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Target Concepts:
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Query: UMLS:C0030567 (
Parkinson's disease
)
63,064
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Cannabinoid CB2 receptors (CB2Rs) are expressed in mouse brain dopamine (DA) neurons and are involved in several DA-related disorders. However, the cell type-specific mechanisms are unclear since the CB2R gene knockout mice are constitutive gene knockout. Therefore, we generated Cnr2-floxed mice that were crossed with DAT-Cre mice, in which Cre- recombinase expression is under dopamine transporter gene (DAT) promoter control to ablate Cnr2 gene in midbrain DA neurons of DAT-Cnr2 conditional knockout (cKO) mice. Using a novel sensitive RNAscope in situ hybridization, we detected CB2R mRNA expression in VTA DA neurons in wildtype and DAT-Cnr2 cKO heterozygous but not in the homozygous DAT-Cnr2 cKO mice. Here we report that the deletion of CB2Rs in dopamine neurons enhances motor activities, modulates anxiety and depression-like behaviors and reduces the rewarding properties of alcohol. Our data reveals that CB2Rs are involved in the tetrad assay induced by cannabinoids which had been associated with CB1R agonism. GWAS studies indicates that the CNR2 gene is associated with
Parkinson's disease
and
substance use disorders
. These results suggest that CB2Rs in dopaminergic neurons may play important roles in the modulation of psychomotor behaviors, anxiety, depression, and pain sensation and in the rewarding effects of alcohol and cocaine.
...
PMID:Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference. 2923 41
The dopamine D
3
receptor (D
3
R) has emerged as a promising pharmacotherapeutic target for the treatment of several diseases including schizophrenia,
Parkinson's disease
, and
substance use disorders
. However, studies investigating the D
3
R's precise role in dopamine neurotransmission or how it may be exploited to modulate responses to drugs of abuse have produced contrasting results, in part because most D
3
R-targeted compounds often also interact with D
2
receptors (D
2
R). To resolve this issue, we set out to systematically characterize and compare the consequences of selective D
2
R or D
3
R antagonists on the behavioral-stimulant properties of cocaine in mice, and to identify putative neurobiological mechanisms underlying their behavior-modifying effects. Pretreatment with the selective D
2
R antagonist L-741,626 attenuated, while pretreatment with the selective D
3
R antagonist PG01037 enhanced, the locomotor-activating effects of both acute cocaine administration as well as sensitization following repeated cocaine dosing. While both antagonists potentiated cocaine-induced increases in presynaptic dopamine release, we report for the first time that D
3
R blockade uniquely facilitated dopamine-mediated excitation of D
1
-expressing medium spiny neurons in the nucleus accumbens. Collectively, our results demonstrate that selective D
3
R antagonism potentiates the behavioral-stimulant effects of cocaine in mice, an effect that is in direct opposition to that produced by selective D
2
R antagonism or nonselective D
2
-like receptor antagonists, and is likely mediated by facilitating D
1
-mediated excitation in the nucleus accumbens. These findings provide novel insights into the neuropharmacological actions of D
3
R antagonists on mesolimbic dopamine neurotransmission and their potential utility as pharmacotherapeutics.
...
PMID:Selective D
2
and D
3
receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens. 3087 21
There are nine subfamilies of TAARs. They are predominantly intracellular, located in the central nervous system and peripherally. They have a role in homeostasis and rheostasis, and also in olfaction. They demonstrate significant cross-talk with the monoamine system and are involved in the regulation of cAMP signalling and K
+
channels. There is evidence to suggest that TAAR1 may be a promising therapeutic target for the treatment of schizophrenia, psychosis in
Parkinson's disease
,
substance use disorders
, and the metabolic syndrome and obesity. TAAR1 expression may also be a prognostic biomarker for cancers. A number of TAAR modulators have been identified, including endogenous ligands and new chemical entities. Some of these agents have shown efficacy in animal models of addiction behaviours, depression and anxiety. Only one agent, SEP-363856, has progressed to randomised clinical trials in humans; however further, larger studies with SEP-363856 are required to clarify its suitability as a new treatment for schizophrenia spectrum disorders. SEP-363856 is an agonist of TAAR1 and 5HT
1A
and it is not clear to what extent its efficacy can be attributed to TAAR1 rather than to other drug targets. However, current research suggests that TAAR1 has an important role in human physiology and pathophysiology. TAAR1 modulators may become an important new drug class for the management of a wide array of mental disorders in the future.
...
PMID:Trace Amine-Associated Receptor 1 (TAAR1): A new drug target for psychiatry? 3303 17
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