Cocaine‐induced synaptic structural modification is differentially regulated by dopamine D1 and D3 receptors‐mediated signaling pathways

Zhang, Lei; Lu, Kangrong; Liu, Yutong; Tu, Genghong; Zhu, Mengjuan; Li, Ying; Zhao, Jinlan; Liu, N.; Guo, Fukun; Lin, Zhihua; Zhang, Lu

doi:10.1111/adb.12462

Cited by 19 publications

(16 citation statements)

References 49 publications

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“…However, when the dose of SCH23390 was increased ten-fold, the D3R antagonist was rendered ineffective, probably because the level of D1-like receptor signaling was no longer sufficient to increase locomotor output. Our electrophysiological and behavioral studies are uniformly consistent with the hypothesis that D3R antagonism renders NAc D1-MSNs hyperresponsive to DA-induced excitation, and also provide mechanistic evidence as to how D3R antagonism functionally enhances the behavioral, cellular, and neurochemical effects of cocaine observed herein and previously by others (38,41,44,74,89,90).…”

Section: Discussionsupporting

confidence: 89%

Selective D₂ and D₃ receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

Manvich¹,

Petko²,

Branco³

et al. 2018

Preprint

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Background:The D3 receptor (D3R) 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 modulatory impact of D3R antagonism on dopamine neurotransmission or the effects drugs of abuse have produced mixed results, in part because D3R-targeted compounds often also interact with D2 receptors (D2R). The purpose of this study was to compare the consequences of selective D2R or D3R antagonism on the behavioral effects of cocaine in mice, and to identify the neurobiological mechanisms underlying their modulatory effects. Methods: We characterized the effects of selective D2R or D3R antagonism in mice on 1) basal and cocaine-induced locomotor activity, 2) presynaptic dopamine release and clearance in the nucleus accumbens using ex vivo fast scan cyclic voltammetry, and 3) dopamine-mediated signaling in D1-expressing and D2-expressing medium spiny neurons using ex vivo electrophysiology. Results: Pretreatment with the selective D2R antagonist L-741,626 attenuated, while pretreatment with the selective D3R antagonist PG01037 enhanced, the locomotor-activating effects of acute and repeated cocaine administration. While both antagonists potentiated cocaine-induced increases in presynaptic DA release, D3R blockade uniquely facilitated DAmediated excitation of D1-expressing medium spiny neurons in the nucleus accumbens. Conclusions: Selective D3R antagonism potentiates the behavioral-stimulant effects of cocaine in mice, an effect that is in direct opposition to that produced by selective D2R antagonism or nonselective D2-like receptor antagonists, likely by facilitating D1-mediated excitation in the nucleus accumbens. These findings provide important insights into the neuropharmacological actions of D3R antagonists on mesolimbic dopamine neurotransmission.

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Section: Discussionsupporting

confidence: 89%

Selective D₂ and D₃ receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

Manvich¹,

Petko²,

Branco³

et al. 2018

Preprint

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“…Pyk2 knockout does not alter cocaine-induced conditioned place preference. We then evaluated in Pyk2 mutant mice the rewarding properties of cocaine, which involve D1R [45][46][47] . We measured cocaine-induced CPP in wild-type and mutant mice (Fig.…”

Section: Cmentioning

confidence: 99%

The non-receptor tyrosine kinase Pyk2 modulates acute locomotor effects of cocaine in D1 receptor-expressing neurons of the nucleus accumbens

