D1 receptor binding in rat striatum: modification by various D1 and D2 antagonists,but not by sibutramine hydrochloride,antidepressants or treatments which enhance central dopaminergic function

Summary [³H]SCH 23390 is a selective high affinity ligand for D₁ receptors in vitro. Using this ligand persistent blockade of D₁ receptors by SCH 23390 and cis-flupenthixol was shown to significantly increase the number of D₁ receptor binding sites in rat striatum. In contrast, repeated administration of the D₂-selective antagonist, clebopride, resulted in a small, but significant, reduction in number. No differences in binding affinity were observed and a single dose of these compounds was without effect. The D₂-selective antagonist, haloperidol, the non-selective D₁/D₂ receptor antagonist, chlorpromazine, the dopamine reuptake inhibitors, bupropion, GBR 12909 and nomifensine, and the dopamine releasing agent, d-amphetamine, had no effect on D₁ receptors. The antidepressant treatments, desipramine, zimeldine, amitriptyline, tranylcypromine, mianserin and ECS and the monoamine reuptake inhibitor, sibutramine, similarly did not alter striatal D₁ sites. Thus, of the treatments investigated only chronic receptor blockade by high affinity antagonists altered D₁ receptor binding in rat striatum.     

SDZ GLC 756, a novel octahydrobenzo[g]quinoline derivative exerts opposing effects on dopamine D1 and D2 receptors

Summary SDZ GLC-756, a novel octahydrobenzo[g]quinoline derivative, is equipotent in displacing [³H]SCH23390 from dopamine D₁ receptors and [³H]205–501 from dopamine D₂ receptor binding sites. It blocks dopamine sensitive adenylate cyclase with the same potency as SCH23390, indicating antagonist properties at dopamine D₁ receptors. On the other hand, SDZ GLC 756 inhibits electrically evoked acetylcholine release from rat striatal slices with the same potency as the selective dopamine D₂ receptor agonist bromocriptine. This effect is blocked by spiperone suggesting that it is mediated by dopamine D₂ receptor activation. The opposing action of SDZ GLC 756 on dopamine D₁ and D₂ receptors is also evident in vivo. SDZ GLC 756, like SCH23390, blocks apomorphine-induced rearing in mice. On the other hand, it inhibits prolactin secretion and produces circling in unilateral 6-OHDA-lesioned rats, which is compatible with stimulant properties at dopamine D₂ receptors. This drug might be a new tool to study linkage between dopamine D₁ and D₂ receptors.     

Autoradiographic comparison of D1-specific binding of [H]SCH39166 and SCH23390 in the primate cerebral cortex

Quantitative autoradiography was used to compare the binding of the novel dopamine D₁ receptor antagonist, [³H]SCH39166, with that of the widely used radioligand, [³H]SCH23390 (in the presence of ritanserin), in the primate cerebral cortex. Specific binding of both radioligands, determined using SCH23390 or cis-flupentixol as displacing agents, had very similar densities and distributions throughout the cortex. However, the specific binding of [³H]SCH39166 obtained with SCH39166 as a blank was significantly higher than that obtained using SCH23390 or cis-flupentixol as displacing agents in some layers of motor, somatosensory and occipital cortices. In addition, the non-specific binding of [³H]SCH39156 obtained in the presence of an excess of SCH23390 of cis-flupentixol displayed a complex laminar pattern very different from that of the specific binding. These observations suggest that [³H]SCH39166 may have a high affinity to more than the D₁ receptor subtype bound by SCH23390 or cis-flupentixol. Also, these additional sites are likely to be different from 5-HT₂ or 5-HT_1C receptors since the latter sites were not displaced by 1 μM SCH23390.     

