In vivo labeling of brain dopamine D2 receptors using the high-affinity specific D2 agonist [3H]CV 205-502

The high-affinity selective dopamine D2 agonist [3H]CV 205-502 was utilized to in vivo label brain dopamine D2 receptors in the rat. Intravenous administration of [3H]CV 205-502 resulted in a selective accumulation of radioactivity in the striatum and in the pituitary. Smaller amounts of binding were found in the hypothalamus and cortex and non-significant binding was seen in the cerebellum. The binding of [3H]CV 205-502 was stereospecifically blocked by (+)-butaclamol but not by (-)-butaclamol. In vivo binding of [3H]CV 205-502 was also dose-dependently blocked by other neuroleptics including sulpiride, haloperidol and spiroperidol, dopamine agonists such as bromocriptin, apomorphine and C1 201-678 but not by dopamine D1 antagonists or serotonin-2 antagonists. The regional distribution of the sites labeled in vivo by [3H]CV 205-502 was investigated by autoradiography and compared with the distribution seen after in vitro labeling in the consecutive sections, following washing of the label. The autoradiograms reveal the labeling of the same areas seen when in vitro autoradiography was used. High densities of binding were localized in the nucleus accumbens, striatum and olfactory tubercle as well as in the olfactory bulb. Lower densities were seen in the substantia nigra pars compacta and in the ventral tegmental area as well as in the stratum lacunosum molecular of the hippocampus and in the superior colliculus. The intermediate lobe of the pituitary also presented high densities while in the anterior pituitary only intermediate densities of receptor binding were observed. These results demonstrate that [3H]CV 205-502 is the first high-affinity agonist useful for the autoradiographic visualization of dopamine D2 receptors after in vivo labeling. This compound could be modified for utilization in positron emission tomography imaging of dopamine D2 receptors in the living animal.     

Autoradiographic study of striatal D1 and D2 dopamine receptors in 6-OHDA-lesioned rats receiving foetal ventral mesencephalic grafts and chronic treatment with L-dopa and carbidopa.

Foetal dopamine cell suspensions or sham preparations were implanted into the denervated striatum of rats with a unilateral 6-hydroxy-dopamine (6-OHDA) lesion of the medial forebrain bundle. Some animals were also treated with L-DOPA (200 mg/kg/24 h) and carbidopa (25 mg/kg/24 h) in the drinking water for 5 weeks, followed by a 3-week drug-free period. Rotational responses to apomorphine and (+)-amphetamine were assessed, and the density of D1 and D2 dopamine receptors was evaluated autoradiographically in striatal slices exposed to [3H]SCH 23390 or [3H]spiperone. Foetal grafts reduces apomorphine-induced contralateral rotation and prevented the development of apomorphine-induced stereotypy. Foetal grafts abolished (+)-amphetamine-induced ipsilateral rotation. These effects of the grafts were not altered by treatment with L-DOPA. A unilateral 6-OHDA lesion of the nigrostriatal pathway resulted in an ipsilateral increase in D2 receptor density most marked in the lateral and dorsomedial quadrants of the striatum compared with the contralateral side. Foetal ventral mesencephalic grafts implanted into the lesioned striatum decreased D2 receptor density to levels found in the contralateral intact striatum. Chronic L-DOPA and carbidopa treatment did not alter the effect of the grafts. A 6-OHDA lesion resulted in a reduction of D1 receptor density in the lateral areas of the lesioned striatum at Level 2. The presence of a foetal ventral mesencephalic graft either alone or together with L-DOPA treatment did not alter the lesion-induced changes in D1 binding density.     

