D3 dopamine receptors interact with dopamine D1 but not D4 receptors in the GABAergic terminals of the SNr of the rat

Cruz-Trujillo, Refugio; Ávalos‐Fuentes, Arturo; Rangel‐Barajas, Claudia; Paz‐Bermúdez, Francisco; Sierra, Arturo; Escartín-Perez, Erick; Aceves, Jorge; Erlij, David; Florán, Benjamí­n

doi:10.1016/j.neuropharm.2012.11.032

Cited by 42 publications

(38 citation statements)

References 36 publications

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“…As the D3 receptor is closely associated with the D1 receptor through heterodimerization (Surmeier et al, 1996; Fiorentini et al, 2008; Maggio et al, 2009; Missale et al, 2010; Cruz-Trujillo et al, 2013), we next tested if the dysfunction of the D3 receptor system leads to changes in the D1 receptor system (Figure 6). We found that in D3KO ( n = 5), D1 receptor expression (49 kDa band) increased significantly from 99.99 ± 4.6% (in WT) to 170.6 ± 8.9% ( n = 5, p < 0.001).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, D1 receptors form heterodimers with D3 receptors (Surmeier et al, 1996; Fiorentini et al, 2008; Maggio et al, 2009; Missale et al, 2010; Cruz-Trujillo et al, 2013) and both play a role in opioid tolerance (Lin et al, 1996; Cook et al, 2000; Richtand et al, 2000; Fazli-Tabaei et al, 2006). We recently found that animals lacking a functional D3 receptor (D3KO) exhibited facilitated pain-associated reflexes (Keeler et al, 2012), and we address here the role of the spinal D3 receptor on MOR functional states and morphine responsiveness.…”

Section: Introductionmentioning

confidence: 99%

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Dopamine D3 receptor dysfunction prevents anti-nociceptive effects of morphine in the spinal cord

Brewer

Baran

Whitfield

et al. 2014

Front. Neural Circuits

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Dopamine (DA) modulates spinal reflexes, including nociceptive reflexes, in part via the D3 receptor subtype. We have previously shown that mice lacking the functional D3 receptor (D3KO) exhibit decreased paw withdrawal latencies from painful thermal stimuli. Altering the DA system in the CNS, including D1 and D3 receptor systems, reduces the ability of opioids to provide analgesia. Here, we tested if the increased pain sensitivity in D3KO might result from a modified μ-opioid receptor (MOR) function at the spinal cord level. As D1 and D3 receptor subtypes have competing cellular effects and can form heterodimers, we tested if the changes in MOR function may be mediated in D3KO through the functionally intact D1 receptor system. We assessed thermal paw withdrawal latencies in D3KO and wild type (WT) mice before and after systemic treatment with morphine, determined MOR and phosphorylated MOR (p-MOR) protein expression levels in lumbar spinal cords, and tested the functional effects of DA and MOR receptor agonists in the isolated spinal cord. In vivo, a single morphine administration (2 mg/kg) increased withdrawal latencies in WT but not D3KO, and these differential effects were mimicked in vitro, where morphine modulated spinal reflex amplitudes (SRAs) in WT but not D3KO. Total MOR protein expression levels were similar between WT and D3KO, but the ratio of pMOR/total MOR was higher in D3KO. Blocking D3 receptors in the isolated WT cord precluded morphine's inhibitory effects observed under control conditions. Lastly, we observed an increase in D1 receptor protein expression in the lumbar spinal cord of D3KO. Our data suggest that the D3 receptor modulates the MOR system in the spinal cord, and that a dysfunction of the D3 receptor can induce a morphine-resistant state. We propose that the D3KO mouse may serve as a model to study the onset of morphine resistance at the spinal cord level, the primary processing site of the nociceptive pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dopamine D3 receptor dysfunction prevents anti-nociceptive effects of morphine in the spinal cord

Brewer

Baran

Whitfield

et al. 2014

Front. Neural Circuits

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“…It should be noted that this receptor characterization was conducted in P14-age mice, and therefore consideration must be given to the potential developmental receptor expression profile in the first 5 postnatal days. Furthermore, consideration must also be given to the possibility of cross-family heterodimers that form, for example, between D 1 and D 2 (George and O'Dowd 2007) or D 1 -D 3 (Cruz-Trujillo et al 2013;Surmeier et al 1996). What is clear is that dopamine is a potent modulator of locomotor network activity; however, if we wish to more fully understand the role of spinal dopamine in motor control we must further examine how dopamine shapes different components of the network.…”

Section: Discussionmentioning

confidence: 99%

Dopaminergic modulation of locomotor network activity in the neonatal mouse spinal cord

