Selective dopamine D4 receptor antagonists reverse apomorphine-induced blockade of prepulse inhibition

 Recent evidence suggests that the dopamine D₄ receptor may play a role in schizophrenia, and that the atypical properties of the antipsychotic clozapine may be attributable in part to its antagonistic actions at this receptor. In the present study, clozapine and three other compounds having D₄ dopamine receptor antagonist properties were examined for their effectiveness in reducing losses in prepulse inhibition (PPI) induced in rats by the dopamine receptor agonist apomorphine. Previously, activity in the PPI model has been shown to correlate highly with the antipsychotic potency of a number of neuroleptics. As previously reported, clozapine (1–5.6 mg/kg) significantly reduced apomorphine-induced PPI deficits. The three D₄-selective compounds, CP-293,019 (5.6–17.8 mg/kg), U-101,387 (3–30 mg/kg) and L-745,870 (1–10 mg/kg), also significantly blocked the losses in PPI produced by apomorphine. Taken together, these results suggest that dopamine receptor antagonists with selectivity for the D₄ dopamine receptor subtype may be effective in the treatment of schizophrenia, while being less likely to produce dyskinesias associated with D₂ receptor antagonists. Received: 13 May 1997/Final version: 15 July 1997     

Differential effects of olanzapine at dopamine D1 and D2 receptors in dopamine depleted animals

We investigated the degree of striatal dopamine-2 (D₂) receptor occupancy in six schizophrenic patients receiving clinically effective antipsychotic treatment with olanzapine 10–25 mg/day in comparison to patients treated with clozapine 300–600 mg/day (n = 6) or haloperidol 5–20 mg/day (n = 10). ¹²³I Iodobenzamide (IBZM) and single photon emission computerized tomography (SPECT) were used for the visualization of striatal D₂ receptors. For the quantification of striatal D₂ receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to that in untreated healthy controls (n = 8) reported earlier. Olanzapine led to a mean striatal D₂ receptor occupancy rate of 75% (range 63–85). Haloperidol-treated patients showed dose-dependently (Pearson r = 0.64; P < 0.05) a significantly higher (P < 0.05) mean occupancy rate of 84% (range 67–94). During clozapine treatment, the mean D₂ receptor occupancy of 33% (range < 20–49) was significantly lower than with olanzapine (P < 0.005). The higher striatal D₂ receptor occupancy of haloperidol was correlated with the incidence and severity of extrapyramidal motor side-effects (EPS). No clinical relevant EPS occurred during treatment with olanzapine or clozapine. There was no correlation between the degree of striatal D₂ receptor occupancy and clinical improvement. Received: 18 March 1998/Final version: 10 June 1998     

Regulation of ionotropic glutamate receptors following subchronic and chronic treatment with typical and atypical antipsychotics

Quantitative in vitro receptor autoradiography was used to examine changes in three ionotropic glutamate receptor subtypes using ³H-MK801 (NMDA-R antagonist), ³H-CNQX (AMPA-R antagonist) and ³H-kainic acid (kainate-R agonist) following subchronic (28 days) and chronic (8 months) treatment of rats with a typical antipsychotic, haloperidol (1.5 mg/kg per day), atypical antipsychotic, clozapine (25 mg/kg per day), the dopamine D₂/D₃ receptor antagonist, raclopride (10 mg/kg per day), and the dopamine D1 (D₁/D₅) receptor antagonist SCH23390 (0.5 mg/kg per day). Subchronic and chronic drug treatments did not significantly alter ³H-CNQX or ³H-kainate binding in any of brain regions examined. Subchronic SCH23390 treatment elevated ³H-MK801 binding in the hippocampal formation with significant increases in the CA₁ and dentate gyrus, suggesting a specific role for dopamine D1 receptors in the regulation of hippocampal NMDA receptor function. Subchronic, but not chronic, haloperidol and clozapine treatment significantly reduced ³H-MK801 binding in the medial prefrontal cortex. This suggests that typical and atypical antipsychotics may exert some of their clinical effects by affecting NMDA receptors in the medial prefrontal cortex. Both subchronic and chronic clozapine treatment decreased ³H-MK801 binding in the caudate putamen. The minimal extrapyramidal side effects produced by clozapine may result, in part, from the reduction in NMDA receptor binding in the caudate putamen. Received: 29 February 1996 /Final version: 15 July 1996     