Intrastriatal Dopamine-rich Implants Reverse the Increase of Dopamine D2 Receptor mRNA Levels Caused by Lesion of the Nigrostriatal Pathway: A Quantitative In Situ Hybridization Study

Changes in striatal dopamine D2 receptor mRNA levels provoked by unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine pathway were studied by in situ hybridization. The influence of embryonic dopaminergic neurons implanted into the dopamine-depleted striatum on the lesion-induced changes was also examined. Changes in D2 mRNA levels were compared with changes in D2 receptor densities measured in the same animals by receptor autoradiography using [3H]spiperone or [3H]SDZ 205-501 as ligands. The distribution of D2 mRNA in the striatum of control animals closely paralleled that of the D2 receptor itself, as assessed by autoradiography, and the highest density of D2 mRNA occurred in the lateral part of the striatum. One month after lesion, levels of D2 mRNA were 34% higher in the dorsolateral part of the dopamine-depleted striatum than in the corresponding region of the contralateral control striatum. D2 receptor density in this region was increased by 40% relative to the control level. No significant increases could be measured in the medial part of the striatum. The increases in the lateral part were similar at 7 months post-lesion; however, at this time the increase in both D2 mRNA and receptor levels had spread to the medial part of the striatum as well. In the graft-bearing striatum levels of both D2 mRNA and D2 receptors reverted to control levels. This study shows that the post-lesion increase in striatal dopamine receptor and mRNA level is a biphasic phenomenon with a late-occurring component in the medial striatum. It also shows that once the increase in striatal D2 receptor gene expression is accomplished, it is maintained unchanged for long periods, similar to that of D2 receptor levels themselves. Moreover, grafts of embryonic dopaminergic neurons are able to modulate the expression of the dopamine D2 receptor gene.     

Cholinergic neuronal modulation alters dopamine D2 receptor availability in vivo by regulating receptor affinity induced by facilitated synaptic dopamine turnover: positron emission tomography studies with microdialysis in the conscious monkey brain.

To evaluate the cholinergic and dopaminergic neuronal interaction in the striatum, the effects of scopolamine, a muscarinic cholinergic antagonist, on the striatal dopaminergic system were evaluated multi-parametrically in the conscious monkey brain using high-resolution positron emission tomography in combination with microdialysis. l-3,4-Dihydroxyphenylalanine (l-[beta-(11)C]DOPA) and 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane ([beta-(11)C]CFT) were used to measure dopamine synthesis rate and dopamine transporter (DAT) availability, respectively. For assessment of dopamine D(2) receptor binding in vivo, [(11)C]raclopride was applied because this labeled compound, which has relatively low affinity to dopamine D(2) receptors, was hypothesized to be sensitive to the striatal synaptic dopamine concentration. Systemic administration of scopolamine at doses of 10 and 100 microg/kg dose-dependently increased both dopamine synthesis and DAT availability as measured by l-[beta-(11)C]DOPA and [beta-(11)C]CFT, respectively. Scopolamine decreased the binding of [(11)C]raclopride in a dose-dependent manner. Scopolamine induced no significant changes in dopamine concentration in the striatal extracellular fluid (ECF) as determined by microdialysis. However, scopolamine dose-dependently facilitated the striatal ECF dopamine induced by the DAT inhibitor GBR12909 at a dose of 0.5 mg/kg. Scatchard plot analysis in vivo of [(11)C]raclopride revealed that scopolamine reduced the apparent affinity of dopamine D(2) receptors. These results suggested that the inhibition of muscarinic cholinergic neuronal activity modulates dopamine turnover in the striatum by simultaneous enhancement of the dynamics of dopamine synthesis and DAT availability, resulting in no significant changes in apparent "static" ECF dopamine level but showing a decrease in [(11)C]raclopride binding in vivo attributable to the reduction of affinity of dopamine D(2) receptors.     

