not in controls (13). Imaging studies of the brain DA system in marijuana abusers have also shown different findings from those reported for other types of substance abusers. Specifically, substance abusers (cocaine, methamphetamine, alcohol, heroin, and nicotine), but not marijuana abusers (14-16), show reduced baseline availability ...

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“…There is an increasing amount of data showing that DRs can participate in G protein-coupled receptor heterodimers, resulting in modulation of their pharmacological properties (Han Y, Moreira I, Urizar E, Weinstein H, and Javitch JA, Nature Chemical Biology, in press). 74,75 Therefore, it is possible that the lower potency of both DA and quinpirole as agonists is due to modulation of D2R by heterodimer partners. This is an ongoing area of study.…”

Section: Discussionmentioning

confidence: 99%

Human Immunodeficiency Virus (HIV) Infection of Human Macrophages Is Increased by Dopamine

Gaskill

Calderon

Luers

et al. 2009

The American Journal of Pathology

119

130

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The prevalence of human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) that result from HIV infection of the central nervous system is increasing. Macrophages, the primary target for HIV within the central nervous system, play a central role in HIV-induced neuropathogenesis. Drug abuse exacerbates HAND, but the mechanism(s) by which this increased neuropathology results in more severe forms of HAND in HIV-infected drug abusers is unclear. The addictive and reinforcing effects of many drugs of abuse, such as cocaine and methamphetamine, are mediated by increased extracellular dopamine in the brain. We propose a novel mechanism by which drugs of abuse intensify HIV neuropathogenesis through direct effects of the neurotransmitter dopamine on HIV infection of macrophages. We found that macrophages express dopamine receptors 1 and 2, and dopamine activates macrophages by increasing ERK 1 phosphorylation. Our results demonstrate for the first time that dopamine increases HIV replication in human macrophages and that the mechanism by which dopamine mediates this change is by increasing the total number of HIV-infected macrophages. This increase in HIV replication is mediated by activation of dopamine receptor 2. These findings suggest a common mechanism by which drugs of abuse enhance HIV replication in macrophages and indicate that the drug abuse-heightened levels of central nervous system dopamine could increase viral replication , thereby accelerating the development of HAND.

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Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioral analysis

Cited by 149 publications

References 26 publications

A Novel Mechanism of Cocaine to Enhance Dopamine D2-Like Receptor Mediated Neurochemical and Behavioral Effects. An In Vivo and In Vitro Study

A Novel Mechanism of Cocaine to Enhance Dopamine D2-Like Receptor Mediated Neurochemical and Behavioral Effects. An In Vivo and In Vitro Study

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

Human Immunodeficiency Virus (HIV) Infection of Human Macrophages Is Increased by Dopamine

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