The dopamine autoreceptor agonist B-HT 920 inhibits in vivo dopamine release into the cerebroventricular system of cats

In anesthetized cats the dopamine autoreceptor agonist B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine), 1 mg/kg i.v., greatly decreased the amount of dopamine in cerebroventricular perfusates. This effect was antagonized by a low dose (50 micrograms/kg i.v.) of haloperidol, but not by the alpha 2-adrenoceptor blocker idazoxan. Our observations provide evidence that B-HT 920 inhibits brain dopamine release in vivo and may be therapeutically valuable in diseases presumed to be accompanied by a predominance of brain dopamine activity, such as Huntington's disease, mania and schizophrenia.     

Evidence for postsynaptic dopamine agonist effects of B-HT 920 in the presence of the dopamine D-1 agonist SKF 38393

The ability of B-HT 920, a selective dopamine (DA) D-2 agonist, to stimulate postsynaptic DA receptors in brain was evaluated by assessing its ability to induce stereotypy and to increase locomotor activity in rats. When administered alone, B-HT 920 (0.03–3.0 mg/kg) did not induce stereotypy and produced only inhibition of locomotor activity, suggesting a lack of postsynaptic DA agonist actions. However, a different pattern of effects emerged when B-HT 920 was administered in combination with the selective DA D-1 agonist SKF 38393 (10 mg/kg): stereotypies (sniffing, licking, and gnawing) were induced and there was an inverted U-shaped function for locomotor activity. These data are consistent with the hypothesis that B-HT 920 has postsynaptic DA D-2 receptor agonist effects in normal rats that are revealed when D-1 receptor stimulation is also increased. Offprint requests to: L.T. Meltzer     

The dopamine autoreceptor agonist, B-HT 920, preferentially reduces brain dopamine release in vivo: biochemical indices of brain dopamine, noradrenaline and serotonin in ventriculocisternal perfusates in the cat

B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine), a candidate for selective dopamine (DA) autoreceptor agonist activity, was tested for its interactions with biochemical parameters of brain dopaminergic, noradrenergic and serotoninergic systems as measured in ventriculocisternal perfusates of chloralose-anaesthetized cats. DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA) and 5-hydroxyindolic acid (5-HIAA) were measured in samples of 30 min collection periods by high-pressure liquid chromatography with electrochemical detection. B-HT 920, in the dose range of 0.03-1 mg/kg i.v., promptly inhibited the efflux of DA and DOPAC in a dose-dependent manner. The 1 mg/kg dose of B-HT 920 reduced the DA levels below 25% of control levels for the whole length of the experiments. The HVA levels were reduced less and in a protracted manner. Only the highest dose of B-HT 920 tested (1 mg/kg) had a significant effect on the level of NA (marked, prompt reduction) and 5-HIAA (delayed, moderate reduction), reflecting its well known alpha 2-adrenoceptor agonist property. The effects of B-HT 920 on the dopaminergic indices were DA receptor-mediated as they were reversed by a low dose (0.05 mg/kg i.v.) of haloperidol. In contrast, the alpha 2-adrenoceptor blocking drug, idazoxan, 4 mg/kg i.v., while it reversed the NA and 5-HIAA reductions did not modify the effect of B-HT 920 on DA, DOPAC and HVA. Thus B-HT 920, in the dose range between 0.03-0.1 mg/kg, selectively affected brain dopaminergic parameters. Our experiments demonstrated that B-HT 920 causes an effective, long lasting and selective suppression of extracellular brain DA levels in vivo. B-HT 920 represents a promising compound for clinical use in pathological conditions known to be ameliorated by a reduction of brain DA activity, such as Huntington's disease, mania and schizophrenia.     

The alpha 2-adrenoceptor antagonists idazoxan and yohimbine can unmask the postsynaptic dopamine agonist effects of B-HT 920

Administration of B-HT 920 alone produced weak stereotypy in a small percentage (4-8%) of rats. In contrast, after combined administration of idazoxane and B-HT 920, stereotyped behaviors (sniffing and licking) were consistently produced in all rats. The appearance of stereotypy after combined treatment with yohimbine and B-HT 920 was inversely related to the dose of yohimbine. These data suggest that the alpha 2-adrenoceptor agonist effects of B-HT 920 can mask it's postsynaptic dopamine agonist effects.     

