Phenotypical characterization of the neurons expressing the D1 and D2 dopamine receptors in the monkey striatum

Aubert, Incarnation; Ghorayeb, Imad; Normand, Elisabeth; Bloch, Bertrand

doi:10.1002/(sici)1096-9861(20000228)418:1<22::aid-cne2>3.0.co;2-q

Cited by 124 publications

(94 citation statements)

References 58 publications

(72 reference statements)

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“…Although strict segregation of D1R and D2R has been suggested (5,6) it was noted in these studies that although ϳ60% of MSNs in nucleus accumbens (NAc) expressed D1R, ϳ50% expressed D2R. This indicated a certain fraction of NAc MSNs expressed both receptors, a finding consistent with numerous studies showing colocalization of D1R and D2R in a proportion of striatal neurons (7)(8)(9)(10)(11).…”

supporting

confidence: 78%

The Dopamine D1-D2 Receptor Heteromer Localizes in Dynorphin/Enkephalin Neurons

Perreault

Hasbi

Alijaniaram

et al. 2010

Journal of Biological Chemistry

162

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The distribution and function of neurons coexpressing the dopamine D1 and D2 receptors in the basal ganglia and mesolimbic system are unknown. We found a subset of medium spiny neurons coexpressing D1 and D2 receptors in varying densities throughout the basal ganglia, with the highest incidence in nucleus accumbens and globus pallidus and the lowest incidence in caudate putamen. These receptors formed D1-D2 receptor heteromers that were localized to cell bodies and presynaptic terminals. In rats, selective activation of D1-D2 heteromers increased grooming behavior and attenuated AMPA receptor GluR1 phosphorylation by calcium/calmodulin kinase II␣ in nucleus accumbens, implying a role in reward pathways. D1-D2 heteromer sensitivity and functional activity was up-regulated in rat striatum by chronic amphetamine treatment and in globus pallidus from schizophrenia patients, indicating that the dopamine D1-D2 heteromer may contribute to psychopathologies of drug abuse, schizophrenia, or other disorders involving elevated dopamine transmission. Dopaminergic signaling within basal ganglia occurs within at least two populations of GABAergic medium spiny neurons (MSNs), 2 containing the neuropeptides dynorphin (DYN) and substance P, or containing enkephalin (ENK) (1, 2). There is controversy as to the colocalization of dopamine D1 and D2 receptors (D1R, D2R) within these two neuronal subtypes. It is generally agreed that whereas D1R is largely segregated to the DYN/substance P-expressing direct striatonigral pathway, D2R is predominantly localized to the ENK-expressing indirect striatopallidal pathway, which is supported by recent studies using fluorophore-tagged promoter elements of D1R and D2R in bacterial artificial chromosome transgenic mice to quantify the cells expressing the receptors within these pathways (3, 4). Although strict segregation of D1R and D2R has been suggested (5, 6) it was noted in these studies that although ϳ60% of MSNs in nucleus accumbens (NAc) expressed D1R, ϳ50% expressed D2R. This indicated a certain fraction of NAc MSNs expressed both receptors, a finding consistent with numerous studies showing colocalization of D1R and D2R in a proportion of striatal neurons (7-11).In keeping with these findings, we have shown that D1R and D2R interacted in striatum to form a D1-D2 heteromeric complex that could be immunoprecipitated (9, 12). The D1-D2 heteromer was distinct from its constituent receptors in that it coupled to Gq/11 to activate phospholipase C and generate intracellular calcium release, representing a novel signaling pathway directly linking dopamine action to calcium (9, 13). However, despite growing evidence that neurons coexpressing D1R and D2R embody a significant fraction of MSNs in NAc, their regional distribution, phenotypic characterization, and functional role within basal ganglia are entirely unknown. Given the apparent relationship between dopamine receptor expression and DYN or ENK content, we hypothesized that neurons expressing the D1-D2 heteromer would contain both DYN and ...