Increment of in vivo binding of [H]SCH 23390, a dopamine D1 receptor ligand, induced by cyclic AMP-dependent protein kinase in rat brain

The effects of cyclic AMP (cAMP)-related compounds on in vivo [(3)H]SCH 23390 binding to striatal dopamine D(1) receptors were investigated using autoradiography in order to clarify the possible regulation of the cAMP-dependent mechanisms in the in vivo ligand-receptor bindings in the living brain. Intrastriatal infusion of the cAMP analogue, N6,2'-O-dibutyryl-cyclic AMP (db-cAMP; 5, 25 and 100 nmol/side) produced a dose-dependent increase of in vivo [(3)H]SCH 23390 binding in conscious rats. This increasing effect of [(3)H]SCH 23390 binding completely disappeared by 6 h after the infusion of db-cAMP. A similar increase of in vivo [(3)H]SCH 23390 binding to striatal D(1) receptors was also observed by intrastriatal injection of 8-bromo-cyclic AMP (8Br-cAMP, 100 nmol/side). Pretreatment with Rp-cyclic AMP triethylamine (Rp-cAMPS, 100 nmol/side), an inhibitor of the cAMP-dependent protein kinase (PKA), completely blocked the increasing effect of [(3)H]SCH 23390 binding induced by db-cAMP. In contrast, in vitro [(3)H]SCH 23390 binding was not significantly altered by intrastriatal infusion of db-cAMP, which indicated that the maximum number of binding sites (B(max)) for D(1) receptors was not changed. The kinetic analysis employed the graphical method indicated that a db-cAMP-induced increase of in vivo [(3)H]SCH 23390 binding was mainly due to an increase in the bimolecular association rate constant (k(on)). These results strongly indicate that the PKA-mediated phosphorylation may play a pivotal role in the regulating the in vivo [(3)H]SCH 23390 dopamine D(1) receptor binding in intact rat brain.     

Characterisation of dopamine receptors in insect (Apis mellifera) brain

In vitro binding experiments using the vertebrate D₁ dopamine receptor ligand [³H]SCH23390 and the vertebrate D₂ dopamine receptor ligand [³H]spiperone were conducted on membrane preparations of honey bee (Apis mellifera) brain. Specific binding of [³H]SCH23390 was saturable and reversible. Analysis of saturation data gave an apparent K_d of 6.3 ± 1.0 nM and B_max of 1.9 ± 0.2 pmol/mg protein for a single class of binding sites. The specificity of high affinity [³H]SCH23390 binding was confirmed in displacement experiments using a range of dopaminergic antagonists and agonists. The rank order of potency for antagonists was: R(+)-SCH23390 > cis-(Z)-flupentixol ≥ chlorpromazine > fluphenazine> S(+)-butaclamol > spiperone. R(±)-SKF38393 and dopamine were the most effective agonists tested. [³H]SCH23390 labels a site in bee brain that is similar, but not identical to the vertebrate D₁ dopamine receptor subtype. [³H]Spiperone also bound with high affinity to bee brain homogenates. Scatchard analysis of [³H]spiperone saturation data revealed a curvilinear plot suggesting binding site heterogeneity. The high affinity site had a apparent K_d of 0.11 ± 0.02 nM and B_max of 9.2 ± 0.5 fmol/mg protein. The calculated values for the low affinity site were a K_d of 19.9 nM and B_max of 862 fmol/mg protein. Kinetic analyses also indicated that [³H]spiperone recognises a heterogeneous population of sites in bee brain. Furthermore, agonist competition studies revealed a phenolaminergic as well as a dopaminergic component to [³H]spiperone binding in bee brain. The rank order of potency of dopaminergic antagonists in competing for [³H]spiperone binding was: spiperone > fluphenazine> S(+)-butaclamol > domperidone> R(+)-SCH23390 > S(−)-sulpiride.     

Dopamine D2 receptor agents, but not dopamine D1, modify brain glucose metabolism

The effects of recently described selective dopamine D₁ and D₂ agonists and antagonists on brain glucose metabolism were studied using the 2-[¹⁴C]deoxyglucose autoradiographic technique. The administration of LY-141865 or YM-09151-2, which behave as a specific D₂ agonist and antagonist respectively, modified brain glucose metabolism in a manner similar to that previously described for more classical dopaminergic agents, such as apomorphine and haloperidol. In contrast, the administration of SKF 38393 or SCH 23390, a specific D₁ agonist and antagonist respectively, was not followed by significant modifications of brain glucose metabolism in any of the brain regions studied. These results indicate that D₂ but not D₁ dopamine receptors are involved in the regulation of local brain glucose metabolism.     