D1 and D2-type dopamine receptors in patients with Parkinson's disease and progressive supranuclear palsy

The densities of D1- and D2-type dopamine receptors were measured with [3H]SCH23390 and [3H]spiperone, in the caudate nucleus and putamen of a large series of patients with Parkinson's disease or progressive supranuclear palsy, in relation to markers of dopaminergic and cholinergic innervation of the striatum ([3H]dihydrotetrabenazine binding and choline acetyltransferase activity). Correlations were sought between these parameters and clinical characteristics of the patients (abnormal involuntary movements, dementia, confusional syndrome or treatment). In Parkinson's disease, the densities of both types of receptors were unchanged, whereas in PSP, the density of D2, but not D1-type dopamine receptors, was decreased in the caudate nucleus and the putamen. No correlations between the biochemical and clinical data were found.     

Behavioral effects of fetal substantia nigra tissue grafted into the dopamine-denervated striatum: responses to selective D1 and D2 dopamine receptor agonists

Grafts of fetal ventral mesencephalon/substantia nigra cell suspensions into the dopamine-denervated striatum have been shown to reduce many of the behavioral alterations associated with striatal dopamine depletion. In this report, the behavioral response to amphetamine, apomorphine, the D1 receptor agonist SKF82958, and the D2 receptor agonist LY171555 were tested before and after intrastriatal grafts of fetal substantia nigra, of fetal striatum or no implantation procedure in animals with unilateral dopamine denervation. Grafts of fetal substantia nigra tissue were associated with significant behavioral recovery, as indicated by decreased turning induced by amphetamine (P ≤ 0.005), SKF82958 (P < 0.005), and LY171555 (P < 0.002). These effects were significantly different from the response in animals that did not receive grafts (P < 0.05) and occurred in the absence of decreased apomorphine-induced turning. These data suggest that the response to selective D1 or D2 dopamine receptor agonists is diminished following grafts of fetal dopaminergic tissue and that this behavioral effect is dissociable from the phenomena of behavioral supersensitivity to apomorphine. In a subset of substantia nigra grafted animals, it was found that D1 or D2 dopamine receptor antagonists administered 30 min prior to apomorphine could significantly reduce apomorphine-induced turning.     

Effect of acetyl-L-carnitine on the dopaminergic system in aging brain.

We studied the effect of acetyl-L-carnitine (ALCAR) on dopamine release and the effect of long-term acetyl-L-carnitine treatment on age-related changes in striatal dopamine receptors and brain amino acid levels. In striatal tissue that had been incubated with [3H]dopamine, acetyl-L-carnitine increased the release of [3H]dopamine evoked by electrical stimulation. In striatal tissue from aged mice administered acetyl-L-carnitine for 3 months, the release of [3H]dopamine evoked by electrical stimulation was higher than that of its aged control; the release after a second stimulation was similar in the two groups. There was a significant decline in the number of D1 striatal dopamine receptors with age. The Bmax was 51% lower in 1.5-year-old mice than in 4-month-old animals. Administration of acetyl-L-carnitine for 3 months diminished the reduction in the binding of [3H]SCH-23390. [3H]Spiperone binding to D2 receptors was not decreased with age and was not affected by acetyl-L-carnitine treatment. Age-related decreases in levels of several amino acids were observed in several brain regions. Acetyl-L-carnitine lessened the reduction in the level of taurine only in the striatum. The findings confirm the multiple effects of acetyl-L-carnitine in brain, and suggest that its administration can have a positive effect on age-related changes in the dopaminergic system.     

Autoradiographic localization of D1 dopamine receptors in the rat brain with [3H]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 (Kd = 2.05 nM); it occurred at a 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.     

