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PubMed2000

Investigation of dopamine receptor (DRD4) and dopamine transporter (DAT) polymorphisms for genetic linkage or association to panic disorder.

Clinical and animal studies suggest a role for the neurotransmitter dopamine in anxiety states. In humans, one such condition is panic disorder, which is typified by recurrent panic attacks accompanied by anticipatory anxiety. Family, segregation, and twin studies imply a genetic component to the pathophysiology of panic disorder. In this study, we examined the genes for the D4 dopamine receptor (DRD4) and the dopamine transporter (DAT) using three common sequence polymorphisms. Two of these polymorphisms were in DRD4, a 12 base-pair insertion/deletion in exon 1 and a 48 base-pair repeat in exon 3, and the third was a 40 base-pair repeat in the 3' untranslated region of DAT. We employed a family-based design, using 622 individuals in 70 families, as well as 82 haplotype relative risk "trios". Subjects were genotyped at the polymorphic loci, and the data were analyzed for genetic association and linkage. There were no significant differences in allele frequencies or occurrence of genotypes within the triads for any of the three polymorphisms. No significant linkage between the DRD4 or DAT polymorphisms and panic disorder was observed in the multiplex families, using a variety of simulations for dominant and recessive models of inheritance. However, LOD scores of approximately 1.1 and 1.05 were observed for the DAT and DRD4 exon 1 loci, respectively. The results reported here provide little support for the role of these polymorphisms in panic disorder.

Alleles↗

PubMed1999

Comparison of dopamine receptor antagonists on hyperlocomotion induced by cocaine, amphetamine, MK-801 and the dopamine D1 agonist C-APB in mice.

RATIONALE: Direct or indirect stimulation of dopamine receptors increases locomotor activity in mice. Determining the role played by D1 and D2 dopamine receptors in the mediation of this activity can be difficult due to the wide variety of experimental paradigms used to investigate these phenomena. OBJECTIVES: This study set out to compare the role of selective antagonism of dopamine D1 and D2 receptors on the hyperactivity induced by a range of stimulants. METHODS: Mice were habituated to perspex locomotor activity boxes (30 x 30 x 30 cm) and activity was measured via photobeam interrupts. RESULTS: Haloperidol and clozapine both reduced the hyperactivity induced by MK-801. Haloperidol did so only at a dose that also decreased spontaneous activity (0.1 mg/kg), whereas clozapine reduced MK-801-induced hyperactivity at a dose that had no effect on spontaneous activity (1.25 mg/kg). The D1 antagonist SCH23390 (0.01 mg/kg) reduced hyperlocomotion induced by amphetamine (2.5 mg/kg), cocaine (10 mg/kg) and C-APB (1.0 mg/kg) at doses that did not consistently alter spontaneous activity, whereas the selective D2 antagonist raclopride only attenuated the hyperlocomotion induced by amphetamine, cocaine and C-APB at doses in excess of the minimum dose required to attenuate spontaneous locomotor activity significantly. The latency to peak levels of hyperlocomotion induced by MK-801 (0.3 mg/kg) was delayed by SCH23390 (0.1 mg/kg) but peak levels of activity were not reduced. CONCLUSIONS: The results of the present study suggest that selective blockade of D1 receptors suppresses amphetamine and cocaine-induced hyperactivity in mice but not MK-801-induced locomotor activity.

Amphetamine↗

PubMed1991

Dopamine D2 receptor binding properties of [3H]U-86170, a dopamine receptor agonist.

U-86170F, an imidazoguinolinone, is a potent dopamine D2 agonist, binding with high affinity to the dopamine D2 receptor. A Kd of 0.99 nM was determined in membranes from Chinese hamster ovarian (CHO) cells transfected with the D2 receptor and a Kd of 1.72 nM was obtained in rat striatal homogenates. GTP sensitivity was demonstrated when its addition (300 microM) reduced [3H]U-86170 binding by 60%. This agonist ligand is especially effective in identifying agonists and partial agonists, as well as antagonists, and affords a more precise evaluation of their affinity for the dopamine D2 receptor, without the use of multiple site analysis, than does an antagonist [3H]-ligand.

