Motor and cognitive functions of the neostriatum during bilateral blocking of its dopamine receptors

In experiments on 60 Sprague-Dawley rats, effects of systemic and intrastriatal injections of se-lective blocker of D1 receptors SCH23390 on elaboration of discriminational conditioned reflex of active avoidance (CRAA) were studied in T-maze and on behavior in test of the "open field". Systemic administration of this inhibitor at doses of 0.025 mg/kg produced a several fold decrease of percentage of correct realizations of the discriminational CRAA and of motor activity in the "open field" test. Bilateral microinjections of SCH23390 into the rat neostriatum at a dose of 0.004-1.0 mkg did not deteriorate learning of the discriminational CRAA as compared with intact control, although a marked inhibition of motor activity was observed in the open field, test. Analysis of the data has also shown a statistically significant decrease of percentage of errors in the starting maze compartment in experiments with intrastriatal injection of SCH23390 to rats. At the same time, the intrastriatal injection to rats of raclopride, a blocker of D2 dopamine receptors, at a dose of 0.004 mkg produced a sharp and prolonged deterioration of learning of the discriminational CRAA. The data obtained have allowed the following conclusions to be made: 1. Difference of effects of the systemic and intrastriatal SCH23390 injections seems to be due to that the behavioral changes observed at the systemic administration can be provided predominanantly by structures differing from neostriatal D1 receptors; 2. Effect of nigrostriatal dopaminergic system on the neostriatum through D1 receptors is complex: activation of motor activity (efferent spine cells of the direct pathway) and a poor modulation of the learning process (large aspine cholinergic interneurons); 3. The modulation of the learning process seems to occur through neostriatal D2 receptors (large aspine cholinergic interneurons).     

SCH23390 causes persistent antidopaminergic effects in vivo: evidence for longterm occupation of receptors

SCH23390 has neurochemical properties characteristic of a specific D1 dopamine receptor antagonist. However, it is a potent inhibitor of dopamine-mediated behaviors which previously had been thought to be linked to D2 receptors. The metabolism of SCH23390 following parenteral administration to rats was much more rapid in the periphery than in brain, and SCH23390 had behavioral effects long after its circulating concentration had declined below detectable levels. Furthermore, the stimulation of adenylate cyclase by dopamine was attenuated in striatal homogenates taken from rats treated with SCH23390 as much as twelve hours before sacrifice. Pretreatment with cis-flupenthixol, a compound with equivalent D1 potency in vitro, failed to inhibit dopamine-stimulated adenylate cyclase activity one or four hours following injection, despite the fact that this dose produced significant behavioral effects. These data indicate that SCH23390 may act with unusual tenacity at certain sites in the central nervous system.     

SCH 23390 dissociated from conventional neuroleptics in apomorphine climbing and primate acute dyskinesia models

SCH 23390 induced only a negligible incidence of the acute dyskinetic syndrome, a predictor of neuroleptic-induced extrapyramidal liability, in squirrel monkeys. However, haloperidol-induced dyskinesias were potentiated by SCH 23390 and were blocked by the D-1 agonist, SKF 38393. When administered orally or intraperitoneally to mice, SCH 23390 showed a considerably wider dose separation than did conventional neuroleptics between antagonism of apomorphine climbing and antagonism of stereotyped sniffing. Clinically relevant distinctions may exist between D-1 and D-2 antagonists, with D-1 antagonists (exemplified by SCH 23390) showing lower, although possibly not negligible, potential to cause extrapyramidal side effects.     

Selective D2 dopamine receptor agonists prevent catalepsy induced by SCH 23390, a selective D1 antagonist

SCH 23390, an apparently selective antagonist of central D1 dopamine receptors, produced profound catalepsy at low doses (0.1 mg/kg, s.c.). Pretreatment with the selective D2 receptor agonists LY 141865, RU 24213 or LY 171555, the active (-) enantiomer of LY 141865, elicited a dose-dependent inhibition of the cataleptic response. Pergolide and apomorphine were also effective. This effect was not due to altered disposition or penetration of SCH 23390 into the brain since pretreatment with a dose of LY 171555 which completely blocked catalepsy had no effect on the ID50 of SCH 23390 to inhibit 3H-cis-piflutixol binding to D1 receptors measured ex vivo. Alternative mechanisms are considered to explain the results, which offer new insights into striatal dopaminergic regulation of motor activity.     

Systemic 1-methyl,4-phenyl,1-2-3-6-tetrahydropyridine (MPTP) administration decreases retinal dopamine content in primates

Following MPTP administration, 4 Cynomolgus monkeys developed a parkinsonian syndrome, accompanied by specific changes of both pattern visual evoked potential and electroretinogram. Retinal dopamine and dihydroxyphenylacetic acid contents were measured in the 4 MPTP-treated monkeys and in 3 normal monkeys. Dopamine and dihydroxyphenylacetic acid levels were significantly lower in the retinas of the MPTP-treated animals (p less than 0.001), suggesting that dopamine has a specific function in the visual system of primates.     

Dopamine D1-like receptor antagonist, SCH23390, exhibits a preventive effect on diabetes mellitus that occurs naturally in NOD mice

Dopamine receptors have five isoforms, termed D1-D5. The D1 and D5 receptors form the D1-like group that couples with the Gαs class of G proteins, while D2, D3 and D4 form the D2-like group that couples with the Gαi class of G proteins. In our previous studies, a D1-like-R antagonist, SCH23390, inhibited DC-mediated Th17 differentiation and exhibited preventive and therapeutic effects on experimental autoimmune encephalomyelitis (EAE) in mice. We herein demonstrate in the current study that in the pancreas obtained from NOD mice, islet infiltrates appear to be composed of mononuclear cells positive for IL-23R, one of the specific markers for Th17. Thereafter, NOD mice were orally administered SCH23390 from week 6 to week 26. At week 26, 67% and 25% of mice developed diabetes in the control and the SCH23390 groups, respectively (p < 0.05). A histological examination of SCH23390-treated mice exhibited a typical normal islet structure with no signs of periductal and perivascular infiltrates, whereas the islets from vehicle controls showed insulitis. In week 26, spleen cells were re-stimulated with anti-CD3 and anti-CD28 antibodies in vitro and exhibited an augmentation of IFNγ induction and the suppression of IL-17 induction in the SCH23390-treated mice. These findings indicate that antagonizing D1-like-R suppresses IL-17 expression, thereby leading to a decreased occurrence of NOD.     

Positive interaction between alpha-1 adrenergic and dopamine-2 receptors in locomotor activity of normo and supersensitive mice

In normosensitive mice either the D1 antagonist SCH 23390 or the D2 antagonist sulpiride inhibited the reversion of reserpine-induced akinesia elicited by the mixed D1/D2 agonist pergolide. In mice rendered supersensitive by a five days' reserpine treatment, sulpiride did not prevent the pergolide-induced reversal of akinesia while SCH 23390 disclosed two subpopulations of mice. One population responded to pergolide with marked locomotor activity whereas in the other subpopulation this response was absent. However, all mice challenged with pergolide failed to reverse reserpine-akinesia after alpha-methyl-p-tyrosine (AMPT) pretreatment. The alpha 1/alpha 2 agonist clonidine restored the ability of pergolide to overcome reserpine akinesia in supersensitive mice pretreated with SCH 23390. Clonidine reversed the akinesia in supersensitive mice but in normal animals it did not. However, in these last conditions, the combined use of clonidine plus the D2 agonist LY 171555 was effective to induce locomotion. Neither AMPT nor SCH 23390 inhibited this response whereas the alpha-adrenergic antagonists prazosin and yohimbine did prevent it. The alpha 2 agonist B-HT 920 failed to induce locomotor responses when given together with LY 171555. The same occurred with the D1 agonist SKF 38393 when given together with clonidine. The combined use of SCH 23390 plus prazosin in chronic reserpinized mice prevented pergolide-induced locomotion. Adrenergic stimulation, acting on alpha 1 receptors, could be an alternative to D1 stimulation as a necessary factor to obtain D2-induced motor responses under normo and supersensitive conditions.     

Stereospecific binding of a new benzazepine, [3H]SCH23390, in cortex and neostriatum

The binding of the D1 antagonist SCH23390 to membrane preparations from rat cerebral cortex was examined using enantiomers of dopamine agonists and antagonists to compete with the bound [3H]SCH23390 at its Kd value. The competition curves were compared with those obtained with preparations from the neostriatum. The results demonstrate that specific [3H]SCH23390 binding in the cerebral cortex has the same pharmacological profile as in the neostriatum, so that this radioligand can be used to label dopamine D1 receptors in brain regions with a sparse dopaminergic innervation.     

Methamphetamine and Dopamine Receptor D1 Regulate Entrainment of Murine Circadian Oscillators

We investigated the effect of methamphetamine (MA) injections on the circadian organization of behavior and individual tissues in the mouse. Scheduled, daily injections of MA resulted in anticipatory activity, with an increase in locomotor activity immediately prior to the time of injection. Daily MA also shifted the peak time of PER2 expression in the liver, pituitary, and salivary glands. It has been suggested that reward pathways, and dopamine signaling in particular, may underlie the effects of MA on the circadian system. To test this hypothesis, we examined the effect of the D1 receptor antagonist {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 (SCH) on circadian rhythms. The MA-induced shift in the phase of pituitary and salivary glands was attenuated by pretreatment with the D1 antagonist {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 (SCH). Interestingly, daily SCH, administered alone, also affected some circadian oscillators. The livers and lungs (but not pituitaries or salivary glands) of mice treated with daily injections of SCH displayed disrupted rhythms of PER2 expression, suggesting that D1 receptor signaling is important for entrainment of these organs. From these results, we conclude that MA has widespread effects within the circadian system, and that these effects are mediated, at least in part, by the dopaminergic system. This study also identifies a role for dopamine signaling in normal entrainment of circadian oscillators.     

Exposure to Far Infrared Ray Protects Methamphetamine-Induced Behavioral Sensitization in Glutathione Peroxidase-1 Knockout Mice via Attenuating Mitochondrial Burdens and Dopamine D1 Receptor Activation

Evidence indicates that stress conditions might lead to drug dependence. Recently, we have demonstrated that exposure to far infrared ray (FIR) attenuates acute restraint stress via induction of glutathione peroxidase-1 (GPx-1) gene. We investigated whether FIR affects methamphetamine (MA)-induced behavioral sensitization and whether FIR-mediated pharmacological activity requires interaction between dopamine receptor and GPx-1 gene. We observed that MA treatment significantly increased GPx-1 expression in the striatum of wild-type (WT) mice. Interestingly, exposure to FIR potentiated MA-induced increase in GPx-1 expression. This phenomenon was also observed in animals receiving MA with dopamine D1 receptor antagonist SCH23390. However, dopamine D2 receptor antagonist sulpiride did not affect MA-induced GPx-1 expression. FIR exposure or SCH23390, but not sulpiride, significantly attenuated MA-induced behavioral sensitization. Exposure to FIR significantly attenuated MA-induced dopamine D1 receptor expression, c-Fos induction and oxidative burdens. FIR-mediated antioxidant effects were also more pronounced in mitochondrial- than cytosolic-fraction. In addition, FIR significantly attenuated against MA-induced changes in mitochondrial superoxide dismutase and mitochondrial GPx activities, mitochondrial transmembrane potential, intramitochondrial Ca²⁺ level, mitochondrial complex-I activity, and mitochondrial oxidative burdens. The attenuation by FIR was paralleled that by SCH23390. Effects of FIR or SCH23390 were more sensitive to GPx-1 KO than WT mice, while SCH23390 treatment did not exhibit any additive effects on the protective activity mediated by FIR, indicating that dopamine D1 receptor constitutes a molecular target of FIR. Our result suggests that exposure to FIR ameliorates MA-induced behavioral sensitization via possible interaction between dopamine D1 receptor and GPx-1 gene.     

Recovery of chronic parkinsonian monkeys by autotransplants of carotid body cell aggregates into putamen

We have studied the effect of unilateral autografts of carotid body cell aggregates into the putamen of MPTP-treated monkeys with chronic parkinsonism. Two to four weeks after transplantation, the monkeys initiated a progressive recovery of mobility with reduction of tremor and bradykinesia and restoration of fine motor abilities on the contralateral side. Apomorphine injections induced rotations toward the side of the transplant. Functional recovery was accompanied by the survival of tyrosine hydroxylase-positive (TH-positive) grafted glomus cells. A high density of TH-immunoreactive fibers was seen reinnervating broad regions of the ipsilateral putamen and caudate nucleus. The nongrafted, contralateral striatum remained deafferented. Intrastriatal autografting of carotid body tissue is a feasible technique with beneficial effects on parkinsonian monkeys; thus, this therapeutic approach could also be applied to treat patients with Parkinson's disease.     

Involvement of D1 dopamine receptors in the cognitive effects of angiotensin IV and des-Phe6 angiotensin IV

An important role for angiotensin IV (Ang IV) in the processes of learning and memory has now been well established. We have previously found that intracerebroventricular (ICV) administration of Ang IV as well as des-Phe6-Ang IV enhances learning of conditioned avoidance responses (CARs), facilitates recall of a passive avoidance (PA) task, and improves object recognition (OR) in rats. Since the dopaminergic system is crucial for the cognitive processes, in this study our aim was to determine the dopaminergic D1 mediation of these effects using SCH 23390 as a selective D1 receptor antagonist. Male Wistar rats (180-200 g), pretreated with SCH 23390 (R-[+]-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) 0.05 mg/kg intraperitoneally (IP), were given Ang IV or des-Phe6-Ang IV (1 nmol ICV) 1 h later and then tested in the above cognitive paradigms, as well as in the open field and an elevated 'plus' maze to control for the unspecific, respectively, motor and emotional, effects of our treatments. Both, Ang IV and des-Phe6-Ang IV effectively enhanced learning of CARs (P < 0.05), recall of PA (P < 0.001), and improved OR (P < 0.001). Pretreatment with SCH 23390 abolished the cognitive effects of both peptides. SCH 23390, Ang IV, and des-Phe6-Ang IV, given at the same doses and routes as in the cognitive tests, did not significantly influence crossings, rearings and bar approaches in the open field, nor the parameters measured in the elevated 'plus' maze, thus making a major contribution of the unspecific effects of our treatments to the results of the memory tests improbable. In conclusion, these results indicate that the functional dopaminergic D1 receptors are necessary for the Ang IV and des-Phe6-Ang IV cognitive effects to occur.     

Endogenous Dopamine Facilitates Striatalln Vivo Acetylcholine Release by Acting on D1 Receptors Localized in the Striatum

Intrastriatal application of the D1 antagonist SCH 23390 by two procedures, reverse dialysis (20 microM) and local injection (0.45 nmol per striatum), elicited a reduction in acetylcholine (ACh) release superimposable on that induced by systemic administration. The novel selective D1 antagonist SCH 39166 produced a similar decreasing effect on striatal ACh release on local injection (0.45 nmol per striatum). On the other hand, local application of SCH 23390 into the frontal cortices (0.45 nmol per side) failed to alter striatal ACh overflow, indicating that the drug does not diffuse out of its injection site to any significant extent. The dopamine release inducer d-amphetamine (2 mg/kg s.c.) and the dopamine uptake inhibitor cocaine raised ACh release like the D1 agonists. These effects were completely blocked by 10 microM SCH 23390 applied by reverse dialysis. The results suggest that D1 receptors regulating ACh release are located in the striatum.     

Identification of D1-like dopamine receptors on human blood platelets

Dopamine is able to inhibit the epinephrine-induced aggregation of human blood platelets, but the mechanism of action has not been elucidated. In this study we report that membranes from human blood platelets possess high affinity, saturable and stereoselective binding sites for the D1 dopamine receptor antagonist (3H) SCH 23390. (3H) SCH 23390 appeared to label a single class of binding sites with a Bmax of 18.6 +/- 1.6 fmol/mg protein and a KD of 0.8 nM. The potencies of different dopaminergic antagonists and agonists in displacing (3H) SCH 23390 from blood platelet membranes were similar to those obtained for striatal membranes. Unlike the classically defined D1 receptors, e.g. those in striatum, the D1 receptor sites on platelets appeared not to be coupled to the adenylate cyclase system, hence the term "D1-like". The D1 agonist SKF 38393 was more potent than dopamine in inhibiting platelet aggregation induced by epinephrine, and the effects of dopamine and SKF 38393 were prevented by SCH 23390. These results suggest that the inhibitory action of dopamine on the epinephrine-induced platelet aggregation is mediated through these D1-like receptors.     

The role of D1-dependent dopaminergic mechanisms in the frontal cortex in the rat latent response

The effects of microinjections of D1 selective dopaminergic substances into the medial frontal cortex (MFC) on information storage and proactive interference during delayed (the delay in 3 s) and non-delayed choice in Y-maze were studied. Bilateral microinjection of D1 receptor antagonist SCH 23390 (1 nM, 1 microliter) impaired both delayed and non-delayed choice. In contrast, microinjections of D1 receptor agonist SKF 38393 (1 nM) into the MFC significantly improved the delayed performance and did not influence the non-delayed choice. The effects of proactive interference caused by SCH 23390 and SKF 38393 injections were more pronounced in delayed choice condition than in the non-delayed task. Spatial bias in animal behavior was revealed after the SCH 23390 injections: during erroneous choices rats more frequently turned in the same direction as preferred in a rotation test. The results suggest that impairment of delayed performance in Y-maze observed under the blockade of D1-mediated neurotransmission in the MFC occurs due to enhancement of the processes of proactive interference and disinhibition of the spatial set.     

Atypical SCH23390 Binding Sites Are Present on Bovine Adrenal Medullary Membranes

D1-selective dopamine receptor agonists inhibit secretagogue-stimulated catecholamine secretion from bovine adrenal chromaffin cells. The purpose of the studies reported here was to use the radiolabeled D1-selective dopamine receptor antagonist, SCH23390, to characterize putative D1-like dopamine receptors responsible for this effect. Characterization of SCH23390 binding sites demonstrated an unusual pharmacological profile inconsistent with classical D1-like receptors. [¹²⁵I]SCH23390 bound to adrenal medullary membranes was competed for by non-radioactive iodo-SCH23390 (Kd = 490 ± 50 nM), but not by (+)butaclamol. Other classical D1 antagonists had little, if any, effect. Competition with dopamine receptor agonists demonstrated a relative rank order of potency profile characteristic of D1-like dopamine receptors, however, K_is were higher than those found in other tissues. The K_is for competition of [¹²⁵I]SCH23390 binding by C1-APB and SKF38393 (16 and 118 M, respectively) are nearly identical to the IC₅₀s previously observed for inhibition of secretion (9 and 100 M, respectively). Combined these data suggest that adrenal medullary membranes contain a novel SCH23390 binding site involved in the inhibition of secretion by D1-selective agonists.     

The binding of SCH 39166 and SCH 23390 to 5-HT1C receptors in porcine choroid plexus

SCH 39166 is a novel benzonaphthazepine, which has been characterized as a potent and selective D1 antagonist. Recently, its D1 selective benzazepine predecessor, SCH 23390, has been shown to bind to 5-HT1C binding sites in the choroid plexus. Therefore, the present studies were undertaken to determine if SCH 39166 has any measurable affinity for 5-HT1C binding sites. Our results indicate that SCH 39166 exhibited poor affinity for the 5-HT1C receptor, with a Ki of 1327 nM. In contrast, SCH 23390 inhibited [3H]-mesulergine binding to 5-HT1C receptors with a Ki of 30 nM. The non-selective 5-HT antagonist, methysergide, inhibited binding with a Ki of 2.4 nM. Finally, studies with the stereoisomers of SCH 39166 and SCH 23390 demonstrated that stereoselectivity at the 5-HT1C site is significantly less than for the D1 site.     

Dopamine Depletion Preferentially Impairs D1 over D2-Receptor Regulation of Striatal In Vivo Acetylcholine Release

The roles of D2 and D1 dopaminergic receptors on the regulation of striatal acetylcholine (ACh) release in vivo were examined for a period of 120 min after acute (2 h) or prolonged (16 h) depletion of brain dopamine (DA) by alpha-methyl-p-tyrosine. The reduction of DA transmission did not affect basal ACh output after 2 h but markedly lowered ACh release by 16 h (50%). Acute alpha-methyl-p-tyrosine pretreatment prevented the reduction of ACh release by the D1 antagonist SCH 23390 and its increase by the D2 antagonist, remoxipride, consistent with a drastic reduction of DA transmission at both DA receptors. However, 16 h after alpha-methyl-p-tyrosine, the effect of remoxipride on ACh release was restored, but SCH 23390 still had no effect, suggesting that the D2 inhibitory tone on ACh release had recovered, whereas the reduction of the D1 facilitatory influence persisted. The D1 facilitatory control of ACh neurotransmission thus appears to be more sensitive than the D2 inhibitory control to a reduction in DA transmission. The new model of DA-ACh interaction resulting from these data casts fresh light on the relationship between changes in DA transmission and extrapyramidal motor function.     

Effects of SCH23390 and raclopride on a run-climb-run behavioral task in rats

The present study was designed to compare the putative differential behavioral consequences of treatment with SCH23390 (a selective dopamine D1 receptor blocker) and raclopride (a selective dopamine D2 receptor blocker) by employing a run-climb-run (RCR) behavioral task of different lengths. Rats were trained to traverse an uncovered floor alleyway (150 cm), climb a vertical rope (70 or 130 cm), and run across an upper board (100 cm) to access water for the reinforcement. At doses of 0.05, 0.10 and 0.15 mg/kg administered intraperitoneally 60 min before the behavioral session, both SCH23390 and raclopride significantly increased the total time to complete the tasks in a dose-related fashion. Microstructural analysis on the RCR behavioral performance revealed that the most apparent impairment induced by either drug was observed as the subject shifted motion from the end of the floor alleyway to the rope when hopping or to initiate climbing. However, the motion shift from climbing to running on the upper board was significantly impaired by raclopride, but not by SCH23390. Surprisingly, neither SCH23390 nor raclopride affected the climbing response itself. Running responses on the floor alleyway board were significantly disrupted by raclopride, whereas those on the upper board were significantly disrupted by SCH23390. Deficits induced by both drugs were more profound for the longer compared to the shorter rope, and were most notably shown at the transition area from running to climbing. These data indicate that both dopamine D1 and D2 receptors are involved in the RCR behavior performance. The results also suggest that the cost of motoric demand for behavioral performance is important for evaluating of the effects of drugs blocking dopamine receptors.