Adaptive properties and heterogeneity of dopamine D2 receptors – Pharmacological implications

doi:10.1016/j.brainresrev.2007.09.007

Brain Research Reviews

Volume 58, Issue 2, August 2008, Pages 374-378

https://doi.org/10.1016/j.brainresrev.2007.09.007 Get rights and content

Abstract

In this review, we focus on the marked adaptability of dopamine D₂ receptors to varying agonist levels and we discuss the extent to which this phenomenon can account for the heterogeneity of these receptors in regard to function and pharmacological responsiveness. We emphasize the significance of a distinction between synaptic and extrasynaptic receptors in this context. For example, the application of this dichotomy appears to shed new light on the various subgroups of antipsychotic drugs and the mechanisms underlying their different profiles.

Introduction

The role of dopamine as a key player in many brain functions and in a variety of neurological and psychiatric disorders is well documented, and drugs acting on dopamine receptors are indispensable tools in brain research. In addition, many such drugs have proved important therapeutic agents. Best understood among the drugs acting on dopamine receptors are those acting on D₁ and D₂, i.e., the majority among the total five receptor subtypes. So far, drugs acting selectively on D₁ receptors have not yet proved very useful therapeutically. The most important drugs acting on dopamine receptors are D₂ agonists and antagonists. In addition, some of these D₂ ligands, mostly agonists, act on D₁ receptors, and others, agonists as well as antagonists, have affinity for both D₂ and D₃ receptors. Although these additional effects are relevant, the pharmacology of D₂ receptors carries a special weight and will be the subject focussed upon in the present review.

Section snippets

Heterogeneity of dopamine D₂ receptors

A salient aspect of dopamine receptor pharmacology is that at least the D₂ receptor population is heterogeneous, both in terms of function and response to drugs. To some extent, this can probably be explained by the occurrence of two splice variants, that is the long (D₂l) and the short (D₂s) variants. However, it is unlikely that all heterogeneity of D₂ receptors can be explained accordingly (Leysen et al., 1993, Malmberg et al., 1993).

At an early stage, members of two Swedish research groups,

Receptor adaptiveness

When tested after acute removal of the endogenous agonist, the responsiveness of dopamine receptors to agonists was found to vary in different locations and under different conditions. This led Carlsson (1983) to propose that the receptor's responsiveness was adapted to the level of endogenous agonist it had been exposed to previously. This would allow the receptor to function in spite of varying baseline transmitter levels. One would probably be dealing with marked variations, when comparing,

Possible mechanisms of receptor adaptation

The mechanism underlying these adaptive properties of dopamine D₂ receptors is unclear. Increases in receptor density and in the coupling of the receptor to G-protein have been observed following denervation, with an accompanying receptor supersensitivity (Cai et al., 2002), but the changes are not pronounced and, in any event, the mechanism underlying the elevated coupling has not been clarified.

In attempts to better understand the nature of the adaptation mechanism, it could be useful to

Possible consequences for antagonist actions

The question arises if components of the postsynaptic density could also influence the action of ligands devoid of intrinsic activity, i.e. pure antagonists. In general, such agents have antipsychotic and antimanic properties. Depending on their pharmacological and clinical profiles and mechanisms of action, they can be divided into several subgroups. The compounds first discovered, represented by chlorpromazine and haloperidol, seem to bind with approximately equal strength to the different

Concluding remarks

The present discussion has focussed on the adaptability of dopamine D₂ receptors and on its role for the heterogeneity of this receptor subtype. It is hypothesized that the adaptation of these receptors to varying ambient extracellular agonist levels is mediated by adjacent molecules located in the cell membrane. This speculation starts out from the postsynaptic density, which must be assumed to somehow regulate the function of the postsynaptic receptor. In favour of a connection between

Acknowledgments

This work was supported by Västra Götalandsregionen, Sweden, grants from the state under the LUA/ALF agreement, the Arvid Carlsson Foundation, the Swedish Lundbeck Foundation and Wilhelm och Martina Lundgrens Vetenskapsfond. We are grateful to Pfizer Inc., Sanofi-Aventis and Lilly Research Laboratories for donating drugs for these studies. We also wish to thank Kenn Johannesen for valuable technical advice.