Aminoquinolines↗

PubMed1995

Regulation of dopamine release and metabolism in rat striatum in vivo: effects of dopamine receptor antagonists.

1. The acute effects of some of typical and atypical antipsychotic drugs on the dopamine release and metabolism in the dorsal striatum of freely moving rats were studied using transcerebral microdialysis technique. 2. Classical neuroleptic drugs haloperidol (0.05, 0.1 and 0.2 mg/kg), thioproperazine (0.1, 0.2 and 0.4 mg/kg) and spiperone (0.02, 0.04 and 0.07 mg/kg) administered i.p. induced pronounced elevation of extracellular level of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) up to 250-300% to basal level while producing less increase in that of dopamine (DA) (up to 150-170%). 3. Atypical neuroleptics clozapine and thioridazine (both 2, 5 and 20 mg/kg) increased striatal DA release and DOPAC level approximately at the same degree (maximally up to 200% and 160%, respectively). 4. Dopamine D3 receptor and autoreceptor preferring antagonists (+)-UH232 and (+)-AJ76 (both 4, 7 and 14 mg/kg) more potently increased DA release in comparison with DOPAC dialysate level (+)-AJ76 elevated DA level maximally up to 330%, DOPAC-up to 250%). 5. The features of typical and atypical neuroleptics in preferential action on DA release or DOPAC output were observed in all doses of the drugs studied. 6. The ability of the drugs to affect preferentially DA release or DOPAC extracellular level in rat striatum correlates to their relative affinities at D3 and D2 DA receptors. 7. It is concluded that typical and atypical antipsychotic drugs might be clearly distinguished on the basis of their ability to affect preferentially DA synthesis/metabolism or release in rat dorsal striatum in vivo.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1998

Associative and limbic regions of monkey striatum express high levels of dopamine D3 receptors: effects of MPTP and dopamine agonist replacement therapies.

The role of the dopamine D3 receptor subtype in the central nervous system is still not well understood. It has a distinct and restricted distribution, mostly associated with limbic territories of the striatum (olfactory tubercle and the shell of nucleus accumbens) in rat brain. Dopaminergic denervation induced by a 6-hydroxydopamine lesion of the nigrostriatal system in rat down-regulates the expression of the D3 receptor. In the present study, we investigated the functional neuroanatomy of the dopamine D3 receptor subtype in the monkey (Macaca fascicularis) basal ganglia. We also studied the effect of administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and chronic D1-like (SKF 82958) or D2-like (cabergoline) agonist treatments on dopamine D3 receptor levels using receptor autoradiography. Our results clearly show that the distribution of D3 receptors in the monkey is more closely related to associative and limbic components of the striatum (caudate-putamen), as compared with its sensorimotor counterpart. Hence, D3 receptors may be more specifically involved in cognitive and motivational aspects of striatal functions, which are elaborated in prefrontal, temporal, parietal, cingulate and limbic cortices. Moreover, MPTP administration significantly decreased levels of D3 receptors and this effect was reversed or compensated by a chronic treatment with a D1-like, but not a D2-like, receptor agonist. The D3 receptor may represent an important target for adjunct or direct therapy designed to improve cognitive deficits observed in patients with Parkinson's disease, schizophrenia and other illnesses with frontal lobe cognitive disturbances.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2001

Mechanisms of inverse agonism of antipsychotic drugs at the D(2) dopamine receptor: use of a mutant D(2) dopamine receptor that adopts the activated conformation.