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confidence: 78%

The Dopamine D1-D2 Receptor Heteromer Localizes in Dynorphin/Enkephalin Neurons

Perreault

Hasbi

Alijaniaram

et al. 2010

Journal of Biological Chemistry

162

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“…Whether the same interaction exists in the primate basal ganglia is at present unknown. However, most GABAergic projection neurons in the monkey striatum express either dopamine D 1 or D 2 receptor mRNA (Aubert et al, 2000). Moreover, muscarinic M 4 receptors have been localized in the human striatum (Flynn et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

The Muscarinic M1/M4 Receptor Agonist Xanomeline Exhibits Antipsychotic-Like Activity in Cebus apella Monkeys

Andersen

Fink-Jensen

Peacock

et al. 2003

Neuropsychopharmacol

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Xanomeline is a muscarinic M 1 /M 4 preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects (EPS) at therapeutically relevant doses. In the present study, we examined whether the xanomeline-induced functional dopamine antagonism found in rodent studies could also be observed in nonhuman primates. In addition, we studied whether the lack of EPS observed in rodents also applies to primates. To this end, we investigated the effects of xanomeline on the behavior induced by D-amphetamine and (À)-apomorphine in drug-naive Cebus apella monkeys. Antipsychotic compounds antagonize amphetamine-induced motor unrest and stereotypies in this species. Xanomeline inhibited D-amphetamine-induced motor unrest, stereotypies and arousal as well as apomorphine-induced stereotypies and arousal in drug-naive Cebus apella monkeys. Xanomeline did not induce EPS but vomiting occurred in some monkeys at high doses, in accordance with emetic events observed in Alzheimer patients following xanomeline administration. Even when xanomeline was tested in EPS-sensitized Cebus apella monkeys, EPS were not observed at the dose range of xanomeline used in the D-amphetamine-apomorphine combination study (0.5-3 mg/kg). However, when xanomeline was tested at 4 mg/kg, moderate dystonia was seen in two out of three monkeys. It is concluded that xanomeline inhibits Damphetamine-and (À)-apomorphine-induced behavior in Cebus apella monkeys at doses that do not cause EPS. These data further substantiate that muscarinic receptor agonists may be useful in the pharmacological treatment of psychosis.

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“…Conversely, striatal NoGo cells project to and inhibit the external segment of the globus pallidus (GPe), releasing the tonic inhibition of GPe onto GPi, and therefore having an opposing effect on motor activity. Dopamine modulates the relative balance of these pathways by exciting synapticallydriven activity in Go cells via D1 receptors, while inhibiting NoGo activity via D2 receptors (Aubert, Ghorayeb, Normand, & Bloch, 2000;Brown et al, 2004;Frank, 2005a;Gerfen, 1992;Hernandez-Lopez, Bargas, Surmeier, Reyes, & Galarraga, 1997;Hernandez-Lopez et al, 2000;Joel & Weiner, 1999). Physiological evidence for this model comes from studies showing opposite effects of D1 and D2 agents on activity within the two types of cells and BG output nuclei (Boraud, Bezard, Bioulac, & Gross, 2002;Gerfen, 2000;Gerfen, Keefe, & Gauda, 1995;Robertson, Vincent, & Fibiger, 1992;Salin, Hajji, & Kerkerian-Le Goff, 1996).…”

Section: Overall Bg Network Functionalitymentioning

confidence: 99%

Hold your horses: A dynamic computational role for the subthalamic nucleus in decision making

2006

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The basal ganglia (BG) coordinate decision making processes by facilitating adaptive frontal motor commands while suppressing others. In previous work, neural network simulations accounted for response selection deficits associated with BG dopamine depletion in Parkinson's disease. Novel predictions from this model have been subsequently confirmed in Parkinson patients and in healthy participants under pharmacological challenge. Nevertheless, one clear limitation of that model is in its omission of the subthalamic nucleus (STN), a key BG structure that participates in both motor and cognitive processes. The present model incorporates the STN and shows that by modulating when a response is executed, the STN reduces premature responding and therefore has substantial effects on which response is ultimately selected, particularly when there are multiple competing responses. Increased cortical response conflict leads to dynamic adjustments in response thresholds via cortico-subthalamicpallidal pathways. The model accurately captures the dynamics of activity in various BG areas during response selection. Simulated dopamine depletion results in emergent oscillatory activity in BG structures, which has been linked with Parkinson's tremor. Finally, the model accounts for the beneficial effects of STN lesions on these oscillations, but suggests that this benefit may come at the expense of impaired decision making.

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Phenotypical characterization of the neurons expressing the D1 and D2 dopamine receptors in the monkey striatum

Cited by 124 publications

References 58 publications

The Dopamine D1-D2 Receptor Heteromer Localizes in Dynorphin/Enkephalin Neurons

The Dopamine D1-D2 Receptor Heteromer Localizes in Dynorphin/Enkephalin Neurons

The Muscarinic M1/M4 Receptor Agonist Xanomeline Exhibits Antipsychotic-Like Activity in Cebus apella Monkeys

Hold your horses: A dynamic computational role for the subthalamic nucleus in decision making

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