Effect of NG-nitro-L-arginine methyl ester a nitric oxide synthase inhibitor on neurotransmitter receptor systems in aged rats

In order to examine the effect of age and nitric oxide synthase inhibitor N^G-nitro-L-arginine methl ester (l -NAME) we studied the changes on major neurotransmitter receptor systems in 6 (adult and 24-month-old (aged) Fischer male rats using receptor autoradiography. l -name was administrated intraperitoneally in aged rats once a day for 4 weeks. [³H]QNB (quinuclidinyl benzilate) ³HC (hemicholinium-3) [³H] muscimol ³H] SCH 23390 ([N-methyl-³H] N-methyl-³H]R[+]-8-chloro-2 3 4 5-tetrahydro-3-methyl-5-phenyl-7-il-benzazepine) ³H] mazindol were used as markers of muscarinic acetylcholine receptors high-high-affinity choline uptake sites GABA_A (γ-aminobutyric acid (SP2)_A) receptors dopamine D₁ receptors dopamine D₂ receptors and dopamine uptake sites respectively. The age-related change in ³H muscimol binding in the brain was more pronounced than that in [³H] QNB ³H]HC ³H]SCH 23390 ³H] nemonapride and ³H] nemonapride and ³H] mazindol binding.Chronic treatment (4 weeks) with l -NAME caused no significant changes in [sp1)³H] muscimol ³H SCH 23390 and [³H] nemonapride binding in most areas of aged rat brain as compared with vehicle-treated aged animals. However chronic treatment with l -NAME caused a significant reduction in ³H] HC and ³H] mazindol binding in any brain regions of aged rats in comparison with the vehicle-treated aged animals. These results demonstrate that the GABAergic system is more susceptible to aging processes than cholinergic and dopaminergic systems in teh brain. Furthermore our findings suggest that nitric oxide may play some role in the regulation of choline uptake and dopamine uptake systems during aging processes.     

Dopamine D1 and D2 receptor binding sites in brain samples from depressed suicides and controls

Dopamine D₁ and D₂ receptors were measured (by saturation binding of [³H]SCH23390 and [³H]raclopride) in caudate, putamen and nucleus accumbens, obtained at post-mortem from suicide victims with a firm retrospective diagnosis of depression and matched controls. There were no differences in the number or affinity of D₁ or D₂ receptors between suicides who had been free of antidepressants for at least three months prior to death, and controls. Increased numbers and decreased affinity of D₂ receptors were however found in each brain region of antidepressant-treated suicides. We argue that these increases are related to concurrent treatment with neuroleptics rather than a direct effect of antidepressants. Increased numbers of D₁ receptors in antidepressant-treated suicides were seen only in nucleus accumbens. This increase could not be clearly attributed to neuroleptics and may be related to antidepressant treatment.     

Dopamine D1 receptor number — a sensitive PET marker for early brain degeneration in Huntington's disease

Summary D₁-dopamine receptor binding in the brain was determined by positron emission tomography (PET) in five patients with Huntington's disease, in one asymptomatic gene carrier and in five control subjects. [¹¹C] SCH 23390 was used as the radioligand. Brain morphology was recorded by MRI. The patients who all had a mild to moderate functional impairment showed an almost 50% reduction of putamen volume as well as D₁-dopamine receptor density as compared to the controls. The total D₁-dopamine receptor number in the putamen was reduced by 75% in the patient group. A similar reduction was found for the caudate nucleus. The asymptomatic gene carrier had volume and density values in the lower range of the control subjects. In the frontal neocortex there also tended to be a reduced D₁-dopamine receptor binding in the symptomatic patients. The results indicate that [¹¹C] SCH 23390 binding in combination with MRI can be used as a sensitive marker for early brain degeneration in Huntington's disease. This marker may be useful to monitor the pathophysiological effect of the disease gene and also to follow therapeutic interventions aiming at preventing the degenerative process.     