The antipsychotic drugs have been shown to be inverse agonists at the D(2) dopamine receptor. We have examined the mechanism of this inverse agonism by making mutations in residue T343 in the base of the sixth transmembrane spanning region of the receptor. T343R, T343S and T343K mutant D(2) dopamine receptors were made and the T343R mutant characterized in detail. The T343R mutant D(2) dopamine receptor exhibits properties of a receptor that resides more in the activated state, namely increased agonist binding affinity (independent of G-protein coupling and dependent on agonist efficacy), increased agonist potency in functional tests (adenylyl cyclase inhibition) and increased inverse agonist effects. The binding of agonists to the mutant receptor also shows sensitivity to sodium ions, unlike the native receptor, so that isomerization of the receptor to its inactive state may be driven by sodium ions. The binding of inverse agonists to the receptor is, however, unaffected by the mutation. We conclude that inverse agonism at this receptor is not achieved by the inverse agonist binding preferentially to the non-activated state of the receptor over the activated state. Rather the inverse agonist appears to bind to all forms of the receptor but then renders the receptor inactive.

1-Methyl-3-isobutylxanthine↗

PubMed2004

Dopamine receptor-mediated regulation of RGS2 and RGS4 mRNA differentially depends on ascending dopamine projections and time.

RGS2 and RGS4 mRNAs are regulated in the rat striatum by dopaminergic agents. The present study further characterizes this regulation in three experiments. First, dopamine type 1 (receptor) (D1)- and dopamine type 2 (receptor) (D2)-mediated regulator of G-protein signalling (RGS) gene regulation was investigated in animals with deleted ascending dopaminergic pathways. We showed that RGS2 expression is controlled by D1 receptors either by direct action on D1 receptors or indirectly by presynaptic D2 receptors. Conversely, RGS4 gene expression is independent of presynaptic D2 receptors. Second, the study of colocalization between RGS2 or RGS4 and D1 or D2 by double labelling in situ hybridization histochemistry revealed broad expression of RGS2 and RGS4 mRNA in striatal subpopulations with colocalization of RGS2 and RGS4 with both D1 and D2 receptors. Finally, to test how far their gene regulation is temporally concerted, changes in RGS2 and RGS4 mRNA levels were measured in parallel with receptor occupancy by specific dopaminergic drugs at different time-points. RGS2 was rapidly/transiently up-regulated by the D1 agonist SKF82958 and the D2 antagonist haloperidol (peak at 0.5 h) and down-regulated by the D1 antagonist SCH23390 and the D2 agonist quinpirole (trough at 1 and 2 h). RGS4 showed a delayed/transient up-regulation with SCH23390 and quinpirole (peak at 4 and 2 h) and down-regulation with haloperidol (trough at 8 h). Depending on the drug used, the degree of receptor occupancy did (D1 agonist and RGS2) or did not (D2 antagonist and RGS2) run parallel to RGS gene expression changes, indicating that certain drug effects are direct and others indirect. The precise control of RGS2 and RGS4 expression by dopamine receptors pleads in favour of their potential contribution to the fine-tuning of D1 and D2 receptor signalling cascades.

Animals↗

PubMed1992

D1-like and D2-like dopamine receptors synergistically activate rotation and c-fos expression in the dopamine-depleted striatum in a rat model of Parkinson's disease.