Disclosure: Arvid Carlsson and Maria Carlsson are shareholders in NeuroSearch A/S which

References (34)

M. Carlsson et al.
The intrinsic activity of (−)-3-PPP (preclamol) on pituitary DA receptors in female rats is enhanced following chronic DA depletion
Life Sci.
(1988)
M. Carlsson et al.
The intrinsic activities of the partial dopamine receptor agonists (-)-3-PPP and TDHL on pituitary dopamine receptors are lower in female than in male rats.
Eur. J. Pharmacol.
(1987)
D. Centonze et al.
Dopamine D₂ receptor-mediated inhibition of dopaminergic neurons in mice lacking D₂L receptors
Neuropsychopharmacology
(2002)
L. Descarries et al.
Ultrastructural evidence for diffuse transmission by monoamine and acetylcholine neurons of the central nervous system
L.S. Pilowsky et al.
Limbic selectivity of clozapine
Lancet
(1997)
P. Seeman et al.
Dopamine partial agonist action of (−)OSU6162 is consistent with dopamine hyperactivity in psychosis
Eur. J. Pharmacol.
(2007)
M. Zoli et al.
Volume transmission in the CNS and its relevance for neuropsychopharmacology
Trends Pharmacol. Sci.
(1999)
J. Arnt et al.
Dopamine receptor agonistic and antagonistic effects of 3-PPP enantiomers
Psychopharmacology (Berl.)
(1983)
V. Bigliani et al.
Striatal and temporal cortical D₂/D₃ receptor occupancy by olanzapine and sertindole in vivo: a [¹²³I]epidepride single photon emission tomography (SPET) study
Psychopharmacology (Berl.)
(2000)
G. Cai et al.
Increased dopamine receptor signaling and dopamine receptor-G protein coupling in denervated striatum
J. Pharmacol. Exp. Ther.
(2002)

A. Carlsson

Dopaminergic autoreceptors

A. Carlsson

Dopamine receptor agonists: intrinsic activity vs. state of receptor

J. Neural Transm.

(1983)

Carlsson. M., 1988. Sex differences in monoaminergic mechanisms in rat. Thesis, University of Gothenburg, pp...

M. Carlsson et al.

The partial dopamine receptor agonists (−)-3-PPP and transdihydrolisuride enhance prolactin secretion in female but not in male rats

J Neural Transm.

(1989)

A. Carlsson et al.

Dopaminergic stabilisers

Adv. Schizophr. Clin. Psychiatry

(2005)

M. Carlsson et al.

Sexually differentiated actions of 3-PPP enantiomers on prolactin secretion

Neuropharmacology

(1986)

M.L. Carlsson et al.

Schizophrenia: from dopamine to glutamate and back

Curr. Med. Chem.

(2004)

Cited by (13)

Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes
2014, Biochemical and Biophysical Research Communications
Citation Excerpt :
These results suggested the existence of a 5-HT2AR-mediated D2LR trans-inhibition phenomenon [1]. The D2LR-5-HT2AR heteromer represents a novel target for antipsychotic drugs since such drugs are well known to exert their therapeutic actions at least with regard to positive symptoms via blockade of D2Rs [3]. Albizu et al. [4] recently observed that activation of D2Rs by quinpirole increases the affinity of the hallucinogenic 5-HT2AR agonist DOI ((±)-2,5-dimethoxy-4-iodoamphetamine) for the 5-HT2AR and reduces the DOI induced Gq/11 coupling to the 5-HT2AR as seen from the diminished production of inositol phosphate by DOI.
Dopamine D2_LR-serotonin 5-HT2AR heteromers were demonstrated in HEK293 cells after cotransfection of the two receptors and shown to have bidirectional receptor–receptor interactions. In the current study the existence of D2_L-5-HT2A heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assays (PLA). The hallucinogenic 5-HT2AR agonists LSD and DOI but not the standard 5-HT2AR agonist TCB2 and 5-HT significantly increased the density of D2like antagonist ³H-raclopride binding sites and significantly reduced the pK_iH values of the high affinity D2R agonist binding sites in ³H-raclopride/DA competition experiments. Similar results were obtained in HEK293 cells and in ventral striatum. The effects of the hallucinogenic 5-HT2AR agonists on D2R density and affinity were blocked by the 5-HT2A antagonist ketanserin. In a forskolin-induced CRE-luciferase reporter gene assay using cotransfected but not D2R singly transfected HEK293 cells DOI and LSD but not TCB2 significantly enhanced the D2_LR agonist quinpirole induced inhibition of CRE-luciferase activity. Haloperidol blocked the effects of both quinpirole alone and the enhancing actions of DOI and LSD while ketanserin only blocked the enhancing actions of DOI and LSD. The mechanism for the allosteric enhancement of the D2R protomer recognition and signalling observed is likely mediated by a biased agonist action of the hallucinogenic 5-HT2AR agonists at the orthosteric site of the 5-HT2AR protomer. This mechanism may contribute to the psychotic actions of LSD and DOI and the D2-5-HT2A heteroreceptor complex may thus be a target for the psychotic actions of hallunicogenic 5-HT2A agonists.
Effects of metoclopramide on the mouse anterior pituitary during the estrous cycle
2011, Clinics
Citation Excerpt :
As a D2 receptor antagonist, metoclopramide affects PRL secretion.7,8,13,18 The long and short isoforms of the dopamine receptor (D2L and D2S) exhibit similar pharmacological properties and are co-expressed in the same cells.19 The D2L isoform is predominant in the rat pituitary, striatum, and olfactory tubercle, whereas D2S is more abundant in the hypothalamus.20–22
Dopamine D2 and 5-hydroxytryptamine 5-HT<inf>2A</inf> receptors assemble into functionally interacting heteromers
2010, Biochemical and Biophysical Research Communications
Citation Excerpt :
Blockade of the D2R especially in the limbic system likely mediates the antipsychotic actions of D2R antagonists in treatment of schizophrenia [1–4].
In view of the co-distribution of dopamine D_2LR and 5-hydroxytryptamine 5-HT_2A receptors (D_2LR and 5-HT_2AR, respectively) within inter alia regions of the dorsal and ventral striatum and their role as a target of antipsychotic drugs; in this study we assessed the potential existence of D_2LR-5-HT_2AR heteromers in living cells and the functional consequences of this interaction. Thus, by means of a proximity-based bioluminescence resonance energy transfer (BRET) approach we demonstrated that the D_2LR and the 5-HT_2AR form stable and specific heteromers when expressed in HEK293T mammalian cells. Furthermore, when the D_2LR-5-HT_2AR heteromeric signaling was analyzed we found that the 5-HT_2AR-mediated phospholipase C (PLC) activation was synergistically enhanced by the concomitant activation of the D_2LR as shown in a NFAT-luciferase reporter gene assay and a specific and significant rise of the intracellular calcium levels were observed when both receptors were simultaneously activated. Conversely, when the D_2LR-mediated adenylyl cyclase (AC) inhibition was assayed we showed that costimulation of D_2LR and 5-HT_2AR within the heteromer led to inhibition of the D_2LR functioning, thus suggesting the existence of a 5-HT_2AR-mediated D_2LR trans-inhibition phenomenon. Finally, a bioinformatics study reveals that the triplet amino acid homologies LLT (Leu-Leu-Thr) and AIS (Ala-Ile-Ser) in TM1 and TM3, respectively of the D₂R-5-HT_2AR may be involved in the receptor interface. Overall, the presence of the D_2LR-5-HT_2AR heteromer in discrete brain regions is postulated based on the existence of D_2LR-5-HT_2A receptor–receptor interactions in living cells and their codistribution inter alia in striatal regions. Possible novel therapeutic strategies for treatment of schizophrenia should be explored by targeting this heteromer.
Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms
2021, Pharmacological Reviews
Effects of hyperprolactinemia and ovariectomy on the tibial epiphyseal growth plate and bone formation in mice
2014, Revista Brasileira de Ginecologia e Obstetricia
The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: Old fashioned, but still in vogue
2014, Frontiers in Psychiatry

View all citing articles on Scopus

View full text

ReviewAdaptive properties and heterogeneity of dopamine D2 receptors – Pharmacological implications

Abstract

Introduction

Section snippets

Heterogeneity of dopamine D2 receptors

Receptor adaptiveness

Possible mechanisms of receptor adaptation

Possible consequences for antagonist actions

Concluding remarks

Acknowledgments

Life Sci.

Eur. J. Pharmacol.

Neuropsychopharmacology

Lancet

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Dopamine receptor agonistic and antagonistic effects of 3-PPP enantiomers

Psychopharmacology (Berl.)

Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [123I]epidepride single photon emission tomography (SPET) study