Compartment-specific changes in the density of choline and dopamine uptake sites and muscarinic and dopaminergic receptors during the development of the baboon striatum: a quantitative receptor autoradiographic study

In the fetal and young primate neostriatum, cholinergic and dopaminergic markers show patches of high density surrounded by a lower-density matrix. In the adult, the same markers display the opposite pattern, a lower density in striosomes, surrounded by a higher-density matrix. In order to understand the developmental sequences leading to the adult compartmental organization of the primate neostriatum, a quantitative technique was used to study the ontogeny of pre- and postsynaptic components of cholinergic and dopaminergic neurons in baboon caudate nucleus and putamen. The development of specific uptake mechanisms for choline and dopamine and receptors was studied by means of quantitative autoradiography of the specific binding of [3H]-hemicholinium-3 [( 3H]-HC3) and [3H]-mazindol [( 3H]-MAZ) to the choline and dopamine uptake systems, respectively. [3H]-pirenzepine [( 3H]-PIR) was used to label M1 muscarinic receptors and [3H]-spiroperidol [( 3H]-SPI) was used to label striatal dopamine D2 receptors. Serial sections were used for each ligand to determine the precise anatomical relationships between the binding patterns of the different markers. Our aim was to determine whether the adult striosomal distribution of the binding sites studied was due to 1) a selective decrease in patch/striosomal binding density or 2) a selective increase in matrix binding density. Our studies show that a postnatal decrease in the density of [3H]-HC3 sites in the patch/striosomes and an increase in the matrix density of [3H]-MAZ sites are the primary, but not the sole, changes in the compartmental distribution of these sites leading to the adult striosomal organization of the striatal cholinergic and dopaminergic innervation. D2 receptors follow the general developmental pattern of [3H]-MAZ and [3H]-HC3, changing their density of distribution in both compartments during the developmental period examined. In addition, M1 muscarinic receptors already display their adult pattern in the newborn baboon striatum, and therefore represent one of the first neurochemical makers to adopt its mature organization.     

Development of specificity and stereoselectivity of rat brain dopamine receptors

Prenatal exposure to the neuroleptic haloperidol has been reported to produce an enduring decrement in the number of dopamine D2 receptors in rat striatum and a persistent diminution of a dopamine dependent behavior, stereotypy. The ontogeny of rat brain dopamine binding sites has been studied in terms of the kinetic properties and phenotypic specificity in rat fetal brain through early postnatal development. Sites showing some properties of the D2 binding site can be found prior to gestational day (GD) 18, can be labeled with [3H]dopamine or [3H]spiroperidol and can be displaced with dopaminergic agonists and antagonists. Saturation kinetics for specific [3H]spiroperidol has previously been found to occur on or about GD 18. It is of interest that the critical period for the prenatal effect of haloperidol to reduce striatal D2 binding sites, GD's 15-18, coincides with the period during which dopamine binding sites lack true specificity, but can be labeled with dopaminergic ligands. In these experiments the development of stereoselectivity of brain dopamine binding sites has been examined. When rat mothers were given either the neuroleptic (+)-butaclamol or its therapeutically inactive isomer (-)-butaclamol during the critical period GD's 15-18, the number of [3H]spiroperidol binding sites in striata of offspring was significantly reduced by both stereoisomers. This is in marked contrast to the postnatal treatment effect by a neuroleptic in which upregulation of striatal D2 binding sites occurs only by treatment with the therapeutically active isomer (+)-butaclamol. In vitro studies of the direct effect of the stereoisomers of butaclamol indicate that the recognition sites detected during fetal brain development with [3H]spiroperidol do not distinguish between the isomers of butaclamol.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Dopamine receptors in human brain: autoradiographic distribution of D1 and D2 sites in Parkinson syndrome of different etiology

The distribution and density of dopamine D1 and D2 receptors were examined by autoradiography in postmortem brain tissue from patients with pathological diagnosis of Parkinson's disease, status lacunaris, clinical parkinsonism without neuropathological lesions and in age-matched controls. The D1 antagonist [3H]SCH 23390 and the D2 agonist [3H]CV 205-502 were used as ligands. No significant differences in the distribution or density of D1 or D2 receptors were found in Parkinson's disease in the areas examined, including the nucleus caudatus, putamen, globus pallidus and substantia nigra. In contrast, cases presenting lacunar lesions in the striatum showed marked decreases in D1 and D2 receptor densities in this region. Patients clinically diagnosed as parkinsonians but without Parkinson's disease lesions or striatal lacunar softenings showed reduced densities of D2 receptors in the nucleus caudatus and putamen, while in the substantia nigra the densities were comparable to controls. In the basal ganglia of these cases D1 receptors were slightly decreased.     

Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum.

A cDNA fragment homologous to other G protein-coupled receptors was isolated from rat brain using the PCR method and demonstrated to be abundantly expressed in striatum. Using this fragment as a probe, a 2.1 kb full-length cDNA was isolated from a rat striatal cDNA library. This cDNA encodes a protein of 410 amino acids and is highly homologous to previously isolated adenosine receptor cDNAs. Expression of this cDNA in COS cells revealed high affinity (Kd = 38.6 nM) and saturable binding of the A2 adenosine receptor-selective ligand [3H]CGS 21680. Agonist displacement profile of [3H]CGS 21680 binding was consistent with an adenosine receptor of the A2 subtype (NECA greater than (R)-PIA greater than CPA greater than (S)-PIA). In situ hybridization demonstrated that rat A2 adenosine receptor mRNA was co-expressed in the same striatal neurons as D2 dopamine receptor mRNA, and never co-expressed with striatal D1 dopamine receptor mRNA. Several lines of evidence have previously suggested that dopamine-induced changes in motor behavior can be modulated by adenosine analogs acting at the A2 subtype of adenosine receptor in the forebrain. The co-expression of D2 dopamine and A2 adenosine receptors in a subset of striatal cells provides an anatomical basis for dopaminergic-adenosinergic interactions on motor behavior.     

Neuronal localization of cannabinoid receptors in the basal ganglia of the rat

Cannabinoid receptors have recently been characterized and localized using a high-affinity radiolabeled cannabinoid analog in section binding assays. In rat brain, the highest receptor densities are in the globus pallidus and substantia nigra pars reticulata. Receptors are also dense in the caudate-putamen. In order to determine the neuronal localization of these receptors, selective lesions of key striatal afferent and efferent systems were made. Striatal neurons and efferent projections were selectively destroyed by unilateral infusion of ibotenic acid into the caudate-putamen. The nigrostriatal pathway was selectively destroyed in another set of animals by infusion of 6-hydroxydopamine into the medial forebrain bundle. After 2- or 4-week survivals, slide-mounted brain sections were incubated with ligands selective for cannabinoid ([3H]CP 55,940), dopamine D1 3H]SCH-23390) and D2 ([3H]raclopride) receptors, and dopamine uptake sites ([3H]GBR-12935). Slides were exposed to 3H-sensitive film. The resulting autoradiography showed ibotenate-induced losses of cannabinoid, D1 and D2 receptors in the caudate-putamen and topographic losses of cannabinoid and D1 receptors in the globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata at both survivals. Four weeks after medial forebrain bundle lesions (which resulted in amphetamine-induced rotations), there was loss of dopamine uptake sites in the striatum and substantia nigra pars compacta but no change in cannabinoid receptor binding. The data show that cannabinoid receptors in the basal ganglia are neuronally located on striatal projection neurons, including their axons and terminals. Cannabinoid receptors may be co-localized with D1 receptors on striatonigral neurons. Cannabinoid receptors are not localized on dopaminergic nigrostriatal cell bodies or terminals.     

Decreased striatal D1 binding density following mesotelencephalic 6-hydroxydopamine injections: an autoradiographic analysis

