Signal Transduction Pathways Modulated by D2-Like Dopamine Receptors

Huff, Rita M.; Chio, Christopher L.; Lajiness, Mary E.; Goodman, Linda

doi:10.1016/s1054-3589(08)60786-3

Cited by 22 publications

(16 citation statements)

References 3 publications

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“…One possible explanation for the observation that increased spine density and ⌬FosB expression was transiently found in D2 receptor-containing neurons is that this occurred in the small fraction of MSNs that coexpress both D1 and D2 dopamine receptors. Thus, the transient nature of these increases may be associated with antagonistic effects of D2 receptor activation on D1-dependent signaling pathways (48). It is of interest that the changes in spine density and ⌬FosB expression were reversible, which may reflect the ability of D2 receptor-dependent signaling pathways to influence the stability of ⌬FosB.…”

Section: Discussionmentioning

confidence: 99%

Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens

Lee

Kim

et al. 2006

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

314

310

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Psychostimulant-induced alteration of dendritic spines on dopaminoceptive neurons in nucleus accumbens (NAcc) has been hypothesized as an adaptive neuronal response that is linked to longlasting addictive behaviors. NAcc is largely composed of two distinct subpopulations of medium-sized spiny neurons expressing high levels of either dopamine D1 or D2 receptors. In the present study, we analyzed dendritic spine density after chronic cocaine treatment in distinct D1 or D2 receptor-containing medium-sized spiny neurons in NAcc. These studies made use of transgenic mice that expressed EGFP under the control of either the D1 or D2 receptor promoter (Drd1-EGFP or Drd2-EGFP). After 28 days of cocaine treatment and 2 days of withdrawal, spine density increased in both Drd1-EGFP-and Drd2-EGFP-positive neurons. However, the increase in spine density was maintained only in Drd1-EGFP-positive neurons 30 days after drug withdrawal. Notably, increased ⌬FosB expression also was observed in Drd1-EGFP-and Drd2-EGFP-positive neurons after 2 days of drug withdrawal but only in Drd1-EGFP-positive neurons after 30 days of drug withdrawal. These results suggest that the increased spine density observed after chronic cocaine treatment is stable only in D1-receptor-containing neurons and that ⌬FosB expression is associated with the formation and͞or the maintenance of dendritic spines in D1 as well as D2 receptor-containing neurons in NAcc.T he mesolimbic dopaminergic pathway is composed of neurons in the ventral tegmental area that innervate the nucleus accumbens (NAcc), olfactory tubercle, prefrontal cortex, and amygdala (1), whereas nigrostriatal dopaminergic neurons in the substantia nigra (pars compacta) provide an ascending projection to dorsal striatum (2). Psychostimulants elevate synaptic concentrations of dopamine in NAcc: cocaine, by blocking dopamine uptake from the synaptic cleft, and amphetamine, by promoting dopamine release from nerve terminals (3-5). Repeated, intermittent administration of psychostimulants results in augmented behavioral responses (sensitization) to the acute stimulatory effects of these drugs (6-8). Most lines of evidence suggest that adaptive changes in the ventral tegmental areaNAcc dopaminergic system are central to alterations in the experience-dependent plasticity that underlies drug-induced behavior.In addition to dopamine, glutamate is required for the development of behavioral sensitization in response to psychostimulants (9, 10). Medium-sized spiny neurons (MSNs) in ventral striatum receive excitatory glutamatergic projections from prefrontal cortex that synapse onto the heads of dendritic spines. MSNs also are the major target for dopaminergic axons that synapse onto spine necks (1,11,12). Therefore, dendritic spines in MSNs represent the cellular compartment where dopaminergic and glutamatergic transmission are initially integrated. Dopamine acts on two major receptor subfamilies, the D1 subfamily (D1 and D5 subtypes) and the D2 subfamily (D2, D3, and D4 subtypes) (13). In dorsal striatum, ...

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Section: Discussionmentioning

confidence: 99%

Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens

Lee

Kim

et al. 2006

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

314

310

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“…In situ , D 2 -like inhibition of adenylate cyclase can lead to presynaptic/autoreceptor decreases in tyrosine hydroxylase activity and in firing of nigrostriatal dopamine neurons. Like other Gα i/o -coupled receptors, D 2 -like receptors modulate many signaling pathways including phospholipases, ion channels, MAP kinases, and the Na + /H + exchanger, as well as adenylate cyclases [94]. D 2 activation has major effects on K + currents via dissociation of G βγ subunits.…”

Section: Impact Of Functional Selectivity and Research Issues For mentioning

confidence: 99%

Third Generation Antipsychotic Drugs: Partial Agonism or Receptor Functional Selectivity?