Autoradiographic studies in animal models of hemi-parkinsonism reveal dopamine D2 but not D1 receptor supersensitivity. I. 6-OHDA lesions of ascending mesencephalic dopaminergic pathways in the rat

The selective dopaminergic antagonist ligands [3H]SCH 23390 and [3H]sulpiride were used to reveal autoradiographically dopamine D1 and D2 receptors, respectively, in brain sections from rats which had received unilateral 6-hydroxydopamine (6-OHDA) injections destroying ascending nigrostriatal neurones. The binding of both ligands to striatal sections was first shown to be saturable, reversible and of high affinity and specificity [( 3H]SCH 23390: Bmax 2.16 pmol/mg protein, Kd 1.4 nM; [3H]sulpiride; Bmax 0.67 pmol/mg protein, Kd 10.7 nM). After unilateral stereotaxic 6-OHDA injections, rats rotated contralaterally when challenged with apomorphine (0.5 mg/kg), or specific D1 or D2 agonists, SKF 38393 (1.0-5.0 mg/kg) and LY 171555 (0.05-0.5 mg/kg), respectively. Loss of forebrain dopaminergic terminals was assessed autoradiographically using [3H]mazindol to label dopamine uptake sites. A loss of approximately 90-95% of uptake sites was reproducibly accompanied by an enhanced density of binding ipsilaterally for the D2 ligand, [3H]sulpiride, in all areas of the striatum, but most markedly in the lateral areas. An increase in the D2 binding site density was also seen in the ipsilateral nucleus accumbens and the olfactory tubercle. In contrast, in the same animals, the striatal D1 receptors were far less affected by dopaminergic denervation, with no consistent changes seen in the binding of [3H]SCH 23390. These results suggest that dopamine D2 receptors are more susceptible than D1 receptors to changes after dopaminergic denervation, which is expressed as an increase in the density of binding sites revealed here with [3H]sulpiride.     

Age-dependent changes in the expression of dopamine receptor subtypes in human peripheral blood lymphocytes

The pharmacological profile and the density of dopamine D₃ and D₅ receptor subtypes expressed by human peripheral blood lymphocytes of subjects of different ages (ranging from 20 to 75 years) were assessed using radioligand binding techniques. Dopamine D₃ receptor was assayed with [³H]7-hydroxy-N,N-di-n-propyl-2-aminotetraline ([³H]7-OH-DPAT) as a ligand. Dopamine D₅ receptor was assayed using [³H][R]-(+)-(-chloro-2,3,4,5,tetrahydro-5-phenyl-1H-3-benzazepin-al-hemimaleate) ([³H]SCH 23390) as a ligand. The affinity and the pharmacological profile of [³H]7-OH-DPAT and [³H]SCH 23390 at dopamine D₃ and D₅ receptor, respectively, were similar in subjects of different ages. The density of dopamine D₃ receptor binding sites was slightly decreased in subjects of 30–39 years in comparison with younger individuals. A remarkable loss of dopamine D₃ receptor was then found between 40 and 49 years of age in comparison with younger subjects. A further slight decrease was noticeable between 50 and 59 years of age. The number of [³H]7-OH-DPAT binding sites was then stabilized after 60 years of age. The density of dopamine D₅ receptor binding sites did not show age-dependent changes. The above findings indicate the occurrence of a decline in the density of lymphocyte dopamine D₃ but not D₅ receptor between adult and mature subjects. The possibility that dopamine D₃ receptor assay in peripheral blood lymphocytes may represent a tool for investigating dopamine receptor function in aging and age-related neurological disorders is discussed.     

Chronic haloperidol-induced changes in regional dopamine release and metabolism and neurotensin content in rats

Chronic neuroleptic administration has previously been shown to alter in vivo measures of dopaminergic function and lead to regionally selective increases in neurotensin levels. In the current study, female rats were administered chronic haloperidol for 6 months via subcutaneous silastic implants. After 24 weeks of administration, microdialysis probes were inserted into the lateral caudate putamen and the medial prefrontal cortex. Basal samples were collected prior to infusion of a high K⁺ concentration (100 mM KCI). Extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid were assessed using HPLC. Chronic haloperidol-treated rats showed increased basal dopamine metabolite levels in the caudate putamen and an altered response to the effects of high K⁺ on 3,4-dihydroxyphenylacetic acid; no significant differences were seen with other analytes in the caudate putamen. Although basal concentrations were not different between groups in the prefrontal cortex, haloperidol-treated rats showed a significant attenuation of response to the effects of high K⁺ infusion on dopamine metabolite concentrations. Radioimmunoassay measurement of tissue neurotensin content showed highly significant elevations of neurotensin concentrations in the caudate putamen and nucleus accumbens, but not in other brain regions analyzed. These results suggest a confluence of altered dopamine and neurotensin function in the caudate putamen which may be related to motor side effects of haloperidol, whereas changes in prefrontal dopamine function are not associated with altered neurotensin levels.     

Effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin on the dopaminergic and cholinergic receptors as evaluated by positron emission tomography in the Rhesus monkey

Summary The effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP) on the central cholinergic and dopaminergic systems in the Rhesus monkey brain were investigated by positron emission tomography (PET) with the muscarinic cholinergic receptor ligands (N-[¹¹C]methyl-benztropine) and dopaminergic receptor ligands selective for D₁ D₂, and D₃ subtypes ([¹¹C]SCH23390, N-[¹¹C]methyl-spiperone, and (+)[¹¹C]UH232, respectively). None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP used significantly affected the regional cerebral blood flow (rCBF as determined by Raichle's H₂ ¹⁵O method), and 10 mg/kg of R-THBP had little effect on the regional cerebral metabolic rate of glucose (rCMRglc) in the Rhesus monkey brain, as assessed by the graphical [¹⁸F]fluoro-deoxyglucose method. The effect of R-THBP on the muscarinic cholinergic system was dose dependent; while 3 mg/kg of R-THBP did not significantly alter the uptake ratio of N-[¹¹C]methyl-benztropine in several brain regions to that in the cerebellum, 10 and 30 mg/kg of R-THBP significantly reduced the uptake ratio in the thalamus, as well as in the frontal and temporal cortices. None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP tested affected [¹¹C]SCH23390 (dopamine D₁ receptor) binding. However, the k3 value for N-[¹¹C]methyl-spiperone (dopamine D₂ receptor) binding, which represents the association rate × B_max value, was significantly decreased in the striatum. The uptake ratio of (+)[¹¹C]UH232 (dopamine D₃ receptor) in the striatum to that in the cerebellum was also decreased by administration of R-THBP (3 and 30 mg/kg i.v.). These findings suggest that R-THBP acts on dopamine D₂ and D₃ receptors selectively without markedly affecting dopamine D₁ receptor binding. Furthermore, the changes in cholinergic and dopamine D₂ and D₃ receptors in vivo can not be attributed to a change in rCBF but may depend on the action of R-THBP.Abbreviations R-THBP 6R-L-erythro-5,6,7,8-tetrahydrobiopterin - PET positron emission tomography - rCBF regional cerebral blood flow - rCMRglc regional cerebral metabolic rate of glucose     

Autoradiographic analysis of D1 and D2 dopaminergic receptors in rat brain after paradoxical sleep deprivation

Previous work had shown that paradoxical sleep deprivation (PSD) results in potentiation of several apomorphine-induced behaviors, leading to the suggestion that PSD induces an upregulation of brain dopamine receptors. In this study, quantitative receptor autoradiography was used to verify whether PSD does, in fact, induce alterations in D₁ or D₂ receptor binding, and to investigate the regional brain specificity of such effects. After 96 h of PSD, [³H]SCH-23390 binding to D₁ receptors was examined in 30 different brain areas of 10 experimental and 10 cage control rats. [³H]Spiperone was used to label D₂ sites in adjacent tissue sections. Results revealed a 39% increase in [³H]SCH 23390 binding in the entorhinal cortex of PSD rats (p < 0.05), but no other changes in any of the remaining 29 brain areas examined. In contrast, [³H]spiperone binding was significantly elevated in the n. accumbens (+45%) and in all subrogions of the caudate-putamen (range: +13% to +23%). These results, thus, provide evidence that PSD increases D₂ but not D₁ receptor binding in brain. The present results also suggest that upregulated D₂ receptors can account for the previously reported changes in apomorphine-induced behaviors after PSD.     