Rotigotine: a novel dopamine agonist for the transdermal treatment of Parkinson's disease

Rotigotine is a D3/D2/D1 dopamine agonist delivered through a silicone-based transdermal patch that is administered once daily. Pharmacokinetic data in humans have shown that steady-state plasma levels of rotigotine can be reached between 8 and 12 hours, and a stable drug release is maintained throughout the 24-hour patch application. Results of several clinical trials demonstrated that the rotigotine transdermal system is safe, well tolerated and effective monotherapy for patients in the early stages of Parkinson's disease. Rotigotine transdermal application also demonstrated the possibility of decreasing levodopa dosage in order to decrease its toxic effects in advanced Parkinson's disease. In addition, rotigotine has shown efficacy in the treatment of restless legs syndrome. Clinical studies on rotigotine, the first transdermally delivered dopamine agonist, are now in progress, and regulatory approval is expected in the near future.     

Lack of a dopamine autoreceptor selective profile of B-HT 920 in functional in vitro model systems of D2 receptors in rat striatum

Based on the results of in vivo studies, the thiazoloazepine derivative B-HT 920 has been proposed to be a selective agonist of dopamine autoreceptors. In the present study, we investigated the effects of B-HT 920 in two functional in vitro model systems of D2 receptors and compared these effects with the effects of the classical D2 agonist LY 171555. B-HT 920 and LY 171555 concentration dependently inhibited the electrically evoked release of radiolabeled dopamine and acetylcholine and the forskolin-induced stimulation of adenylate cyclase activity in rat striatal tissue slices with comparable efficacies. In striatal tissue slices prepared after 6-hydroxydopamine-induced destruction of dopaminergic terminals, both drugs were still able to inhibit forskolin-stimulated adenylate cyclase activity with a efficacy similar to that in tissue obtained from unlesioned rats. It is concluded that, in vitro, B-HT 920 is an agonist at both presynaptic and 'normosensitive' postsynaptic D2 receptors showing relatively high intrinsic activity.     

Effects of B-HT 920 and B-HT 933 on dopamine and noradrenaline autoreceptors in the rat brain

B-HT 920 at low doses inhibited the accumulation of DOPA following treatment with reserpine and a DOPA decarboxylase inhibitor in the dopamine-, but not in the noradrenaline-predominant regions of the rat brain. B-HT 933 selectively inhibited this DOPA accumulation in the noradrenaline-predominant regions. These effects of B-HT 920 and B-HT 933 were completely antagonized by haloperidol and yohimbine, respectively. The rat motor activity was reduced by B-HT 920 and it was restored following apomorphine. B-HT 933 decreased the motor activity by a yohimbine-sensitive mechanism. The results indicate that B-HT 920 can selectively and potently stimulate the dopamine autoreceptors whereas B-HT 933 can selectively stimulate the noradrenaline autoreceptors.     

Inhibition of K+-stimulated [3H]dopamine and [14C]acetylcholine release by the putative dopamine autoreceptor agonist,B-HT 920

Summary The inhibition of K¹-stimulated [³H]dopamine and [¹⁴C]acetylcholine release from preloaded rat striatal slices was used to examine the presynaptic selectivity of the putative dopamine autoreceptor agonist, B-HT 920. In the micromolar range, B-HT 920 caused a concentration-dependent inhibition of the release of both labeled neurotransmitters as evoked by 20 mM K⁺. The effect of B-HT 920 on both [³H]dopamine and [¹⁴C]acetylcholine release was completely blocked by (+) butaclamol but not by (–) butaclamol. Sulpiride, a selective D₂ antagonist, similarly blocked the inhibitory effect of B-HT 920 on the release of both labeled neurotransmitters indicating both responses were mediated by D₂ receptors. (+) Butaclamol alone elevated stimulated [³H]dopamine release suggesting a significant amount of autoreceptor occupancy by endogenously released dopamine. Experiments with tolazoline and the alpha₂ agonist, B-HT 933, did not suggest any involvement of alpha-adrenoceptor activity in the inhibitory effects of B-HT 920 on the release of either transmitter. Inhibition of release was a selective effect of B-HT 920 as the drug was without effect on the K⁺-stimulated release of [³H]serotonin. The results indicate that in vitro B-HT 920 is active of both pre-and postsynaptic dopamine receptors in contrast to the pattern of effects observed after its in vivo administration.     

Ropinirole: a dopamine agonist for the treatment of Parkinson's disease.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosage and administration, and formulary considerations of ropinirole are reviewed. Ropinirole is a nonergoline dopamine agonist that binds to dopamine D2-receptors; the drug is indicated for use in the symptomatic treatment of early and late Parkinson's disease (PD). Ropinirole is rapidly absorbed after oral administration and undergoes extensive hepatic metabolism to active metabolites. The elimination half-life averages about six hours. Ropinirole has a low potential to interact with other drugs likely to be administered to PD patients. In patients with early PD, initial monotherapy with ropinirole was more effective than placebo or bromocriptine in the absence of selegiline and was as effective as bromocriptine in the presence of selegiline. Ropinirole was as effective as levodopa in patients with earlier stages of PD. In one subset of patients with advanced PD not adequately controlled by levodopa, adjunctive ropinirole was more effective than placebo and bromocriptine. Ropinirole was more effective than bromocriptine in patients previously given high-dose levodopa and was as effective in patients previously given low-dose levodopa or adjunctive dopamine agonist therapy. The most frequent adverse effects are nausea, somnolence, and dizziness; the dosage should be increased gradually to minimize adverse effects. Ropinirole is less expensive than bromocriptine and pergolide and similar in cost to pramipexole. Ropinirole appears to be a useful addition to existing therapeutic approaches to PD and is approved for both early and later stages of the disease.     

Transdermal rotigotine: a new non-ergot dopamine agonist for the treatment of Parkinson's disease

An important conceptual development to avoid the occurrence of motor dyskinesias in Parkinson's disease is continuous dopaminergic stimulation. Studies in animal models and humans suggest that continuous dopaminergic stimulation could be achieved by the infusions of different dopamine agonists or levodopa, and may significantly reduce the risk of dyskinesias associated with treatment strategies utilising pulsatile treatment options. However, so far, these techniques have either necessitated frequent intake of oral therapy or invasive parenteral treatment. The rotigotine transdermal delivery system represents a significant development that allows a constant delivery of a non-ergot dopamine agonist using a once-daily regimen, achieving steady plasma levels. Clinical trials demonstrate the efficacy of rotigotine in early and advanced Parkinson's disease, with important implications for treatment of non-motor symptoms of Parkinson's disease.     

Electroconvulsive treatment and haloperidol: Effects on pre- and postsynaptic dopamine receptors in rat brain

Electroconvulsive treatment (ECT) has a transitory benefical effect on patients with Parkinson's disease (PD). The possibility that this effect is mediated by dopamine (DA) receptors was investigated in the rat brain. Repeated ECT or chronic haloperidol treatment induced supersensitivity of putative autoreceptors in the nigrostrital and mesolimbic DA pathways as reflected by enhanced apomorphine-induced inhibition of DA synthesis. Effect of simultaneous administration of ECT plus haloperidol on DA receptor sensitivity were not additive. Chronic haloperidol treatment induced significant elevations in the density of ³[H]-spiperone striatal binding sites. Concurrent administration of ECT had no effect on the neuroleptic-induced supersensitivity. ECT alone was also without effect on ³[H]-spiperone binding. Thus, ECT-induced increases in the sensitivity of presynaptic autoinhibition of DA release was not reflected by changes in the striatal ³[H]-spiperone binding sites. This suggests that effects of ECT on the DA system are not mediated by dopamine D2 receptors.     

Roxindole,a dopamine autoreceptor agonist,in the treatment of major depression

Roxindole is a potent autoreceptor-“selective” dopamine agonist originally developed for the treatment of schizophrenic syndromes. The drug also inhibits 5-HT uptake and has 5-HT_1A agonistic actions. In this open clinical trial 12 in-patients suffering from a major depressive episode (DSM-III-R) were treated with roxindole for 28 days in a fixed dosage of 15 mg per day. A reduction of at least 50% in HAMD-17 total scores was observed in 8 out of 12 patients after 4 weeks (mean HAMD-17 reduction of 56% in all patients), while 4 patients did not respond to roxindole treatment. Half of the patients showed a complete psychopathological remission (HAMD-17 <8). Roxindole's onset of antidepressant action was remarkably rapid. Seven out of eight responders improved within the first 2 weeks of treatment (at least 50% decrease in HAMD-17 total score), and four patients were nearly asymptomatic within 1 week. Our results indicate that roxindole may possess potent antidepressant properties and that its efficacy should be further evaluated by double-blind controlled studies against reference drugs.     

