The dopamine D4 receptor: biochemical and signalling properties

Dopamine is an important neurotransmitter that regulates several key functions in the brain, such as motor output, motivation and reward, learning and memory, and endocrine regulation. Dopamine does not mediate fast synaptic transmission, but rather modulates it by triggering slow-acting effects through the activation of dopamine receptors, which belong to the G-protein-coupled receptor superfamily. Besides activating different effectors through G-protein coupling, dopamine receptors also signal through interaction with a variety of proteins, collectively termed dopamine receptor-interacting proteins. We focus on the dopamine D4 receptor, which contains an important polymorphism in its third intracellular loop. This polymorphism has been the subject of numerous studies investigating links with several brain disorders, such as attention-deficit hyperactivity disorder and schizophrenia. We provide an overview of the structure, signalling properties and regulation of dopamine D4 receptors, and briefly discuss their physiological and pathophysiological role in the brain.     

Acute changes in dopamine metabolism in the medio-basal hypothalamus following adrenalectomy

During the first hour following adrenalectomy the alpha-MPT-induced disappearance of dopamine was increased in the arcuate nucleus compared to that in sham-operated rats. In a number of other brain regions of both adrenalectomized and sham-adrenalectomized rats only stress-induced changes were observed in catecholamine utilization. These data suggest that corticosterone selectively modulates dopamine utilization in the medio-basal hypothalamus.     

A radioenzymatic method to measure picogram amounts of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in small samples of brain tissue

Summary A radioenzymatic method for simultaneous determination of dopamine and DOPAC in small brain areas is described. By using this assay, 250 pg of dopamine and 150 pg of DOPAC can be estimated. The present method has been applied to compare the effect of different psychotropic drugs on the dopamine and DOPAC levels in the caudate nucleus, substantia nigra and medial basal hypothalamus.     

Serotoninergic modulation of mesolimbic and frontal cortical dopamine neurons

Summary Potentiation of the effect of haloperidol on dopamine metabolism by the 5-HT uptake inhibitor CGP 6085 A, and antagonism of this effect by the 5-HT antagonist mianserin were observed in the mesolimbic area and the frontal cortex of the rat brain. A similar effect was reported earlier in the corpus striatum. This suggests that serotoninergic modulation of dopamine neurons is a generally-occurring phenomenon in the brain.     

Accumulation of 3H-dopamine by synaptic vesicles from rat striatum in an impermeant medium

The accumulation of 3H-dopamine by synaptic vesicles from rat striatum was significantly stabilized in a membrane impermeant medium. The characteristics of dopamine accumulation by striatal vesicles were quite similar to those reported for dopamine accumulation by a whole brain vesicle preparation in the same medium, and were significantly different from the characteristics previously reported for vesicular accumulation of norepinephrine.     

Serotoninergic modulation of mesolimbic and frontal cortical dopamine neurons

Potentiation of the effect of haloperidol on dopamine metabolism by the 5-HT uptake inhibitor CGP 6085 A, and antagonism of this effect by the 5-HT antagonist mianserin were observed in the mesolimbic area and the frontal cortex of the rat brain. A similar effect was reported earlier in the corpus striatum. This suggests that serotoninergic modulation of dopamine neurons is a generally-occurring phenomenon in the brain.     

Brain adenylate cyclase activation in the jaundiced rat

Summary Adenylate cyclase responses of brain cortex and neostriatum to noradrenaline and dopamine are increased in rats with jaundice in proportion to its severity. In comparing the situation with uraemia, the relevance of phenols has to be considered.     

Brain adenylate cyclase activation in the jaundiced rat.

Adenylate cyclase responses of brain cortex and neostriatum to noradrenaline and dopamine are increased in rats with jaundice in proportion to its severity. In comparing the situation with uraemia, the relevance of phenols has to be considered.     

Accumulation of3H-dopamine by synaptic vesicles from rat striatum in an impermeant medium

Summary The accumulation of³H-dopamine by synaptic vesicles from rat striatum was significantly stabilized in a membrane impermeant medium. The characteristics of dopamine accumulation by striatal vesicles were quite similar to those reported for dopamine accumulation by a whole brain vesicle preparation in the same medium, and were siginificantly different from the characteristics previously reported for vesicular accumulation of norepinephrine.Acknowledgments. This work was supported by grant NS 18752 (NIH) of the United States Public Health Service. Reprint requests to J. A. R.     

Acute changes in dopamine metabolism in the medio-basal hypothalamus following adrenalectomy

Summary During the first hour following adrenalectomy the -MPT-induced disappearance of dopamine was increased in the arcuate nucleus compared to that in sham-operated rats. In a number of other brain regions of both adrenalectomized and sham-adrenalectomized rats only stress-induced changes were observed in catecholamine utilization. These data suggest that corticosterone selectively modulates dopamine utilization in the medio-basal hypothalamus.Acknowledgment. The skilful technical assistance of Ms Joke Van Put, Ms Henny De Vos Burchart-Lodewijks and Mr Henk Spierenburg is gratefully acknowledged.     

