Getting specialized: presynaptic and postsynaptic dopamine D2 receptors

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Dopamine (DA) signaling controls many physiological functions ranging from locomotion to hormone secretion, and plays a critical role in addiction. DA elevation, for instance in response to drugs of abuse, simultaneously activates neurons expressing different DA receptors; how responses from diverse neurons/receptors are orchestrated in the generation of behavioral and cellular outcomes, is still not completely defined. Signaling from D2 receptors (D2Rs) is a good example to illustrate this complexity. D2Rs have presynaptic and postsynaptic localization and functions, which are shared by two isoforms in vivo. Recent results from knockout mice are clarifying the role of site and D2 isoform-specific effects thereby increasing our understanding of how DA modulates neuronal physiology.

Introduction

Responses to natural rewards (i.e. food) and addictive drugs share hedonic properties and elevate dopamine (DA) levels in the mesolimbic system, in areas such as the NAcc, which has been shown to be a preferential anatomical substrate for reward [1, 2, 3]. Drugs of abuse exploit the dopaminergic system to elicit their behavioral and cellular effects and by enhancing DA responses facilitate the study of the system.

DA effects are elicited through the interaction with membrane receptors that belong to the G-protein coupled receptor family [4]. Thus, upon drug intake DA signaling, controlled by any of the five DA receptors, is strongly activated leading to stimulation or inhibition of pathways regulated by the D1-like (D1 and D5) and D2-like receptor family (D2, D3 and D4), which translates into activation/inhibition of specific neurons and circuitries. In this article we will focus on the presynaptic and postsynaptic DA D2 receptor (D2R)-mediated signaling and functions in vivo.

D2Rs, widely expressed in the brain, are localized both on presynaptic dopaminergic neurons, but also on neurons targeted by dopaminergic afferences (Figure 1). In addition to having a dual localization, D2 receptors are a heterogeneous population formed by two molecularly distinct isoforms, named D2S (S = short) and D2L (L = long) generated by alternative splicing of the same gene [4]. Genetically engineered mice deleted or altered [5, 6, 7, 8, 9] in D2Rs expression have been critical in identifying D2R-mediated functions in vivo [10]. We will discuss the relative contribution of presynaptic versus postsynaptic D2R-mediated mechanisms in response to DA elevation generated by drugs of abuse or by DA agonists by comparing results from wild-type (WT) and knockout mice.

Section snippets

Signal transduction by D2L and D2S differently affects presynaptic versus postsynaptic responses

The best characterized intracellular effect of DA is activation of the cAMP pathway [4]. This pathway is activated through D1-like receptors and inhibited by D2-like receptors. In striatal medium spiny neurons (MSNs), elevation of cAMP level leads to the activation of the Protein Kinase A (PKA) [11] and consequently to phosphorylation of a large series of cellular targets and importantly of the DA- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) [12] (Figure 1). Blockade of D2R stimulates

D2R-mediated presynaptic functions in postsynaptic neurons

Nigrostriatal and mesolimbic afferences, respectively from the SN and VTA, gate sensory, motor and reward information to the striatum. In response to salient events glutamate reward signals originated in the orbitofrontal cortex and basolateral amygdala reach the ventral striatum where DA is a gatekeeper of these inputs. Similarly, DA modulates glutamate inputs to the dorsal striatum from sensory and motor cortical areas [1], where it filters the noise amplifying the impact of salient stimuli

Presynaptic D2R-mediated function on dopaminergic neurons

Studies on D2R−/− mice have determined that D2 receptors are the ‘bona fide’ autoreceptors regulating DA synthesis and release [26, 27, 28, 29]. Interestingly, while the mean baseline concentration of DA in striatal dialysates is similar in WT and D2R−/− siblings, the release of DA evoked by cocaine injection is dramatically higher in D2R−/− mutants as compared to WT animals and well above the range of DA increase normally observed in WT animals [27]. Similar results were also obtained in

The motor stimulating effect of cocaine is impaired by absence of D2S

Largely abused by humans, cocaine elicits its psychomotor and cellular effects by blocking DAT activity on dopaminergic neurons [35]. Glutamate and dopaminergic antagonists abolish the transcriptional activation of immediate early genes (IEGs) induced by cocaine [36, 37]. In this respect, activation of D1Rs is an absolute requirement for the induction of the cellular and behavioral response to cocaine, as demonstrated by studies performed in D1R−/− mice [38]. Recent studies, using transgenic

Rewarding and reinforcing properties of addictive drugs in the absence of D2Rs

The rewarding properties of cocaine in D2R−/− mice, as assessed by conditioned place preference (CPP), are attenuated [40]. However, self-administration studies showed that D2R−/− mice self-administer more cocaine than WT mice [44]. The contribution of other neuromodulators (i.e. noradrenalin, serotonin) [45] in expression of CPP and self-administration to cocaine in D2R−/− cannot be excluded and awaits further analyses. This point is of particular relevance in light of the numerous data

Conclusions

Results obtained from the analysis of D2R mutants have provided evidence of the different involvement of D2L and D2S in D2R-mediated signaling evoked by drugs of abuse and direct agonists. Absence of D2L-mediated signaling impairs the regulation of PKA and AKT pathways by D2Rs, but does not affect the motor and rewarding response to cocaine. Conversely, D2S-mediated signaling appears to be an absolute requirement for the motor and rewarding effects of cocaine and most probably of other

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Work in the laboratory of E Borrelli related to this review was supported by funds from NIDA (DA024689) and European Community (EC LSHM-CT-2004-005166).

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