Sharples

Humphreys

Jensen

et al. 2015

Journal of Neurophysiology

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Sharples SA, Humphreys JM, Jensen AM, Dhoopar S, Delaloye N, Clemens S, Whelan PJ. Dopaminergic modulation of locomotor network activity in the neonatal mouse spinal cord. J Neurophysiol 113: 2500 -2510, 2015. First published February 4, 2015 doi:10.1152/jn.00849.2014.-Dopamine is now well established as a modulator of locomotor rhythms in a variety of developing and adult vertebrates. However, in mice, while all five dopamine receptor subtypes are present in the spinal cord, it is unclear which receptor subtypes modulate the rhythm. Dopamine receptors can be grouped into two families-the D 1/5 receptor group and the D 2/3/4 group, which have excitatory and inhibitory effects, respectively. Our data suggest that dopamine exerts contrasting dose-dependent modulatory effects via the two receptor families. Our data show that administration of dopamine at concentrations Ͼ35 M slowed and increased the regularity of a locomotor rhythm evoked by bath application of 5-hydroxytryptamine (5-HT) and N-methyl-D(L)-aspartic acid (NMA).This effect was independent of the baseline frequency of the rhythm that was manipulated by altering the NMA concentration. We next examined the contribution of the D 1 -and D 2 -like receptor families on the rhythm. Our data suggest that the D 1 -like receptor contributes to enhancement of the stability of the rhythm. Overall, the D 2 -like family had a pronounced slowing effect on the rhythm; however, quinpirole, the D 2 -like agonist, also enhanced rhythm stability. These data indicate a receptor-dependent delegation of the modulatory effects of dopamine on the spinal locomotor pattern generator. dopamine; locomotion; monoamine; spinal cord NEURAL CIRCUITS that produce basic rhythmic motor patterns of locomotion, in vertebrates, reside primarily in the spinal cord and are subject to neuromodulation from a wide range of sources both intrinsic and extrinsic to the spinal cord (Dunbar et al.

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“…Despite the low abundance of D3Rs are expressed in the direct pathway [21], we previously reported functional response in the GABAergic striato-nigral terminals [161], where presynaptic D3Rs are modulated by the calcium calmodulin kinase IIα (CAMKIIα) [162]. The mRNA codifying to D3Rs remains unchanged during dopamine denervation [163].…”

Section: Alterations Of Dopamine Receptors In Neurodegenerative Diseasesmentioning

confidence: 99%

“…Interestingly several reports have shown that targeting D3Rs reduces LID, in addition to that D3Rs interact with D1Rs [168,169] and enhances D1Rs stimulated GABA release in SNr [161], the functional effects and dynamic of this interaction seems to be mediated by CAMKIIα [162] and could be involved in LID and other pathological conditions. All these recent evidences about the modulation of D3Rs over the D1Rs might lead to novel approaches to treat PD and LID, however further studies are needed to examine potential side effects when targeting D3Rs in this pathological conditions since D3Rs exhibit a higher expression in other brain regions.…”

Section: Alterations Of Dopamine Receptors In Neurodegenerative Diseasesmentioning

confidence: 99%

Dopamine Receptors and Neurodegeneration

Rangel‐Barajas¹,

Coronel²,

Florán³

2015

Aging and disease

187

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Dopamine (DA) is one of the major neurotransmitters and participates in a number of functions such as motor coordination, emotions, memory, reward mechanism, neuroendocrine regulation etc. DA exerts its effects through five DA receptors that are subdivided in 2 families: D1-like DA receptors (D1 and D5) and the D2-like (D2, D3 and D4). All DA receptors are widely expressed in the central nervous system (CNS) and play an important role in not only in physiological conditions but also pathological scenarios. Abnormalities in the DAergic system and its receptors in the basal ganglia structures are the basis Parkinson's disease (PD), however DA also participates in other neurodegenerative disorders such as Huntington disease (HD) and multiple sclerosis (MS). Under pathological conditions reorganization of DAergic system has been observed and most of the times, those changes occur as a mechanism of compensation, but in some cases contributes to worsening the alterations. Here we review the changes that occur on DA transmission and DA receptors (DARs) at both levels expression and signals transduction pathways as a result of neurotoxicity, inflammation and in neurodegenerative processes. The better understanding of the role of DA receptors in neuropathological conditions is crucial for development of novel therapeutic approaches to treat alterations related to neurodegenerative diseases.

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D3 dopamine receptors interact with dopamine D1 but not D4 receptors in the GABAergic terminals of the SNr of the rat

Cited by 42 publications

References 36 publications

Dopamine D3 receptor dysfunction prevents anti-nociceptive effects of morphine in the spinal cord

Dopamine D3 receptor dysfunction prevents anti-nociceptive effects of morphine in the spinal cord

Dopaminergic modulation of locomotor network activity in the neonatal mouse spinal cord

Dopamine Receptors and Neurodegeneration

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