Autoradiographic experiments performed on rats with unilateral mesotelencephalic 6-hydroxydopamine (6-OHDA) injections revealed reduced binding of [3H]SCH23390 to D1 receptors in the striatum ipsilateral to the neurotoxin as well as increased binding of [3H]spiroperidol to D2 receptors in that hemisphere. These opposite influences of injury on the dopamine receptor subtypes occurred in rats sacrificed at 2 weeks or 11 months postoperatively, but neither change was evident at 4 days postoperatively. Equilibrium saturation analysis performed on rats sacrificed at 8 weeks postoperatively indicated that D1 and D2 receptor changes reflected altered Bmax values without KD modifications. Topographic analysis of the D1 decline by quantitative autoradiography revealed that the D1 decrease was greater in dorsal striatum than ventrally. Those striatal regions that showed greater declines in D1 density correspondingly had the greater losses of [3H]mazindol binding after the denervation, suggesting that the decline of D1 binding is a postsynaptic consequence of the reduced mesostriatal dopaminergic innervation. The findings indicate opposite influences of injury on D2 and D1 receptor levels and raise important questions concerning the mechanism by which 6-OHDA injection affects the D1 sites.     

3H]spiperone binds selectively to rat striatal D2 dopamine receptors in vivo: a kinetic and pharmacological analysis

We have determined the kinetic, equilibrium saturation, and pharmacological characteristics of [3H]spiperone ([3H]SPIP) binding to rat brain regional particulate fractions following i.v. injections of [3H]SPIP and compared these parameters to those determined in vitro with traditional ligand-homogenate binding assays. [3H]SPIP binding to rat striatum in vivo and in vitro occurs to a single class of non-interacting binding sites which possess the pharmacological properties of a D2 dopamine (DA) receptor. The potencies of neuroleptic drugs in inhibiting DA receptor-mediated behaviors correlate with their potencies at displacing striatal [3H]SPIP binding in vivo. While striatum possesses a similar density of [3H]SPIP binding sites in vivo (34 pmol/g) and in vitro (31 pmol/g), binding affinity in vivo is about 200 times lower than in vitro. This difference in binding affinities appears to arise from alterations of [3H]SPIP association and dissociation rate constants brought about by tissue homogenization. The implications of our findings for external imaging of DA receptors and studies of DA receptor function in human brain homogenates are discussed.     

Chronic lithium administration has no effect on haloperidol-induced supersensitivity of pre- and postsynaptic dopamine receptors in rat brain

We have studied the effect of chronic lithium administration on haloperidol-induced dopaminergic supersensitivity in rat brain. Lithium had no effect on haloperidol-induced increases in apomorphine inhibition of dopamine synthesis in the striatum and mesolimbic regions. Similarly, lithium was without effect on haloperidol-induced increases in density of [³H]spiperone binding sites in the striatum. These results indicate that lithium has no effect on haloperidol-induced supersensitivity of presynaptic dopamine receptors in the striatum and mesolimbic regions and on postsynaptic dopamine receptors in the striatum.     

Localization of dopamine D2 receptors on cholinergic interneurons of the dorsal striatum and nucleus accumbens of the rat

Striatal cholinergic interneurons located in the dorsal striatum and nucleus accumbens are amenable to influences of the dopaminergic mesolimbic pathway, which is a pathway involved in reward and reinforcement and targeted by several drugs of abuse. Dopamine and acetylcholine neurotransmission and their interactions are essential to striatal function, and disruptions to these systems lead to a variety of clinical disorders. Dopamine regulates acetylcholine release through dopamine receptors that are localized directly on striatal cholinergic interneurons. The dopamine D2 receptor, which attenuates acetylcholine release, has been implicated in drug relapse and is targeted by therapeutic drugs that are used to treat a variety of neurological disorders including Tourette Syndrome, Parkinson's disease and schizophrenia. The present study provides the first direct evidence for the localization of dopamine D2 receptors on striatal cholinergic interneurons of the rat brain using dual labeling immunocytochemistry procedures. Using light microscopy, dopamine D2 receptors were localized on the cell somata and dendritic and axonal processes of striatal cholinergic interneurons in the dorsal striatum and nucleus accumbens of the rat brain. These findings provide a foundation for understanding the specific roles that cholinergic neuronal network systems and interacting dopaminergic signaling pathways play in striatal function and in a variety of clinical disorders including drug abuse and addiction.