Effect of centrally active drugs on dopamine oxidation by rat brain catecholamine oxidase.

Centrally active drugs of the phenothiazine-, butyrophenone- and iminodibenzyl class markedly decreased the rate of dopamine oxidation in the presence of rat brain catecholamine oxidase.     

Effect of benzatropine on the O-methylation of striatal dopamine]

After treatment by nialamid, benztropine administered to Rats produced an increase in the level of 3-O-methyldopamine in the corpus striatum. It produced a slight increase in the level of striatal dopamine and no change in the level of norepinephrine. The monoamine oxydase and catechol-O-methyltransferase activities of remaining brain showed no variations by benztropine. The results suggest the possible involvement of striatal dopamine and its extraneuronally catabolism in the antiparkinsonian effect of benztropine.     

Effects of S-adenosylmethionine and S-adenosylhomocysteine on in vivo synthesis of noradrenaline and serotonin in different parts of the rat brain]

S-adenosylmethionine (0,1 mg/kg/ip) decreases in vivo, norepinephrine (NE) synthesis and does not affect 5-hydroxytryptamine (5 HT) synthesis in the Rat brain. S-adenosylhomocysteine (7 mg/kg/ip) increases NE synthesis and decreases 5 HT synthesis. Neither nucleoside affects dopamine synthesis.     

Changes in brain dopamine levels and aggressive behavior with aging in 2 mouse strains

The genetic programming of brain monoamine changes with aging show remarkable differences in 2 mouse strains. A marked increase in dopamine occurred in 32-week-old grouped ICR mice and the males showed intense irritability and aggressive behavior. Brain amines changed only slightly in old C57BL6J mice and behavior remained benign. Old females showed similar amine changes but aggresive behavior did not occur in either strain.     

Changes in brain dopamine levels and aggressive behavior with aging in 2 mouse strains

Summary The genetic programming of brain monoamine changes with aging show remarkable differences in 2 mouse strains. A marked increase in dopamine occurred in 32-week-old grouped ICR mice and the males showed intense irritability and aggressive behavior. Brain amines changed only slightly in old C57BL6J mice and behavior remained benign. Old females showed similar amine changes but aggressive behavior did not occur in either strain.     

Effect of centrally active drugs on dopamine oxidation by rat brain catecholamine oxidase

Summary Centrally active drugs of the phenothiazine-, butyrophenone- and iminodibenzyl class markedly decreased the rate of dopamine oxidation in the presence of rat brain catecholamine oxidase.The financial support from Gotfred Lie and Marie Lie's Fond is gratefully acknowledged.     

Interaction of CDP-choline with synaptosomal transport of biogenic amines and their precursors in vitro and in vivo in the rat corpus striatum.

Added to a striatal synaptosomal homogenate of rat brain, CDP-choline 10(-4) M inhibits the uptake of norepinephrine (NE), dopamine (DA) and serotonin (5 HT) in a competitive fashion and enhances the uptake of tyrosine and tryptophan; administered to animals, CDP-choline (50 mg/kg/l h/i.v.) inhibits only the in vitro uptake of DA but enhances the uptake of precursors.     

In vitro inhibition by dopamine of 5-hydroxytryptamine-stimulated ovarian maturation in the red swamp crayfish,Procambarus clarkii

Dopamine inhibits 5-hydroxytryptamine-stimulated maturation of the ovaries of the red swamp crayfish,Procambarus clarkii, in vitro just as it does in vivo. This in vitro inhibition appears to be due to inhibition of release of the gonad-stimulating hormone from the brain and thoracic ganglia. However, it is possible that in vivo dopamine also triggers release of the gonad-inhibiting hormone.     

Activation by S-adenosylhomocysteine of norepinephrine and serotonin in vitro uptake in synaptosomal preparations from rat brain.

S-Adenosylhomocysteine (10(-7)-10(-5) M) activated norepinephrine (NE) and serotonin (5HT) in vitro uptake in synaptosomal preparations from rat brain, but did not affect dopamine (DA) uptake. When administered to rats (7 mg/kg i.p.), it has the same effect on in vitro NE and 5HT uptake. It did not affect NE and 5HT release.     

Microspectrophotometric study of biogenic amines in ganglions of the central nervous system of Crepidula fornicata (Phil.)]

The fluorescent products formed from biogenic amines treated with formaldehyde according to the method of Falck and Owman have been studied in the brain of Crepidula fornicata. The microspectrophotometric analysis of cellular indolamines shows excitation emission maxima at 385--525 nm (serotonine) and catecholamine at 410--475 nm upon HCl treatment catecholamine products show a shift of the excitation peak from 410 to 370 nm (dopamine).