Selective agonists for D1-like and D2-like dopamine receptors can interact synergistically to enhance each other's actions on locomotion and behavior in experimental animals. Clinically, the combination of the D2 agonist bromocriptine with L-dopa (which has pronounced D1 effects) is a highly effective treatment for Parkinson's disease. The mechanisms underlying this important receptor interaction are poorly understood and are the subject of intense study in vitro. In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway, D1-selective (but not D2-selective) dopamine agonists produce a marked increase in expression of the immediate-early gene c-fos in the striatum ipsilateral to the 6-OHDA lesion. In the experiments reported here, we have used this in vivo model to explore the possibility that combinations of D1-selective and D2-selective agonists might have effects on c-fos transcription that are different from those exhibited by D1 or D2 agonists administered alone. We examined the effects of the D1-selective agonist SKF-38393 and the D2-selective agonist quinpirole (LY 171555) on the expression of Fos-like protein and c-fos mRNA in the caudoputamen and made parallel behavioral observations in the same animals. A low dose of SKF-38393 produced little contraversive rotation and little induction of Fos-like immunoreactivity in the striatum. A low dose of quinpirole elicited contralateral rotation but little or no induction of Fos-like immunoreactivity in the caudoputamen; there was, however, induction of Fos in the globus pallidus ipsilateral to the 6-OHDA lesion. Combination of the low dose of SKF-38393 and quinpirole produced a synergistic effect on rotation and elicited, in the dopamine-depleted caudoputamen, a striking pattern of Fos-like protein expression in which Fos-positive neurons were concentrated in striosomes and in the dorsolateral caudoputamen. Northern blot analysis showed that c-fos mRNA was expressed following combined agonist treatment but was not detectable after the single-agonist treatments. Both the contraversive rotation and the induction of Fos-like immunoreactivity were blocked by the preadministration of the D1-preferring antagonist SCH-23390 and the D2-selective antagonist raclopride in combination. Pretreatment with the glutamate NMDA receptor antagonist MK-801 also blocked the induction of Fos-like immunoreactivity, and it reversed the rotation. These findings suggest a D1/D2 synergistic mechanism that involves the participation of D1-responsive striatonigral and D2-responsive striatopallidal output pathways, and that is sensitive to glutamatergic modulation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1994

Dopamine in the lobster Homarus gammarus. I. Comparative analysis of dopamine and tyrosine hydroxylase immunoreactivities in the nervous system of the juvenile.

As a catecholamine, dopamine belongs to a class of molecules that have multiple transmitter and hormonal functions in vertebrate and invertebrate nervous systems. However, in the lobster, where many central neurons have been identified and the peripheral innervation pattern is well known, the distribution of dopamine-containing neurons has not been examined in detail. Therefore, immunocytochemical methods were used to identify neurons likely to contain dopamine and tyrosine hydroxylase in the central nervous system of the juvenile lobster Homarus gammarus. Approximately 100 neuronal somata stain for the catecholamine and/or its synthetic enzyme in the brain and ventral nerve cord. The systems of neurons labeled with dopamine and tyrosine hydroxylase antibodies have the following characteristics: 1) the two systems are nearly identical; 2) every segmental ganglion contains at least one pair of labeled neurons; 3) the positions and numbers of cell bodies labeled with each antiserum are similar in the various segmental ganglia; 4) six labeled neurons are anatomically identified; two interneurons from the brain project within the ventral cord to reach the last abdominal ganglion, two neurons from the commissural ganglia are presumably neurosecretory neurons, and two anterior unpaired medial abdominal neurons project to the hindgut muscles; and 5) no cell bodies are labeled in the stomatogastric ganglion, but fibers and terminals in the neuropil are stained. The remarkably small numbers of labeled neurons and the presence of very large labeled somata with far-reaching projections are distinctive features consistent with other modulatory aminergic systems in both vertebrates and invertebrates.

Animals↗

PubMed1986

Dopamine agonist-induced stereotypic grooming and self-mutilation following striatal dopamine depletion.

Rats with bilateral 6-OHDA-induced striatal lesions exhibit altered apomorphine-induced behavior compared to the typical response seen in intact rats. This response is characterized by stereotypic grooming behavior which is transformed to compulsive and intense biting at higher doses. Other agonists, pergolide, bromocriptine, N-n-propylnorapomorphine and L-dopa/carbidopa, caused the same response. Direct intrastriatal infusion of apomorphine after 6-OHDA-induced lesions of the striata also produced this response, while similar SKF 38393 infusion caused more licking than biting, directed at the abdomen instead of the forepaws. The dopamine receptor antagonists haloperidol, SCH 23390 and sulpiride effectively blocked apomorphine-induced behaviors in dopamine-depleted animals. This altered behavior was not observed in rats with dopamine depletion in nucleus accumbens (NAS), nor did additional NAS lesions in rats with existing striatal lesions affect the behavior. Further, high doses of apomorphine (up to 60 mg/kg) failed to induce stereotypic grooming in unlesioned rats. We therefore propose that altered apomorphine-induced behavior is a unique consequence of striatal dopamine depletion and not just an intense form of normal stereotypic activity.