Mailman¹,

Murthy²

2010

CPD

255

191

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Functional selectivity is the term that describes drugs that cause markedly different signaling through a single receptor (e.g., full agonist at one pathway and antagonist at a second). It has been widely recognized recently that this phenomenon impacts the understanding of mechanism of action of some drugs, and has relevance to drug discovery. One of the clinical areas where this mechanism has particular importance is in the treatment of schizophrenia. Antipsychotic drugs have been grouped according to both pattern of clinical action and mechanism of action. The original antipsychotic drugs such as chlorpromazine and haloperidol have been called typical or first generation. They cause both antipsychotic actions and many side effects (extrapyramidal and endocrine) that are ascribed to their high affinity dopamine D 2 receptor antagonism. Drugs such as clozapine, olanzapine, risperidone and others were then developed that avoided the neurological side effects (atypical or second generation antipsychotics). These compounds are divided mechanistically into those that are high affinity D 2 and 5-HT 2A antagonists, and those that also bind with modest affinity to D 2 , 5-HT 2A , and many other neuroreceptors. There is one approved third generation drug, aripiprazole, whose actions have been ascribed alternately to either D 2 partial agonism or D 2 functional selectivity. Although partial agonism has been the more widely accepted mechanism, the available data are inconsistent with this mechanism. Conversely, the D 2 functional selectivity hypothesis can accommodate all current data for aripiprazole, and also impacts on discovery compounds that are not pure D 2 antagonists.Keywords functional selectivity; antipsychotic drugs; schizophrenia; receptor mechanisms; G protein-coupled receptors; dopamine receptors; serotonin receptors; drug action A. The first two generations of antipsychotic drugsThe serendipitous observations about antipsychotic actions of chlorpromazine [1] ultimately led to the finding that these antipsychotic effects were due to antidopaminergic actions [2]. Numerous antipsychotics were subsequently developed that, like chlorpromazine, work primarily as dopamine D 2 receptor antagonists. Drugs of this type (first called typical and now named first generation antipsychotics) include a variety of different chemical classes. These NIH Public Access Author ManuscriptCurr Pharm Des. Author manuscript; available in PMC 2011 January 1. Published in final edited form as:Curr Pharm Des. 2010 ; 16(5): 488-501. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript typical drugs can be classified as high, intermediate, or low potency based on their average daily dose range, with their clinical potency often highly correlated with their affinity for the dopamine D 2 receptor [3]. Thus, actions at dopamine systems have been a critical mechanism in all currently approved antipsychotic drugs and many of the compounds in the discovery and development pipeline. Dopamine systems and their rece...

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“…D2-like receptor signaling is mediated through inhibitory Gα i/o class of G-proteins which are sensitive to pertussis toxin and cause inhibition of adenylate cyclase activity. Adenylate cyclase further activates Protein Kinase A (PKA) that results in the phosphorylation of specific downstream effector molecules some of which influence gene expression [6,17,18]. Both D1-like and D2-like receptors can also alternatively couple to other Gα proteins and Gβγ subunits.…”

Section: Introductionmentioning

confidence: 99%

A synergistic approach towards understanding the functional significance of dopamine receptor interactions

Pandey

Mersha

Dhillon

2013

JMS

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The importance of the neurotransmitter dopamine (DA) in the nervous system is underscored by its role in a wide variety of physiological and neural functions in both vertebrates and invertebrates. Binding of dopamine to its membrane receptors initiates precise signaling cascades that result in specific cellular responses. Dopamine receptors belong to a super-family of G-protein coupled receptors (GPCRs) that are characterized by seven trans-membrane domains. In mammals, five dopamine receptors have been identified which are grouped into two different categories D1- and D2-like receptors. The interactions of DA receptors with other proteins including specific Gα subunits are critical in deciding the fate of downstream molecular events carried out by effector proteins. In this mini-review we provide a synopsis of known protein-protein interactions of DA receptors and a perspective on the potential synergistic utility of Caenorhabditis elegans as a model eukaryote with a comparatively simpler nervous system to gain insight on the neuronal and behavioral consequences of the receptor interactions.

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Signal Transduction Pathways Modulated by D2-Like Dopamine Receptors

Cited by 22 publications

References 3 publications

Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens

Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens

Third Generation Antipsychotic Drugs: Partial Agonism or Receptor Functional Selectivity?

A synergistic approach towards understanding the functional significance of dopamine receptor interactions

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