Autoradiographic localization of D1 dopamine receptors in the rat brain with [H]SCH 23390

The regional distribution of D₁ dopamine (DA) receptors in the rat brain has been studied by quantitative autoradiography using the specific D₁ antagonist [³H]SCH 23390 as a ligand. The binding of [³H]SCH 23390 to striatal sections was saturable, stereospecific, reversible and of high affinity (K_d = 2.05nM); it occurred at single population of sites and possessed the pharmacological features of the D₁ DA receptor. The highest densities of [³H]SCH 23390 binding sites were found in the caudate-putamen, olfactory tubercle, nucleus accumbens and substantia nigra (especially in the pars compacta). High densities were also observed in the nucleus interstitialis striae terminalis, the anterior olfactory nucleus, the entopeduncular nucleus, the subthalamic nucleus, the claustrum and the amygdalohippocampal area. An intermediate labelling was found in the anteromedial and suprarhinal DA terminal fields of the cerebral cortex, the basolateral, medial and lateral amygdaloid nuclei, the endopiriform nucleus, the primary olfactory cortex, the globus pallidus, the superior colliculus (especially the superficial layer), the nucleus amygdaloideus corticalis and the dorsal hippocampus (molecular layer of the CA₁ and dentate gyrus). In the anteromedial and suprarhinal cortices, [³H]SCH 23390 binding was more concentrated in layers V and VI. Moderate levels of [³H]SCH 23390 were found in the thalamus, hypothalamus, the habenula, the ventral tegmental area, the posterior cingulate and entorhinal cortices, the supragenual dopamine terminal system and the cerebellum (molecular layer). This regional distribution of [³H]SCH 23390 closely correlated (except for the cerebellum) with the reported distribution of dopaminergic terminals. The topographical distribution of [³H]SCH 23390 has also been studied in detail in striatal subregions. The density of D₁ receptors was much greater in the ventrolateral sector and medial margin of the striatum than in the ventromedial and dorsolateral sectors. A rostrocaudal decrease in the densities of D₁ sites was also found along the rostrocaudal axis of the caudate-putamen. These lateral to medial and anteroposterior gradients overlapped with the density of the dopaminergic afferents.     

Increased transport of 3,4-dihydroxyphenylacetic acid from brain during performance of operant behavior in the rat

Although the performance of positively reinforced operant behavior is accompanied by increased turnover of brain dopamine in the rat, the accumulation of 3,4-dihydroxyphenylacetic acid (DOPAC), the major metabolic product of dopamine in brain, is not increased during operant performance. The hypothesis that the lack of increased DOPAC accumulation stems from an increase in the rate at which DOPAC is eliminated from the brain was tested by measuring the relative rate of DOPAC transport from brain in rats performing operant behavior and in control rats. The transport of DOPAC was estimated following inhibition of monoamine oxidase with pargyline. The pargyline-induced depletions of DOPAC in the caudate putamen and amygdala were significantly greater in rats that performed operant behavior than in control rats. In the caudate putamen, the concentrations of homovanillic acid and 5-hydroxyindoleacetic acid were also depleted by pargyline to a greater extent in operant performing rats than in controls. These results suggest that in addition to the increased turnover of dopamine in central neurons during operant behavior, the rate of elimination of acidic amine metabolites from brain is also accelerated.     

Striatal D1- and D2-dopamine receptor sites are separately detectable in vivo

We have characterized in particulate fractions of normal rat striatum the in vivo binding kinetics, binding affinity, and pharmacological profiles of [3H]SCH 23390, a ligand selective for the D1-subtype of dopamine (DA) receptor, and compared these to [3H]spiperone, a ligand classically associated with the D2 DA receptor subtype. The pharmacological specificity of each ligand's in vivo binding is very similar to binding to striatal homogenates in vitro. While similar maximum numbers (Bmax) of striatal binding sites exist in vivo compared to in vitro for both ligands, binding affinities in vivo for both ligands are reduced 125- to 200-fold compared to in vitro. In vivo binding of [3H]SCH 23390 to striatum is not increased by dopamine denervation produced by 6-hydroxydopamine lesions of the nigrostriatal pathway. In vivo binding of [3H]SCH 23390 and [3H]spiperone to striatum is not significantly reduced by increased synaptic concentration of dopamine following D-amphetamine administration. 125I-SCH 23982, the iodinated analogue of SCH 23390, localizes very highly to dopaminergic forebrain areas following i.v. administration. External imaging of mammalian and human brain D1-receptors is potentially feasible with this ligand.     