Animals↗

PubMed1983

Inhibition of dopamine-activated adenylate cyclase and dopamine binding by opiate receptors in rat striatum.

Low-affinity (micromolar) 3H-dopamine binding was measured under conditions which permitted dopamine activation and opiate inhibition of adenylate cyclase in rat striatal membranes. Opiate drugs and peptides inhibited the dopamine binding in the presence of both GTP and Gpp(NH)p. Opiate inhibition of adenylate cyclase was, however, observed only in the presence of GTP. It is suggested that the dopamine D1 receptor in striatum may be modulated by the opiate delta receptor through a shared guanine nucleotide binding subunit.

Adenylyl Cyclase Inhibitors↗

PubMed1988

Development of dopamine-containing neurons and dopamine uptake in embryos of Hirudo medicinalis.

The embryonic development of neurons which contain or take up dopamine was studied with glyoxylic acid histofluorescence in Hirudo medicinalis. Beginning at the time of the formation of the tail ganglion, one pair of dopamine-containing neurons was stained per segmental ganglion. The normal outgrowth of the cell bodies into the anterior roots was prevented in isolated and cultured chains of embryonic ganglia. Preincubation of intact embryos in dopamine led to the staining of additional neurons at certain developmental stages. These neurons presumably are the precursors of serotonin-containing cells, which have a temporary capability of taking up and storing dopamine.

Animals↗

PubMed1982

Interaction of the putative dopamine autoreceptor agonists, 3-PPP and TL-99, with the dopamine-sensitive adenylate cyclase of carp retina.

The putative dopamine autoreceptor agonists, 3-PPP and TL-99 were examined for their ability to stimulate postsynaptic dopamine receptors associated with adenylate cyclase (D1-receptors) in the carp retina. In intact pieces of retina, 3-PPP had no significant effect on cyclic AMP production at concentrations up to 100 microM, whereas the aminotetralin, TL-99, caused a concentration-dependent increase in cyclic AMP levels with an approximate EC50 of 3.6 microM. Dopamine and ADTN had EC50 values of 3.5 and 3.1 microM respectively. Furthermore, in homogenates of the retina, 100 microM ADTN and 100 microM TL-99 stimulated adenylate cyclase activity 92 and 79% respectively as compared to the stimulation evoked by 100 microM DA. In contrast, 100 microM 3-PPP was essentially inactive at stimulating adenylate cyclase in carp retinal homogenates. These findings suggest that TL-99 can interact with postsynaptic D1-receptors and is not as selective a dopamine autoreceptor agonist as 3-PPP, which has no apparent activity at the D1-receptor.

Adenylyl Cyclases↗

PubMed1993

Blockade of tachykinin NK1 receptors by CP-96345 enhances dopamine release and the striatal dopamine effects of methamphetamine in rats.

The nonpeptide, tachykinin NK1 receptor antagonist, CP-96345, permits the study of the physiological role of extrapyramidal substance P systems. Using microdialysis, we observed that locally applied CP-96345 (200 nM) caused a significant increase in dopamine release in the striatum as well as substantially enhancing striatal dopamine release caused by a low dose of methamphetamine (0.5 mg/kg s.c.). In addition, multiple systemic administrations of CP-96345 almost doubled the dopamine-mediated responses of the striatal neurotensin and dynorphin systems to high doses of methamphetamine (10 mg/kg/dose s.c.). Our findings suggest that the physiological role of substance P released in the striatum is to decrease the activity of the nigrostriatal dopamine pathway.