The differential behavioural effects of benzazepine D1 dopamine agonists with varying efficacies,co-administered with quinpirole in primate and rodent models of Parkinson's disease

The effects of co-administration of quinpirole with benzazepine D₁ dopamine (DA) agonists possessing full/supramaximal (SKF 80723 and SKF 82958), partial (SKF 38393 and SKF 75670) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) were investigated in rodent and primate models of Parkinson's disease (PD). In rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle, co-administration of SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), SKF 75670 (3-CH₃ analogue), SKF 80723 (6-Br analogue), SKF 83959 (6-Cl, 3-CH₃, 3-CH₃ analogue) and SKF 82958 (6-Cl, 3-C₃H₅ analogue) strongly potentiated the contralateral circling induced by quinpirole. In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of quinpirole alone increased locomotor activity and reversed motor deficits. Grooming and oral activity were unaltered. Co-administration of SKF 38393 and SKF 75670 inhibited the quinpirole-induced changes in locomotor activity and motor disability. The combined treatment of SKF 80723 or SKF 82958 with quinpirole had no overall effect on locomotor activity or motor disability. In contrast, SKF 83959 extended the duration of the quinpirole-induced increase in locomotor activity with corresponding decreases in motor disability. Co-administration of high doses of SKF 82958 and more especially SKF 83959 and SKF 80723, with quinpirole induced hyperexcitability and seizures. Oral activity and grooming were unaltered following the co-administration of benzazepine derivatives with quinpirole. The ability of some benzazepine D₁ DA agonists to prolong the antiparkinsonian effects of quinpirole in the MPTP-treated marmoset may indicate a role for certain D₁ DA agonists in the clinical treatment of PD. In general, the behavioural responses to the combined administration of benzazepines with quinpirole in the 6-OHDA lesioned rat and more especially the MPTP-treated marmoset failed to correlate with their ability to stimulate AC. These observations further implicate a behavioural role for D₁ DA receptors not linked to AC.     

Tolcapone: a novel approach to Parkinson's disease.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of tolcapone are reviewed. Tolcapone is the first drug brought to market from the new class of selective and reversible inhibitors of catechol-O-methyltransferase. Tolcapone is indicated for use in the treatment of Parkinson's disease as an adjunct to levodopa-carbidopa therapy in patients who are experiencing fluctuations in symptoms and who are not responding to or are not appropriate candidates for other adjunctive therapies. The absolute bioavailability of tolcapone after an oral dose is about 65%. Clinical trials have demonstrated that tolcapone 50-200 mg three times daily reduces "off" time in patients refractory to levodopa-carbidopa, Unified Parkinson's Disease Rating Scale scores, and the dosage of levodopa-carbidopa required for symptom suppression. The most frequent adverse effects of tolcapone are dyskinesia, nausea, sleep disorders, dystonia, orthostatic hypotension, diarrhea, dizziness, and hallucinations; also, there is a potential for elevation of liver transaminase concentrations in the blood. To date, three deaths from fulminant hepatic failure in association with tolcapone have been reported. Extensive liver function testing is required of all patients before and during therapy. The recommended starting dosage is 100 mg orally three times daily as an adjunct to levodopacarbidopa therapy; a concurrent reduction in the levodopa dosage of about 30% is suggested. Patient response should be monitored carefully during the first three weeks of therapy; treatment should be discontinued in patients failing to respond during this initial use. Tolcapone is of benefit in fluctuating Parkinson's disease, but benefits must be carefully weighed against risks in individual patients.     

The enantiomers of the D-2 dopamine receptor agonist N-0437 discriminate between pre- and postsynaptic dopamine receptors

The (+) and (-) enantiomers of the substituted 2-aminotetralin, N-0437 were evaluated in vivo for their dopaminergic activity, using biochemical as well as behavioural models. In presynaptic models, i.e. antagonism of gamma-butyrolactone-induced dihydroxyphenylalanine elevations and the induction of hypomotility, both enantiomers exhibited a similar high degree of potency. Following postsynaptic stimulation, (-)N-0437 was able to induce stereotypy in rats in a dose-dependent manner. Moreover this compound was able to produce rotation in 6-hydroxy-dopamine-lesioned rats. In contrast, at the doses tested (i.e. 1 and 10 mumol/kg, i.p.), (+)N-0437 displayed virtually no activity at all in either of these postsynaptic models. From in vitro evoked release studies of [3H]acetylcholine it became clear that (-)N-0437 is a postsynaptic dopamine agonist, while (+)N-0437 is a weak antagonist at these receptors. Taken together, the results indicate that (-)N-0437 is very selective for the stimulation of postsynaptic dopamine receptors, while (+)N-0437 stimulates presynaptic dopamine receptors and blocks postsynaptic receptors. These properties make (+)- and (-)N-0437 very promising candidates for psychotherapeutic use.     

Evaluation of the mGluR2/3 agonist LY379268 in rodent models of Parkinson's disease

The aim of the present studies was to examine the ability of a potent, systemically active, selective Group II mGlu receptor (mGluR2/3) agonist, 1R,4R,5S,6R-2-oxa-4-minobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) to provide both functional relief and neuroprotection in rodent models of Parkinson's disease (PD). In functional studies, intracerebroventricular administration of LY379268 (1, 5, 10, 20 nmol/2 microl) produced a dose-dependent increase in locomotor activity in the reserpine (5 mg/kg ip)-treated rat. In contrast, systemic administration of LY379268 (0.1, 1, 10 mg/kg ip) did not reverse reserpine-induced akinesia and failed to effect rotational behaviour 1 month after unilateral lesioning of the nigrostriatal tract by 6-hydroxydopamine (6-OHDA; 4 microg infused into the substantia nigra (SN)). In neuroprotective studies, animals were treated with LY379268 (10 mg/kg/day ip) either for 7 days following 6-OHDA injection into the SN (4 microg) or for 21 days following 6-OHDA injection into the striatum (10 microg) before measurement of tyrosine hydroxylase immunoreactivity in the striatum and/or SN as an index of neuroprotection. LY379268 provided some protection against nigral infusion of 6-OHDA and also some functional improvement and correction of dopamine turnover was observed. The compound also provided significant protection in the striatum and some protection in the SN against striatal infusion of 6-OHDA. These data suggest that activation of Group II mGlu receptors can provide some protection in models of PD, while their role in providing functional improvement is less clear.     

The neuroendocrinological profile of roxindole,a dopamine autoreceptor agonist,in schizophrenic patients

Roxindole is a potent autoreceptor-selective dopamine agonist with additional properties as a serotonin reuptake inhibitor and 5-HT_1A agonist. In order to get more insight into its mode of action in various psychiatric populations, we evaluated the effects of subchronic roxindole treatment on pituitary and adrenal hormone secretion, i.e. release of prolactin, thyroid stimulating hormone (TSH), growth hormone (GH), luteinizing hormone (LH), and cortisol. Fifteen schizophrenic patients with positive and negative symptomatology, respectively, were treated with roxindole for 28 days. Both basal and thyrotropin releasing hormone (TRH) -induced prolactin secretion diminished significantly to 26.4% and 22.8% of baseline levels, respectively, under roxindole. Basal GH secretion was insignificantly elevated by 89%, whereas GH levels increased nearly 3-fold after stimulation by TRH. TSH levels decreased insignificantly to 57.5% of baseline levels, while TRH-induced TSH release was not affected by subchronic roxindole. Roxindole treatment influenced neither LH secretion nor cortisol release. Our results indicate that roxindole's dopaminergic actions might prevail over its serotonergic effects, at least as far as the regulation of anterior pituitary hormone secretion is concerned.     

Imidazole and yohimbine antagonize hypomotility, penile erection, stretching and yawning induced in rats by BHT 920, a selective dopamine autoreceptor agonist

When the azepine derivative BHT 920, a putative agonist at dopamine autoreceptors, was injected i.p. into adult male rats at 100 micrograms/kg, it induced numerous penile erections, stretching and yawning and sedation, all considered typical signs of central DA autoreceptor stimulation, but did not elicit stereotyped behaviour. Imidazole (37.5-150 mg/kg i.p.) and the alpha 2 antagonist yohimbine (0.5-1 mg/kg i.p.) both antagonized the behavioural effects of BHT 920. In the light of the proposed selective action of the drugs used, the possible involvement of specific receptors for the modulation of these forms of behaviour, as well the possible relevance of the data presented, are briefly discussed.     

Dopexamine: a novel agonist at peripheral dopamine receptors and beta 2-adrenoceptors.

Dopexamine is an agonist at peripheral dopamine receptors and at beta 2-adrenoceptors. Dopexamine has approximately one-third the potency of dopamine in stimulating the vascular DA1-receptor in the dog, resulting in a fall in renal vascular resistance of 20% at 2.3 X 10(-8) mol kg-1 (i.a.). Prejunctional DA2-receptors are also stimulated by dopexamine, resulting in a reduction of neurogenic vasoconstriction in the rabbit isolated ear artery (IC50 of 1.15 X 10(-6)M) and of neurogenic tachycardia in the cat (ID50 of 5.4 X 10(-8) mol kg-1, i.v.), with a potency six and four times less respectively than that of dopamine. By contrast, dopexamine is approximately 60 times more potent than dopamine as an agonist at the beta 2-adrenoceptor of the guinea-pig isolated tracheal chain, with an EC50 of 1.5 X 10(-6)M. Both dopexamine and dopamine are weak agonists at the guinea-pig atrial beta 1-adrenoceptor over the concentration range 10(-7) to 10(-4) M, but dopexamine has an intrinsic activity of only 0.16 relative to dopamine. Dopexamine does not stimulate postjunctional alpha 1- or alpha 2-adrenoceptors in the canine isolated saphenous vein, whereas dopamine is an agonist, approximately 120 times less potent than noradrenaline. Unlike dopamine and salbutamol, dopexamine does not cause arrhythmias in the guinea-pig isolated perfused heart at doses of up to 10(-5) mol, which is a thousand times the minimum cardiostimulant dose. The combination of agonist properties at peripheral dopamine receptors and at beta 2-adrenoceptors, with little or no activity at alpha- and beta 1-adrenoceptors gives dopexamine a novel pharmacological profile. This may confer advantages over dopamine in the treatment of acute heart failure.     

Clozapine binds preferentially to cortical D1-like dopamine receptors in the primate brain: a PET study

Rationale The D₁-like dopamine receptors have been suggested to play a role in the pathophysiology and treatment of schizophrenia. Previous positron emission tomography studies have demonstrated that the atypical antipsychotic clozapine occupies D₁-like dopamine receptors in the striatum in clozapine-treated patients. Objectives The aim of the present study was to compare striatal and cortical D₁-like dopamine receptor occupancy by clozapine in the primate brain. Methods Three monkeys were each examined three times at the same day with the radioligand (+)−[¹¹C]NNC 112. The first measurement was at baseline conditions, the second after 1.5 mg/kg and the third after 6 mg/kg clozapine IV. To compare regional levels of nonspecific binding in brain regions, an additional monkey was examined using the inactive enantiomer (−)−[¹¹C]NNC 112. Receptor occupancy was calculated using both the equilibrium–ratio analysis and the simplified reference tissue model. Results After 1.5 mg/kg the D₁-like dopamine receptor occupancy ranged from 30 to 38% in the striatum, whereas the range was 51 to 57% in the frontal cortex. After 6.0 mg/kg the occupancy was 53 to 64% in the striatum and 63 to 83% in the frontal cortex. The differences between striatal and cortical D₁-like receptors occupancy were between 12 and 25%. The study with (−)−[¹¹C]NNC 112 did not show regional differences in nonspecific binding that might explain the regional differences in occupancy. Conclusions The higher D₁-like dopamine receptor occupancy in the frontal cortex may reflect a different distribution of the D₁ and D₅ dopamine receptor subtypes among brain regions and different affinity of clozapine for the two subtypes. The finding supports the suggestion that binding to D₁-like dopamine receptors may explain clozapine’s atypical drug actions.