Age-dependent decline of dopamine D1 receptors in human brain: A PET study

Radioligand binding studies in animals have demonstrated age-related loss of dopamine receptors in the caudate and putamen. In humans, while age-related declines in dopamine D2 receptors have been consistently reported, the effects of ageing on D1 receptors have been controversial. We used positron emission tomography (PET) with [¹¹C]SCH 23390 to investigate dopamine D1 receptor binding in 21 normal volunteers aged 22–74 years. We also assessed their motor function with a Modified Columbia Score (MCS) and the Purdue Pegboard Test (PPBT). D1 binding potentials were derived using a graphical analysis with a cerebellar tissue input function. Standard linear regression techniques were used to determine the age-related rate of decline of D1 binding. We found an age-dependent decrease of D1 receptor binding in the caudate (6.9% per decade) and putamen (7.4% per decade). There was also a significant inverse correlation between [¹¹C]SCH 23390 binding in the occipital cortex and age (8.6% decline per decade). PPBT score also decreased with age (P = 0.007). There was a direct correlation between PPBT score and D1 binding potential. We conclude that dopamine D1 receptor density declines with age and that the effects of physiological ageing may play a role in the expression of extrapyramidal disorders in the elderly. Synapse 30:56–61, 1998. Published 1998 Wiley-Liss, Inc.     

Distribution of dopamine D1 and D2 receptors in rabbit cortical areas, hippocampus, and neostriatum in relation to dopamine contents

The densities of dopamine D1 and D2 receptors were measured by using [3H]SCH23390 and [3H]raclopride, respectively, in the rabbit cingulate, visual, sensorimotor, and entorhinal-piriform cortical areas; the dorsal and ventral hippocampus; and the putamen as well as the medial and lateral caudate. Endogenous dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 4-hydroxy-3-methoxyphenylacetic acid (HVA), and 3-methoxytyramine (3-MT) were assayed by HPLC with electrochemical detection. The distributions of [3H]SCH23390 and [3H]raclopride binding were heterogenous with the greatest densities in the neostriatum. The concentrations of DA and its metabolites were also highest in this structure. Regions with low DA content, i.e., cortex and hippocampus, had lower densities of [3H]SCH23390 and [3H]raclopride binding. Furthermore, these sites were differentially localized within the various regions and there were substantially more D1 than D2 receptors. The functional significance and heterogeneities in the distribution of D1 and D2 receptors are discussed in relation to the dopaminergic innervation and the turnover estimated by the ratios between endogenous DA and its metabolites.     

GABAergic and dopaminergic transmission in the brain of Roman high-avoidance and Roman low-avoidance rats

The GABAergic and dopaminergic pathways in the central nervous system (CNS) play a pivotal role in the control of emotions and in the adaptive responses to stressful stimuli. The present study was aimed at characterizing a range of biochemical markers of GABA- and dopamine-mediated neurotransmission in the CNS of Roman high-avoidance (RHA/Verh) and Roman low-avoidance (RLA/Verh) rats, two psychogenetically selected lines that differ in their level of emotionality. The stimulatory effect of GABA on ³⁶Cl⁻ uptake was less pronounced in the cerebral cortex of RLA/Verh rats as compared to RHA/Verh rats, whereas no line-related changes were detected in [³H]GABA and [³H]flunitrazepam binding. On the other hand, the density of D₁ dopamine receptors labeled with [³H]SCH 23390 was lower in the nucleus accumbens of RLA/Verh rats as compared to their RHA/Verh counterparts, whilst no line-dependent changes were observed in the binding parameters of D₁ dopamine receptors in the striatum, amygdala, and prefrontal cortex. These biochemical differences may contribute to the distinct emotionality and responsiveness to the effects of psychoactive drugs of RHA/Verh and RLA/Verh rats.