Animals↗

PubMed1995

Binding of d-threo-[11C]methylphenidate to the dopamine transporter in vivo: insensitivity to synaptic dopamine.

The regional distribution of [11C]d-threo-methylphenidate in mouse brain was very similar to that of [3H]WIN 35,428 ((-)-2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane), and the two radioligands were displaced from striatum similarly after administration of the potent cocaine analog RTI-55 ((-)-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane). However, while striatal [3H]WIN 35,428 increased between 5 and 30 min, striatal [11C]d-threo-methylphenidate halved. Thus [11C]d-threo-methylphenidate binds similarly to but more reversibly than [3H]WIN 35,428. The methyl ester of L-DOPA (L-3,4-dihydroxyphenylalanine; 200 mg/kg) plus benserazide plus clorgyline, which markedly elevates rat striatal extracellular dopamine (Wachtel and Abercrombie, 1994, J. Neurochem. 63, 108), decreased the mouse striatum-to-cerebellum ratio for [11C]d-threo-methylphenidate at 30 min by 13% (P < 0.05). In positron emission tomographic (PET) baboon studies [11C]d-threo-methylphenidate binding was insensitive to drugs expected to lower endogenous dopamine. These experiments suggest that normal synaptic dopamine does not compete for binding with [11C]d-threo-methylphenidate, and will not affect PET measures of dopamine transporter availability.

Animals↗

PubMed1989

Metaphit inhibits dopamine transport and binding of [3H]methylphenidate, a proposed marker for the dopamine transport complex.

Metaphit, an acylating derivative of phencyclidine, was shown to interact with components of the dopamine nerve terminal in rat striatal tissue. This compound, previously demonstrated to be an irreversible inhibitor at the phencyclidine receptor, was shown in these experiments to irreversibly inhibit synaptosomal [3H]dopamine uptake. It also inhibited binding of [3H]methylphenidate to its recognition site, which is thought to be a subunit of the dopamine transporter. Although the inhibition was due primarily to a reduction in the binding and transport capacity of the systems studied, increases in the apparent KD of [3H]methylphenidate and the Km of [3H]dopamine were also observed. Differences in the behavior of Metaphit and phencyclidine in these dopaminergic systems compared to their effects on the NMDA receptor-linked phencyclidine receptor suggest that Metaphit may be interacting with two distinct molecular sites in the rat striatum.

Animals↗

PubMed1989

Dopamine D1 receptor and dopamine D2 receptor binding activity changes during chronic administration of nicotine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice.

The effect of nicotine on MPTP-induced changes in striatal dopamine receptors binding activity was investigated. Dopamine D1 and D2 receptors were labeled with [3H]SCH-23390 and [3H]spiperone respectively in BALB/cBy mice. With administration of only MPTP, which caused more than an 80% decrease in striatal dopamine level, binding of 0.15 nM [3H]spiperone was increased by 37%; whereas 0.3 nM [3H]SCH-23390 binding was unchanged. With chronic nicotine treatment (0.4 mg/kg twice daily for 7-9 days), [3H]SCH-23390 binding activity was increased by 27% and [3H]spiperone binding activity was unchanged. When nicotine was administered after MPTP, their separate effects could be seen in that both the D1 and D2 dopamine receptor ligand binding activities were increased and that nicotine elevated the ratio of D1/D2 receptor binding activities in MPTP-treated mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1986

Evidence that dopamine receptors identified by [3H]dopamine in the ventricles of guinea-pig heart are of DA2 type.

Apomorphine and LY 171555, but not SKF 38393 displaced [3H]Dopamine binding to membranes of guinea-pig heart. Domperidone and 1-sulpiride but not SCH 23390 competitively antagonize the [3H]Dopamine binding performed with 100 microM cold dopamine as displacer. In conclusion the DA2 receptor agonists and antagonists used are able to interfere with the receptors labelled by [3H]Dopamine in cardiac muscle.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