IBZM SPECT imaging of striatal dopamine-2 receptors in psychotic patients treated with the novel antipsychotic substance quetiapine in comparison to clozapine and haloperidol

We investigated the striatal dopamine-2 (D₂) receptor occupancy caused by different antipsychotic substances in 18 psychotic patients (16 with schizophrenic and two with schizoaffective disorder according to DSM-IV) with single photon emission computed tomography (SPECT) using ¹²³I-iodobenzamide (IBZM) as tracer substance. Four patients were treated with the novel antipsychotic compound quetiapine (300–700 mg/day), six with clozapine (300–600 mg/ day) and eight with haloperidol (10–20 mg/day). They were compared with eight healthy controls. Measurement of S/F ratios and consecutive calculation of D₂ receptor occupancy revealed a significantly lower striatal D₂ occupancy rate with quetiapine and clozapine in comparison to haloperidol. In correspondence with the low striatal D₂ receptor occupancy rates and again in contrast to the haloperidol treatment group, there were no extrapyramidal motor side-effects (EPS) in the quetiapine and clozapine treatment groups. Therefore, the reported data support the position that quetiapine can be considered to be an atypical antipsychotic substance due to its relatively weak striatal D₂ receptor blocking property and therefore its low propensity to induce EPS. Received: 12 August 1996/Final version: 11 May 1997     

Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia: associations with dopamine and serotonin receptor and transporter polymorphisms

Background Little is known about the influence of polymorphisms of the dopamine and serotonin system on the risk for extrapyramidal symptoms (EPS) during treatment with antipsychotic drugs. Methods Of 119 subjects with schizophrenia treated with antipsychotics, 63 had current or previous EPS (acute dystonia, parkinsonism, tardive dyskinesia), and 56 had no such symptoms. All subjects were genotyped for a total of eight dopamine and serotonin receptor and transporter polymorphisms: the Taq1A polymorphism of the dopamine D₂ receptor (DRD2) gene, the Msc1 polymorphism of the dopamine D₃ receptor (DRD3) gene, the variable number of tandem repeat (VNTR) polymorphism of the dopamine transporter (DAT1) gene, four polymorphisms (102T/C, His452Tyr, 516 C/T, and Thr25Asn) of the serotonin 5-HT_2A receptor (5HTR2A) gene, and the 5HTTLPR polymorphism of the serotonin transporter (5HTT) gene. Results The frequency of the A1 allele of the DRD2 Taq1A polymorphism was significantly higher in the EPS group than in the control group [16% vs. 7%, P = 0.040; odds ratio (OR) 2.4; 95% confidence interval (CI) 1.1–5.7]. Also, the 9 repeat allele of the DAT1 VNTR polymorphism was significantly more common in the EPS group (42% vs. 28%, P = 0.030; OR 1.9; 95% CI 1.1–3.3). Being a carrier of both DRD2 Taq1A A1 and DAT1 VNTR 9 repeat alleles was also significantly associated with the occurrence of EPS (19% vs. 6%, P = 0.040; OR 4.0; 95% CI 1.05–15.2) No significant differences in allele frequencies were found for the other polymorphisms. Conclusion Presence of the Taq1A A1 allele of the DRD2 and the 9 repeat allele of the DAT1 VNTR polymorphisms might be risk factors for EPS caused by antipsychotic drugs.     

Time course of central nervous dopamine-D2 and 5-HT2 receptor blockade and plasma drug concentrations after discontinuation of quetiapine (Seroquel®) in patients with schizophrenia

Quetiapine (Seroquel) is a novel antipsychotic with an atypical profile in animal models and a relatively short plasma half-life of 2.5–5 h. In the present study, we used PET to compare the time course of blockade of dopamine D₂ and serotonin 5HT₂ receptors of quetiapine using C¹¹-raclopride and C¹¹-N-methyl-spiperone as ligands, parallel to monitoring plasma drug concentrations. It was an open study in 11 schizophrenic men using a fixed dose of 450 mg quetiapine. Eight men completed the 29 days treatment, followed by four PET scans performed over a 26-h period after withdrawal of the compound. Quetiapine was shown to bind to dopamine D₂ receptors in striatum and 2 h (t_max) after the last dose, 44% receptor occupancy was calculated. After 26 h it had dropped to the same level as was found in untreated healthy volunteers. Serotonin 5HT₂ receptor blockade in the frontal cortex was 72% after 2 h, which declined to 50% after 26 h. The terminal plasma half-life of quetiapine was 5.3 h. Clinically, our eight patients had good antipsychotic effect without any extrapyramidal side-effects. Our data shows that quetiapine has a relatively low affinity for dopamine D₂ receptors, with an occupancy half-life (10 h), which was about twice as long as that for plasma. A more prolonged blockade of the serotonin 5HT₂ receptors was found in the frontal cortex, with receptor occupancy half-life of 27 h. Compared to clozapine, as demonstrated in other studies, quetiapine has much the same ratio of D₂/5HT₂ occupancy. This could suggest that the combination of D₂/5HT₂ receptor blockade contributes to the antipsychotic effect and a low incidence of EPS seen with quetiapine in comparative phase three trials. Our results also confirm the clinical data that quetiapine can be administered twice daily. Received: 13 December 1996/Final version: 13 June 1997     

Comparative characterisation of the discriminative stimulus properties of clozapine and other antipsychotics in rats

 The discriminative stimulus properties of the prototypical atypical neuroleptic clozapine (5 mg/kg, IP) were characterised in rats using a fixed ratio assay. Clozapine induced full dose-related generalization in the absence of response suppression. Amphetamine and pentylenetetrazol failed to generalise at doses known to be discriminable, showing a degree of specificity for the clozapine cue. The typical neuroleptics haloperidol and loxapine induced minimal (20%) generalization at doses with marked behavioural effects; thus clozapine discrimination dissociates clozapine from typical neuroleptics. Atypical neuroleptics which are not clozapine congeners produced weak partial generalization when tested up to the highest doses that could be studied. The maximal levels of generalization induced by these agents were: amisulpiride 28%, risperidone 40% and sertindole 50%. Clozapine congeners typically caused more generalization, the novel pyridobenzoxapine JL13 inducing 70% maximal generalization. Most generalization (83%) was seen with the clozapine congener seroquel, although in contrast to clozapine, it only generalised at doses with marked effects on responding, so that no drug mimicked clozapine fully. Surprisingly, the clozapine congener olanzapine only induced a maximal level of 38% generalization. This apparently anomalous finding is attributed to an inability to test high doses of the drug due to its rate-suppressant actions. The clozapine cue can be used to rank atypical neuroleptics in terms of their similarity to clozapine in vivo. The clozapine cue is probably a compound cue, since only agents showing “polyvalent” receptor pharmacology induced substantial generalization. Received: 19 May 1997 / Final version:25 July 1997     

The relationship between D2 receptor occupancy and plasma levels on low dose oral haloperidol: a PET study

The purpose of this study was to determine the relationship between dopamine D₂ receptor occupancy and plasma haloperidol. Twelve patients treated with 1–5 mg/day of haloperidol had their D₂ occupancy measured using [¹¹C]-raclopride and positron emission tomography and haloperidol plasma levels measured using gas chromatograph mass spectrophotometer. The patients exhibited haloperidol plasma levels ranging from 0.5 to 5.8 ng/ml and D₂ occupancy from 53 to 88%. The D₂ occupancy was related to the plasma level as a saturating rectangular hyperbola relationship (r ² = 0.84) and it showed that, on average, 50% D₂ occupancy was achieved with 0.51 ng/ml and 80% D₂ occupancy with 2.0 ng/ml. Our findings demonstrate that 2–5 mg/day of haloperidol, which usually leads to plasma levels of 1–2 ng/ml, would be expected to induce 60–80% dopamine D₂ receptor occupancy. If, as has been claimed, 70% D₂ occupancy is adequate for typical neuroleptic response, then the conventional use of >10 mg/day may have been too high, since 70% occupancy can be achieved in most patients by 2–5 mg/day. On the other hand, if as others have suggested, 8–12 ng/ml of haloperidol is the correct therapeutic window for plasma levels, then the required therapeutic D₂ occupancy is closer to 90%, not 70%. The implications of the D₂ occupancy findings for the optimal dosing of neuroleptics are discussed. Received: 6 August 1996/Final version: 22 November 1996     

D4 dopamine receptor binding affinity does not distinguish between typical and atypical antipsychotic drugs

The affinities of 13 atypical and 12 typical antipsychotic drugs for the cloned rat D₄ dopamine receptor and the D₄/D₂ ratios were examined. Of the atypical antipsychotic drugs tested, only clozapine, risperidone, olanzapine, zotepine and tiospirone had affinities less than 20 nM. In fact, many atypical antipsychotic drugs had relatively low affinities for the cloned rat D₄ receptor, with Ki values greater than 100 nM (Seroquel, fluperlapine, tenilapine, FG5803 and melperone). Additionally, several typical antipsychotic drugs had high affinities for the cloned rat D₄ receptor, with K_is less than 20 nM (loxapine, chlorpromazine, fluphenazine, mesoridazine, thioridazine and trifluoroperazine). The ratios of D₂/D₄ affinities did not differentiate between these two types of antipsychotic drugs. Thus, D₄ dopamine receptor affinity, used as a single measure, does not distinguish between the group of typical and atypical antipsychotic drugs analyzed.     

The effects of dopamine D3/D2 receptor agonists on intracranial self stimulation in the rat

The effects of the dopamine D₃/D₂ receptor agonists quinpirole, quinelorane and (±)7-OH-DPAT [(±) 7-hydroxy-2(N,N-di-n-propylamino) tetralin] on intracranial self-stimulation (ICSS) were investigated. Rats implanted with bipolar electrodes into the lateral hypothalamus were trained to lever press on a continuous reinforcement schedule for positively reinforcing trains of electrical stimulation. Three measures of responding were calculated; the frequency at which responding was 50% of the maximum (M50), the asymptotic response rate and the total area under the curve (AUC) for each frequency sweep. Quinpirole (2.2–66.0 μg/kg SC) significantly increased M50 and reduced both asymptote and AUC. Quinelorane (0.25–79.0 μg/kg SC) had no significant effect on M50 values but significantly reduced both asymptote and AUC. (±)7-OH-DPAT (2.5–74.0 μg/kg) did not significantly affect any of the measures. The data show that low doses of quinpirole and quinelorane, but not (±)7–OH–DPAT, inhibit ICSS maintained by electrodes in the lateral hypothalamus. Either dopamine D₂ or dopamine D₃ receptor stimulation may play a role in mediating ICSS inhibition, but studies with more selective receptor agonists and antagonists are required to define the role of each receptor. Received: 18 August 1997/Final version: 17 April 1998     

Effect of chronic treatment with typical and atypical neuroleptics on the expression of dopamine D2 and D3 receptors in rat brain

The effect of chronic treatment (21 days) with typical and atypical neuroleptics on the expression of striatal and limbic D₂ and D₃ dopamine receptors was investigated in rat brain by in situ hybridization and receptor autoradiography. Haloperidol and sulpiride increased D₂ receptor expression in striatal and limbic areas. In contrast, clozapine had no effect on D₂ receptor expression. Haloperidol decreased D₃ receptor expression in limbic areas, with the exception of the islands of Calleja where an increase occurred. Sulpiride and clozapine increased D₃ receptor expression in limbic and striatal regions but decreased D₃ receptor expression in the islands of Calleja. This study demonstrates that chronic treatment with typical and atypical neuroleptics produces different regionally specific changes in limbic and striatal D₂ and D₃ receptor expression. The alterations in dopamine receptor expression were different for each drug, but a distinction between the effects of atypical and typical neuroleptics could be made. Comparison of mRNA levels in animals which were not withdrawn from drug treatment with those that were withdrawn, demonstrated that some changes in receptor expression occurred during drug treatment, whilst others only manifested when drug treatment had ceased. The different regulation of dopamine D₂ and D₃ receptor expression by typical and atypical neuroleptics may have relevance to the ability of these drugs to cause extrapyramidal side-effects. Received: 26 February 1996 /Final version: 28 July 1996     

Activation of midline thalamic nuclei by antipsychotic drugs

The thalamus has been proposed as a site which may be involved in the production of the syndrome of schizophrenia and the response of schizophrenic symptoms to treatment. These studies test whether, consistent with this hypothesis, the activation of thalamic nuclei is a shared property of neuroleptic antipsychotic drugs. Rats were given single doses of the typical high and low potency neuroleptics haloperidol (1 mg/kg) and chlorpromazine (20 mg/kg), the atypical neuroleptics thiroridazine (20 mg/kg) and clozapine (20 mg/kg), the specific dopamine antagonist raclopride (3 mg/kg), the mixed dopamine/serotonin antagonist risperidone (3 mg/kg) or drug-free vehicle. Increased expression of Fos-like protein was utilized as a marker of cellular activation. All drugs tested, including typical and atypical antipsychotic agents, led to similar effects on the midline thalamic paraventricular, centromedian and rhomboid nuclei and the nucleus reuniens. These results suggest that midline thalamic nuclei may participate in neural circuits mediating some of the shared effects of antipsychotic drugs. Received: 9 January 1997/Final verion: 13 June 1997     

The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D1, D2, D3, 5HT2A and muscarinic receptors

The atypical antipsychotic olanzapine was compared to other atypical as well as typical antipsychotic agents for in vivo occupancy of D₁, D₂, D₃, 5HT₂, and muscarinic receptors in rat brain. Blockade of D₂ receptors was determined by measuring the levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). To assess the interaction with phosphoinositide (PI)-coupled 5HT_2A and muscarinic receptors in vivo, we used a novel radiometric technique to measure in vivo PI hydrolysis. The antagonism of olanzapine and other antipsychotic agents on 5HT_2A and muscarinic receptors was determined by in vivo blockade of PI hydrolysis, stimulated by the 5HT₂ agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) or the muscarinic agonist pilocarpine. Olanzapine inhibited 5HT₂, D₂, and D₃ in vivo binding with high potency (ID₅₀ = 0.15, 0.6 and 1.2 mg/kg, IP, respectively), while inhibiting D₁ and muscarinic in vivo binding with much less potency (ID₅₀ > 10 mg/kg, IP). The binding of olanzapine to D₂ receptors in neostriatum was well correlated with the increase of DOPAC (ED₂₀₀ = 0.8 mg/kg, IP) in vivo, indicating dopamine D₂ antagonism. In vivo PI hydrolysis was increased by DOI in frontal cortex and by pilocarpine in hippocampus up to 2- and 7-fold above the basal level, respectively. The agonist-induced increases in PI hydrolysis were fully blocked by the 5HT_2A antagonist MDL100907 and the muscarinic antagonist scopolamine, indicating the mediation by 5HT_2A receptors in frontal cortex and PI-coupled muscarinic receptors (m1, m3, and m5) in hippocampus, respectively. Olanzapine was about 8-fold more potent in vivo in blocking DOI-induced stimulation of PI hydrolysis (ID₅₀ = 0.1 mg/kg, IP) than pilocarpine-induced stimulation of PI hydrolysis (ID₅₀ = 0.8 mg/kg, IP). In conclusion, olanzapine is more potent in blocking the 5HT_2A receptor than D₁, D₂, D₃ and muscarinic receptors in vivo, consistent with its favorable clinical profiles. In addition, the novel in vivo PI hydrolysis assay proved to be a useful and reliable in vivo method to assess the functional efficacy of compounds that interact with the 5HT₂ and muscarinic receptors. Received: 10 February 1998/Final version: 22 April 1998     

Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine — a123 IBZM single photon emission tomography (SPET) study

We have studied striatal D₂ dopamine binding in schizophrenic patients treated with the novel atypical antipsychotic drug, olanzapine.¹²³I iodobenzamide (IBZM) single photon emission tomography (SPET) was used to estimate striatal dopamine D₂ receptor binding in vivo. Patients were recruited from a prospective, double blind controlled trial of olanzapine versus haloperidol treatment. In vivo striatal D₂ binding data from olanzapine treated patients (n=6) were compared with previously reported data from typical antipsychotic responsive (n=10); clozapine (n=10); and risperidone (n=6) treated patient groups. Mean % Brief Psychiatric Rating Scale score (BPRS) improvement following olanzapine treatment was 49% (SD 44). The hypothesis that clinical improvement in olanzapine treated patients would be associated with higher mean striatal D₂ binding of¹²³I IBZM (reflecting lower levels of D₂ occupancy) than typical antipsychotic (1.25±0.05) or risperidone (1.24±0.04) treatment was confirmed. Olanzapine treated patients had similar levels of striatal D₂ binding in vivo (1.41±0.06) as those treated with clozapine (1.49±0.04). This preliminary evidence suggests olanzapine is another atypical antipsychotic drug in which therapeutic response is not associated with a high degree of striatal D₂ receptor occupancy in vivo.     

Effects of dopamine antagonists in a two-way active avoidance procedure in rats: interactions with 8-OH-DPAT,ritanserin, and prazosin

Using a conditioned avoidance procedure in rats, the present study examined the ability of 8-OH-DPAT, ritanserin, and prazosin to alter the effects of the dopamine antagonists, raclopride and haloperidol, on avoidance- and on escape responding. The 5-HT_1A agonist 8-OH-DPAT (0.16 mg/kg) significantly enhanced the inhibitory effects of both raclopride and haloperidol on the conditioned avoidance response and produced a small enhancement of the effects of haloperidol on escape failures. The α₁-adrenoceptor antagonist prazosin (0.63 mg/kg) significantly enhanced the effects of raclopride on the conditioned avoidance response, but enhanced the effects of only a single dose of haloperidol; prazosin did not alter the effects of either dopamine antagonist on escape failures. The 5-HT₂ antagonist ritanserin (0.16 mg/kg) failed significantly to alter the effects of the dopamine antagonists examined here. These findings suggest that blockade of 5-HT₂ receptors may not enhance the antipsychotic efficacy of D₂-like antagonists. Further, they confirm previous findings with respect to interactions between 5-HT_1A agonists and neuroleptics, and support the hypothesis that combined 5-HT_1A agonist/D₂-like antagonist properties may be of clinical importance. Received: 19 April 1996/Final version: 1 July 1996     

Effect of atypical antipsychotic drugs on 5-HT2 receptors in the rat orbito-frontal cortex: an in vivo electrophysiological study

Low doses of the atypical antipsychotic drug risperidone are effective in patients with obsessive compulsive disorder (OCD) not responding to serotonin (5-HT) reuptake inhibitors, although higher doses have been reported to induce OCD symptoms in psychotic patients. Since such atypical antipsychotics exert, in addition to dopamine, 5-HT₂ receptor antagonistic properties, it was deemed essential to investigate the electrophysiological effect of these agents on 5-HT₂ receptors in the rat orbito-frontal cortex (OFc), a brain region implicated in OCD. Microiontophoretic application of the GABA_A receptor antagonist bicuculline had no effect on the suppressant effect of neuronal activity in the OFc induced by microiontophoretic application of the preferential 5-HT_2A and 5-HT_2C receptor agonists (+)-1-(4-iodo-2, 5-dimethoxyphenyl)-2-aminopropane (DOI) and m-chlorophenyl-piperazine (mCPP), respectively, but it antagonized the effect of GABA on the same neurons. These results indicate a lack of involvement of GABA interneurons in the suppressant effect of DOI and mCPP. While the 5-HT₂ receptor antagonist ritanserin (2 mg/kg, IV) attenuated the inhibitory effect of DOI and mCPP in the medial prefrontal cortex (mPFc), the inhibition was unaffected in the OFc. In the mPFc, the effect of DOI and mCPP was blocked by both clozapine (1.0 and 10 mg/kg, IV) and risperidone (0.1 and 1.0 mg/kg, IV). In the OFc, only the suppressant effect of mCPP was attenuated by both doses of clozapine but only by the high dose of risperidone. These results suggest that the 5-HT₂ response in the OFc is more akin to the 5-HT_2C subtype and that the deleterious effect sometimes observed with high doses of risperidone and clozapine may be due to a decrease in 5-HT neurotransmission. In contrast, the beneficial effect of low doses of risperidone may be due, in part, to the antagonism of dopamine receptors. Received: 22 June 1998/Final version: 8 October 1998     

Previous treatment as a confounding variable in studies with novel antipsychotics: two cases of high dopamine-2 receptor occupancy with quetiapine

Previous treatment can be a confounding variable in studies with novel antipsychotics. Quetiapine is a new antipsychotic substance with a low affinity for dopamine-2 (D₂) receptors. Preliminary SPECT and PET investigations revealed only a low striatal D₂ receptor occupancy rate. However, we present two cases of high striatal D2 receptor occupancy (51% and 71%) measured with ¹²³I IBZM SPECT during quetiapine monotherapy. Both patients had previously received continuous treatment with typical neuroleptics. We present evidence that the previous antipsychotic therapy influenced D₂ receptor binding of ¹²³I IBZM during quetiapine treatment weeks after cessation of typical neuroleptics. This might be of importance for the design of clinical trials and brain imaging studies in the future. Received: 14 April 1997 /Final version: 14 May 1997     

Clozapine, SCH 23390 and α-flupenthixol but not haloperidol attenuate acute phencyclidine-induced disruption of conditional discrimination performance

Rationale Forebrain dopamine (DA) manipulation has recently been shown to selectively disrupt a conditional discrimination task whose design parameters approximate tasks repeatedly shown to be impaired in schizophrenia. Objective To investigate the reversal potential of the D₁/D₂ receptor antagonist α-flupenthixol, the selective D₁ antagonist SCH 23390, the typical antipsychotic haloperidol and the atypical antipsychotic clozapine on acute phencyclidine (PCP)-induced disruption of a conditional discrimination task dependent on the ability to use task-setting cues that inform goal-directed performance. Materials and methods Rats learned a conditional discrimination task where reinforcement was contingent on an appropriate lever press during a specific auditory stimulus. Results PCP disrupted task performance at 1.5 mg/kg, attenuated correct lever pressing at 2.5 mg/kg and abolished overall responding at 5 mg/kg (experiment 1). Pavlovian-instrumental transfer task results (experiment 2) showed that 1.5 and 2.5 mg/kg PCP had no disruptive effects on basic sensory, motor or motivational processes; however, such deficits were evident in 5-mg/kg-treated animals. PCP (1.5 mg/kg) disruption of conditional discrimination was attenuated by acute pretreatment with clozapine, SCH 23390 and α-flupenthixol; however, pretreatment with haloperidol did not attenuate task disruption. Conclusion The predictive validity of the conditional discrimination model is enhanced as the selective task disruption by the preeminent psychotomimetic PCP is reversed by clozapine (known to ameliorate cognitive deficits in schizophrenia) and the role of DA D₁ receptors as mediators of tasks that require conditional relationships is discussed.     

Clozapine pretreatment modifies haloperidol-elicited forebrain Fos induction: a regionally-specific double dissociation

Rationale:Acute administration of typical antipsychotic drugs, such as haloperidol, results in the induction of the immediate-early gene c-fos in the dorsolateral striatum. In contrast, the atypical antipsychotic drug clozapine, which lacks significant extrapyramidal side effect liability, does not induce Fos protein in the dorsal striatum. Several studies have attempted to define the mechanisms through which typical antipsychotic drugs induce striatal Fos, often by pretreating animals with specific receptor antagonists. Despite the broad receptor profile of clozapine, there has been no study of the effect of clozapine pretreatment on haloperidol-elicited striatal Fos expression. Methods: We examined the effects of clozapine pretreatment of rats on haloperidol-elicited forebrain Fos expression, using both immunoblot and immunohistochemical methods. The effects of clozapine pretreatment were assessed in the dorsal striatum and in the different nucleus accumbens compartments, the septum, and the prefrontal cortex. Results: Clozapine pretreatment markedly decreased haloperidol-elicited striatal Fos induction and blocked haloperidol-induced catalepsy. Clozapine also attenuated haloperidol-elicited Fos expression in the nucleus accumbens, but in the prefrontal cortex and ventrolateral septum the effects of haloperidol and clozapine were additive. Conclusions: An emerging body of literature suggests a high incidence of rapid relapse in schizophrenic patients when clozapine treatment is discontinued. This psychosis is relatively resistant to haloperidol and other neuroleptics, even in patients who had previously responded well to neuroleptics. The present data may shed light on the central sites associated with and perhaps model certain aspects of the relapse associated with clozapine discontinuation. Received: 3 August 1998/Final version: 5 November 1998     

Role of D1 and D2 dopamine receptors in the discriminative stimulus properties of the atypical antipsychotic clozapine in rats

The purpose of the present study was to assess the role of dopamine D₁ and D₂ receptors in the discriminative stimulus properties of the atypical antipsychotic clozapine (CLZ). Two groups of rats were trained to discriminate either a moderate dose of clozapine (5.0 mg/kg) from vehicle or a high dose of clozapine (10.0 mg/kg) from vehicle in a two‐lever drug discrimination paradigm. Generalization testing with clozapine yielded an ED₅₀ of 0.9 mg/kg (95% confidence limits = 0.5–2.0 mg/kg) for the 5.0 CLZ group and 2.0 mg/kg (95% confidence limits = 1.4–2.8 mg/kg) for the 10.0 CLZ group. Substitution testing with the D₁ antagonist SCH 23390 and the D₂ dopamine antagonist haloperidol failed to produce clozapine‐appropriate responding for either of the clozapine training doses. The antipsychotic drug thioridazine (which binds to a number of neurotransmitters in addition to dopamine) produced partial substitution (64.5% drug lever responding) in the 5.0 CLZ group at the 5.0 mg/kg dose. These results suggest that antagonism of D₁ and D₂ dopamine receptors alone is not sufficient to produce clozapine‐appropriate responding, even with the higher training dose of 10.0 mg/kg. Drug Dev. Res. 46:139–147, 1999. © 1999 Wiley‐Liss, Inc.