Pins

Montalban

Vanhoutte

et al. 2020

Sci Rep

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The striatum is critical for cocaine-induced locomotor responses. Although the role of D1 receptorexpressing neurons is established, underlying molecular pathways are not fully understood. We studied the role of Pyk2, a non-receptor, calcium-dependent protein-tyrosine kinase. The locomotor coordination and basal activity of Pyk2 knockout mice were not altered and major striatal protein markers were normal. Cocaine injection increased Pyk2 tyrosine phosphorylation in mouse striatum. Pyk2-deficient mice displayed decreased locomotor response to acute cocaine injection. In contrast, locomotor sensitization and conditioned place preference were normal. Cocaine-activated ERK phosphorylation, a signaling pathway essential for these late responses, was unaltered. Conditional deletion of Pyk2 in the nucleus accumbens or in D1 neurons reproduced decreased locomotor response to cocaine, whereas deletion of Pyk2 in the dorsal striatum or in A 2A receptor-expressing neurons did not. In mice lacking Pyk2 in D1-neurons locomotor response to D1 agonist SKF-81297, but not to an anticholinergic drug, was blunted. Our results identify Pyk2 as a regulator of acute locomotor responses to psychostimulants. They highlight the role of tyrosine phosphorylation pathways in striatal neurons and suggest that changes in Pyk2 expression or activation may alter specific responses to drugs of abuse, or possibly other behavioral responses linked to dopamine action. The striatum is the main input structure of the basal ganglia, involved in motor coordination, motivation, and action selection. The GABAergic striatal projection neurons (SPNs, a.k.a. medium-size spiny neurons) constitute the vast majority of striatal neurons (~95% in rodents). They integrate cortical and thalamic excitatory inputs and are modulated by dopaminergic inputs and striatal interneurons 1. Two major populations of SPNs can be distinguished according to their projection targets and their molecular profile 1-3. SPNs enriched in enkephalin, D2 dopamine (D2R), and A 2A adenosine (A 2A R) receptors project to the external globus pallidus (GPe) thus participating in the indirect striatonigral pathway, while SPNs enriched in substance P, dynorphin, and D1 dopamine receptor (D1R) innervate the internal globus pallidus (GPi) and the substantia nigra pars reticulata (SNr), forming the direct pathway 1,2,4. Striatal dysfunction is associated with several pathologies ranging from movement disorders in Parkinson's or Huntington's diseases to addiction 5. The striatum is a major site of action of drugs of abuse, which all share the ability to increase extracellular dopamine levels in the ventral part of the striatum, the

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“…We then evaluated the rewarding properties of cocaine in Pyk2 mutant mice, which involve D1 receptors [41][42][43]. We measured cocaine-CPP in wild-type and mutant mice ( Figure S7).…”

Section: Pyk2 Knockout Has Minor Effects On Cocaine-induced Signalingmentioning

confidence: 99%

Pyk2 in D1 receptor-expressing neurons of the nucleus accumbens modulates the acute locomotor effects of cocaine

Pins

Montalban

Vanhoutte

et al. 2019

Preprint

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The striatum is a critical brain region for locomotor response to cocaine. Although the D1 receptor-expressing neurons are centrally involved in mediating the locomotor effects of cocaine, the molecular pathways controlling this response are not fully understood. Here we studied the role of Pyk2, a non-receptor calcium-dependent protein-tyrosine kinase, in striatum-related functions. We discovered that cocaine injection increases Pyk2 phosphorylation in the striatum of mice in vivo. Pyk2-deficient mice displayed an altered locomotor response to acute cocaine injection. In contrast, they developed normal locomotor sensitization and cocaine-conditioned place preference. Accordingly, a cocaine-activated signaling pathway essential for these late responses, ERK phosphorylation, was not altered.Specific deletion of Pyk2 in the nucleus accumbens or in D1 neurons reproduced this phenotype, whereas deletion of Pyk2 in the dorsal striatum or in A2A receptor-expressing neurons did not. Mice lacking Pyk2 in D1-neurons also displayed lower locomotor response to the D1 receptor agonist SKF-81297 but not to an anticholinergic drug. Our results identify Pyk2 as a regulator of acute locomotor responses to psychostimulants and suggest that changes in Pyk2 expression or activation may alter specific responses to drugs of abuse, or possibly other behavioral responses linked to dopamine action.

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Cocaine‐induced synaptic structural modification is differentially regulated by dopamine D1 and D3 receptors‐mediated signaling pathways

Cited by 19 publications

References 49 publications

Selective D₂ and D₃ receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

Selective D₂ and D₃ receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

The non-receptor tyrosine kinase Pyk2 modulates acute locomotor effects of cocaine in D1 receptor-expressing neurons of the nucleus accumbens

Pyk2 in D1 receptor-expressing neurons of the nucleus accumbens modulates the acute locomotor effects of cocaine

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Cocaine‐induced synaptic structural modification is differentially regulated by dopamine D1 and D3 receptors‐mediated signaling pathways

Cited by 19 publications

References 49 publications

Selective D2 and D3 receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

Selective D2 and D3 receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

The non-receptor tyrosine kinase Pyk2 modulates acute locomotor effects of cocaine in D1 receptor-expressing neurons of the nucleus accumbens

Pyk2 in D1 receptor-expressing neurons of the nucleus accumbens modulates the acute locomotor effects of cocaine

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Selective D₂ and D₃ receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

Selective D₂ and D₃ receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens