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.     

Identification of extrastriatal dopamine D2 receptors in post mortem human brain with [I]epidepride

The regional distribution of striatal and extrastriatal dopamine D₂ receptors in human brain was studied in vitro with(S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-[¹²⁵I]iodo-2,3-dimethoxybenzamide, [¹²⁵I]epidepride, using post mortem brain specimens from six subjects. Scatchard analysis of the saturation equilibrium binding in twenty-three regions of post mortem brain revealed highest levels of binding in the caudate (16.5 pmol/g tissue) and putamen (16.6 pmol/g tissue) with lower levels seen in the globus pallidus (7.0 pmol/g tissue), nucleus accumbens (7.2 pmol/g tissue), hypothalamus (1.8 pmol/g tissue), pituitary (1.3 pmol/g tissue), substantia innominata (1.0 pmol/g tissue), and amygdala (0.87 pmol/g tissue). Of note was the presence of dopamine D₂ receptors in the four thalamic nuclei studied, i.e. anterior nucleus (1.0 pmol/g tissue), dorsomedial nucleus (0.96 pmol/g tissue), ventral nuclei (0.72 pmol/g tissue), and pulvinar (0.86 pmol/g tissue), at levels comparable to the amygdala (0.87 pmol/g tissue) and considerably higher than levels seen in anterior cingulate (0.26 pmol/g tissue) or anterior hippocampus (0.36 pmol/g tissue). The frontal cortex had very low levels of dopamine D₂ receptors (0.17–0.20 pmol/g tissue) while the inferior and medial temporal cortex had relatively higher levels (0.31–0.46 pmol/g tissue). Inhibition of [¹²⁵I]epidepride binding by a variety of neurotransmitter ligands to striatal, ventral thalamic and inferior temporal cortical homogenates demonstrated that [¹²⁵I]epidepride binding was potently inhibited only by dopamine D₂ ligands. The present study demonstrates that dopamine D₂ receptors are present in basal ganglia, many limbic regions, cortex and in the thalamus. The density of thalamic D₂ receptors is comparable to many limbic regions and is considerably higher than in cortex. Very few frontal lobe D₂ receptors are present in man.     

Synergistic effects of D1 and D2 dopamine agonists on turning behaviour in rats

In rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, a specific D1 dopamine receptor agonist, SKF 38393A, at a dose that does not itself produce turning, significantly increased the contralateral rotation observed following a low dose of the specific D2 agonist LY 171555. Doses of SKF 38393A or the D2 agonist bromocriptine, which would themselves not induce turning, in combination produced a high rate of turning. These results suggest a synergistic interaction between D1 and D2 dopamine receptors in this system.     

Possible role of dopamine D1 receptor in the behavioural supersensitivity to dopamine agonists induced by chronic treatment with antidepressants

The effect of chronic treatment with antidepressants (ADs) on the behavioral responses to LY 171555, a selective D₂ receptor agonist, SKF 38393, a selective D₁ receptor agonist, and B-HT 920, a selective DA autoreceptor agonist, was studied in rats. In normal rats small, intermediate and high doses of LY 171555 produced hypomotility, hyperactivity and stereotypies, respectively. Chronic but not acute pretreatment with imipramine (IMI) greatly potentiated the motor stimulant effect of LY 171555, but failed to modify its stereotypic and sedative effect. The potentiation of the motor stimulant effect of LY 171555 was observed also after chronic, but not acute, treatment with desmethylimipramine (DMI), mianserin (MIA) or repeated electroconvulsive shock (ECS). Chronic treatment with IMI failed to modify the effect of SKF 38393 (motor stimulation, grooming and penile erection), but reversed the sedative effect of B-HT 920 into a motor stimulant response. The motor stimulant response to LY 171555 in IMI-pretreated animals was suppressed byl-sulpiride, a D₂ antagonist, and by a combination of reserpine with α-methyltyrosine (α-MT), but it was only partially antagonized by high doses of SCH 23390, a selective D₁ antagonist. The results indicate that chronic treatment with ADs potentiates the behavioural responses mediated by the stimulation of postsynaptic D₂ receptors in the mesolimbic system and suggest that this behavioural supersensitivity is due to enhanced neurotransmission at the D₁ receptor level.     

Effects of D2 dopamine receptor agonist and antagonist on brain activity in the rat assessed by functional magnetic resonance imaging

The effects of D₂ dopamine receptor agonist, bromocriptine (BROMO), and antagonist, haloperidol (HPD), on brain activity were investigated in rats by functional magnetic resonance imaging. T2^*-weighted signal intensity was increased in the hypothalamus at 120 min after acute administration of BROMO, and in the ventral posterior and dorsomedial nuclei of the thalamus from 30 to 120 min. In contrast, the signal intensity was decreased in the caudate–putamen at 30 min after acute administration of HPD, in the hypothalamus from 30 to 60 min, and in the perirhinal cortex at 30 min. After chronic (2 weeks) HPD treatment, acute administration of HPD decreased signal intensity in the caudate–putamen at 60 min, in the hypothalamus at 30 min, the perirhinal cortex from 2 to 120 min, the dorsomedial and ventral posterior nuclei of the thalamus from 2 to 120 min, and the medial nucleus of the amygdala from 60 to 120 min. These results suggest that (1) the D₂ receptor agonist increased the activity of the thalamic nuclei and the hypothalamus, while the D₂ receptor antagonist suppressed brain activity in the regions where D₂ receptors were present, (2) the suppression of brain activity in the thalamic nuclei and the perirhinal cortex by acute HPD administration was enhanced by chronic HPD treatment, and (3) the effects of antipsychotic drugs on the thalamus, amygdala, and perirhinal cortex may be related to their therapeutic efficacy, since clinical improvement in schizophrenic patients appears several days after the start of HPD treatment.     

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.     

The role of dopamine in the maintenance and breakdown of D1/D2 synergism

The neurochemical factors involved in the maintenance and breakdown of dopamine D₁/D₂ receptor synergism were investigated by giving rats various pharmacological treatments that diminish the ability of dopamine to interact with its D₁ and/or D₂ receptors. Following these treatments, rats were observed for the expression of stereotyped motor behavior in response to independent stimulation of D₁ or D₂ receptors. Independent D₂-mediated responses were observed: (a) 2 h after the last of three daily reserpine (1 mg/kg) injections, (b) 48 h after bilateral 6-hydroxydopamine (6-OHDA) lesions of the mesostriatal pathways, (c) 24 h after a concentrated 48-h regimen (one injection/6 h) of eticlopride (0.5 mg/kg) or eticlopride + SCH 23390 (0.5 mg each), and (d) 2 h after a concentrated 48-h regimen (one injection/6 h) of α-methyl-p-tyrosine (αMPT; 100 mg/kg), but not after control treatments or a concentrated regimen of SCH 23390 alone. By contrast, independent D₁-mediated responses were observed only after three daily reserpine injections or 48 h after bilateral 6-OHDA lesions. Independent D₁-mediated stereotypy was not observed under control conditions or following a concentrated 48-h regimen of (a) SCH 23390 or eticlopride (0.5 mg/kg each) alone or in combination, (b) a high dose of SCH 23390 (1.0 mg/kg), (c) αMPT (100 mg/kg), or (d) αMPT (100 mg/kg)+SCH 23390 (1.0 mg/kg). Reserpine, bilateral 6-OHDA, and αMPT treatments produced striatal dopamine depletions of 96%, 92%, and 71%, respectively. These data indicate that the breakdown in D₁/D₂ synergism consists of two components: (a) D₁ independence from the controlling influence of D₂ receptors, and (b) D₂ independence from the controlling influence of D₁ receptors. The interaction of synaptic DA with its D₂ receptors plays a major role in determining whether these receptors can function independently of D₁ receptors, whereas reduced DA-D₁ activity alone appears insufficient to elicit D₁ independence.     

Selective unilateral inactivation of striatal D1 and D2 dopamine receptor subtypes by EEDQ: turning behavior elicited by D2 dopamine receptor agonists

The unilateral intrastriatal injection of the irreversible dopamine (DA) receptor blockerN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) induces a marked decrease in the density of D₁ (-48%) and D₂ (-51%) DA receptors available for binding to [³H]SCH 23390 and [³H]raclopride, respectively. A challenge dose of the D₂ agonist LY 171555 (1 mg/kg, i.p., 24 h after EEDQ) causes intensive ipsiversive circling behavior, whereas the selective D₁ agonist SKF 38393 (20 mg/kg, i.p., 24 h after EEDQ) is unable to induce rotations. The density of D₁ and D₂ DA receptors returns to basal levels by 7 days after the intrastriatal infusion of EEDQ. This biochemical recovery is associated with a progressive decrease in the number of rotations elicited by a challenge dose of LY 171555, suggesting the EEDQ does not cause any relevant neuronal damage. A selective inactivation of striatal D₁ or D₂ DA receptors can be obtained by injecting EEDQ 30 min after the administration of the D₂ antagonist raclopride (20 mg/kg, i.p.) or of the D₁ antagonist SCH 23390 (2 mg/kg, s.c.), respectively. The intensity of the circling behavior induced by LY 171555 24 h after EEDQ in animals with a selective inactivation of D₂ DA receptors is similar to that found in rats in which both D₁ and D₂ DA receptors have been inactivated. In contrast, LY 171555 does not cause rotations when the density of D₁ DA receptors is selectively decreased by EEDQ in rats pretreated with raclopride. These results indicate that the imbalance in striatal D₂ receptors, but not in D₁ receptors, is a critical factor for the expression of the motor effects elicited by LY 171555 in EEDQ-treated rats.     

A single (−)-nicotine injection causes change with a time delay in the affinity of striatal D2 receptors for antagonist, but not for agonist, nor in the D2 receptor mRNA levels in the rat substantia nigra

The in vitro and in vivo effects of (−)-nicotine on dopamine D₂ receptors in the rat neostriatum have been studied using biochemical binding, in situ hybridization and immunocytochemistry. A single i.p. injection (1 mg/kg) of (−)-nicotine resulted in a reduction of theK_D value of the D₂ antagonist [³H]raclopride binding sites in rat neostriatal membrane preparations at 12 h without any significant change in theB_max value. This action of (−)-nicotine was counteracted by pretreatment 15 min earlier with the nicotine antagonist mecamylamine (1 mg/kg, i.p.). However, theK_D and theB_max values of the D₂ agonist [³H]NPA binding sites in the rat neostriatal membrane preparations were not significantly affected 0.5–48 h after a single i.p. injection with 1 mg/kg of (−)-nicotine. No significant change in neostriatal D₂ receptor mRNA levels was observed at any time interval after the (−)-nicotine injection. No significant change was observed in tyrosine hydroxylase (TH) immunoreactivity in either the substantia nigra or the neostriatum, nor in nigral TH mRNA levels during the time interval studied (4–24 h posttreatment). Furthermore, addition of low (10 nM) or high (1 μM) concentrations of (−)-nicotine in vitro to rat neostriatal membranes did not alter the characteristics of [³H]raclopride or [³H]NPA binding. These results indicate that a single (−)-nicotine injection can produce a selective and delayed increase in the affinity of D₂ receptors for the antagonist, but not for the agonist without modifying the levels of D₂ receptor mRNA, probably via the activation of central nicotinic receptors.     

Effect of aging on vulnerability of striatal D1 And D2 dopamine receptor-containing neurons to kainic acid

Kainic acid lesions elicit reductions in ligand binding to both D₁ and D₂ striata dopamine receptors in young and old rats. Relative reductions are greatest for both receptors in young animals than old. In addition, D₁ receptor binding is reduced more than D₂ at both ages. These findings support the idea that those dopamine receptor neurons lost during aging may reside in a kainic acid sensitive population.     

Specific bindings of prostaglandin D2, E2 and F2α in postmortem human brain

Binding activities specific for each of [³H]prostaglandin (PG) D₂, E₂ and F_2α were detected in the P₂ fraction of the human brain homogenates. The bindings were time-dependent, saturable and of high affinity;K_dvalues were 30 nM for all the PG bindings. Regional distribution of these binding activities was determined by measuring specific bindings with 10 nM [³H]PG-D₂, [³H]PG-E₂ and [³H]PG-F_2α in the P₂ fractions from 17 brain regions. The PG-D₂ binding activity was high in the hypothalamus, amygdala and hippocampus followed by cerebellar nuclei, thalamus, nucleus accumbens and cerebral cortex. The PG-E₂ binding sites were similarly concentrated in the hypothalamus and the limbic system, but, unlike the PG-D₂ binding, no significant binding of [³H]PG-3₂ was observed in cerebellar nuclei, cerebellar cortex and putamen. Compared with these two PG bindings, PG-F_2α binding activity was low in many areas, but significant binding was detected in the amygdala, cingulate cortex, cerebellar medulla, hippocampus, nucleus accumbens, midbrain and hypothalamus. These results suggest the presence and specific distribution of three distinct types of PG binding activities, i.e. specific binding of PG-D₂, PG-E₂ and PG-F_2α, in the human brain.     

Local injection of alkylating and nonalkylating dopamine receptor antagonists into rat basal forebrain: autoradiographic assessment of D2-like and D3 sites

N-chloroethyl derivatives of 7-hydroxy-1,2,3,4-tetrahydronaphthalene (7-OH-DPAT), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), or fluphenazine were microinjected into rat nucleus accumbens (Acc), and receptor binding quantified autoradiographically after 24 h. EEDQ reduced

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nemonapride (D₂-like receptors) binding in Acc (by 84%) and islands of Calleja (IC; 44%), without affecting

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(+)-7-OH-DPAT (D₃); N-chloroethyl-7-OH-DPATs blocked both radioligands in Acc and IC (30%–70%); fluphenazine had no effect.     

Localization of putative dopamine D2-like receptors in the chick retina, using in situ hybridization and immunocytochemistry

The actions of dopamine are mediated by 5 or more receptor subtypes, any ofwhich may be coupled by G-proteins to adenylate cyclase (D₁-family: stimulatory, D₂-family: inhibitory or no action). Postnatal ocular growth in the chick is a vision-dependent mechanism which involves D₂-type receptors in either the retina or the retinal pigment epithelium (RPE). Although the dopaminergic amacrine cells are well described in the chick retina, only D₂-receptors, but not D₃- and D₄-receptors have been clearly localized, and the cells that express them have not been identified. In this study we showed that immunoreactive D₂₃-receptor protein is localized to the photoreceptor inner segments, outer and inner plexiform layer and ganglion cell layer, as described previously (Wagner et al., J. Comp. Neurol., 330 (1993) 1–13). D₂-receptor mRNA was localized to cell bodies in all nuclear layers of the retina, whereas D₄-receptor mRNA was restricted to the inner half of the retina. Immunoreactive D₂-type receptors and their mRNA were observed also in the basal region of the RPE. because of the widespread distribution of both D₂- and D₄-receptor mRNA in the chick retina and RPE and the lack of D₃- and D₄-receptor-specific antibodies, we were unable to identify which of the D_2/34-receptor-bearing cells are involved in controlling ocular growth.     

D1 and D2 receptor modulation in rat striatum and nucleus accumbens after subchronic and chronic haloperidol treatment

The antipsychotic effects of neuroleptic drugs are believed to be achieved by chronic blockade of dopaminergic transmission in the limbic system. Nevertheless, the effects of chronic (3-12 months) haloperidol administration on the dopaminergic transmission in the nucleus accumbens of rodents remains poorly understood. Studies of spontaneous locomotor activity (SLA), a behavioral measure related to limbic dopamine transmission, and of dopamine D2 receptor density in the nucleus accumbens after chronic oral haloperidol treatment have yielded conflicting results. We evaluated these indices after 8 months of parenteral administration of haloperidol decanoate. We report here that, after 8 months of parenteral treatment, SLA stays significantly decreased and D2 receptors in the nucleus accumbens exhibit the same up-regulation as in the striatum (about 50%). These results fail to support the notion of a different pattern of D2 receptor adaptation to neuroleptic treatment between the nucleus accumbens and the striatum. In contrast, dopamine D1 receptors were found to be unaffected in the nucleus accumbens but decreased in the striatum by 22% after 8 months of treatment. This observation could be relevant to the pathogenesis of tardive dyskinesia.     

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.     

Involvement of dopamine D1 and D2 receptors in the ethanol-associated place preference in rats exposed to conditioned fear stress

The present study was designed to investigate: (1) the involvement of dopamine D₁ and D₂ receptors, and (2) the roles of these receptors and endogenous opioid systems (endorphinergic and enkephalinergic systems) in the ethanol-induced place preference in rats exposed to conditioned fear stress using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) induced a significant place preference. The selective D₁ receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H3-benzazepine)hydrochloride (SCH23390; 0.01 and 0.03 mg/kg, s.c.) and the selective D₂ receptor antagonist S(−)-5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxybenzamide (sulpiride; 20 and 40 mg/kg, s.c.) significantly attenuated the ethanol-induced place preference. The administration of ethanol (75 mg/kg, i.p.) tended to produce a place preference, but this effect was not significant. SCH23390 (0.03 mg/kg, s.c.) and sulpiride (40 mg/kg, s.c.) significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the μ-opioid receptor agonist morphine (0.1 mg/kg, s.c.). In addition, SCH23390 (0.03 mg/kg, s.c.) also significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the selective δ-opioid receptor agonist 2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydroquinolino[2,3,3,-g]isoquinoline (TAN-67; 20 mg/kg, s.c.). On the other hand, sulpiride (40 mg/kg) had no significant effect on the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by TAN-67. These results suggest that D₁ and D₂ receptors may be involved in the rewarding mechanism of ethanol under psychological stress. In addition, D₁ receptors may participate in the rewarding effect of ethanol modulated by the activation of μ- and δ-opioid receptors, whereas D₂ receptors may participate in the rewarding effect of ethanol modulated by the activation of μ-opioid receptors, but not in that modulated by the activation of δ-opioid receptors.     

Postnatal lead exposure induces supersensitivity to the stimulus properties of a D2-D3 agonist

To examine the impact of lead (Pb) exposure during the ontogeny of dopaminergic (DA) systems on resultant DA function, rats were exposed postnatally (0–21 days of age) via the lactating dam to 0, 100 or 350 ppm Pb acetate in drinking water. At 2 months of age, the postnatally Pb-exposed rats were trained to discriminate the stimulus properties of either the D₁ receptor agonist SKF38393 (6.0 mg/kg) or the D₂-D₃ receptor family subtype agonist quinpirole (0.05 mg/kg) from saline using a standard two-lever operant food-reinforced drug discrimination paradigm. In each training group, dose-effect curves describing drug lever responding to lower doses of the training drug and to preadministration of selective DA antagonists were obtained to examine Pb-induced changes in DA sensitivity. Doses of other DA agonists were substituted for the training drug to determine the generality of any changes in DA sensitivity, and doses of non-DA compounds were substituted to determine the specificity of any changes in DA sensitivity. In the D₁/saline training condition, Pb exposure was not associated with any specific or consistent changes in DA sensitivity. In contrast, exposure to Pb was associated with D₂-D₃ receptor subtype supersensitivity as was indicated by significantly elevated levels of drug lever responding in the presence of quinpirole and haloperidol and to at least one dose of apomorphine. No differences in the dose-effect curves for either (+)-amphetamine or NMDA were observed in the D₂-D₃-trained control and Pb-exposed groups, but an increase in drug lever responding in the presence of pentobarbital was noted in the Pb-exposed group relative to control. Taken together, these findings are consistent with a Pb-induced functional D₂-D₃ supersensitivity possibly mediated via autoreceptors. Moreover, this functional D₂-D₃ supersensitivity necessarily represents a permanent effect of postnatal Pb exposure since both blood and brain Pb levels were negligible at the time drug discrimination training began.