The neurotensin-1 receptor agonist PD149163 inhibits conditioned avoidance responding without producing catalepsy in rats

Agonists for neurotensin (NT)-1 receptors have produced antipsychotic-like effects in many animals, including reversal of prepulse inhibition deficits and psychostimulant-induced increases in spontaneous activity. The present study sought to provide a basic assessment of the putative antipsychotic effects of PD149163 in rats using a two way conditioned avoidance response task, which is highly validated for screening antipsychotic drugs, and an inclined grid assessment, which is used to assess extrapyramidal side effect liability. PD149163 (0.0625-8.0 mg/kg) significantly suppressed conditioned avoidance responding (CAR) following administration of a 1.0 or 8.0 mg/kg dose. PD149163 failed to significantly increase catalepsy scores. The typical antipsychotic drug haloperidol (0.01-1.0 mg/kg) significantly suppressed CAR at a 0.1, 0.3, and 1.0 mg/kg dose, and a significant increase in catalepsy scores was found at the 1.0 mg/kg dose. The atypical antipsychotic drug clozapine (2.5-10.0 mg/kg) also produced a significant inhibition of CAR, which occurred following administration of a 10.0 mg/kg dose. Clozapine failed to significantly increase catalepsy scores. Finally, d-amphetamine (1.0 mg/kg), serving as a negative control, failed to suppress CAR or increase catalepsy scores. These data further suggest that PD149163 may have atypical antipsychotic-like properties.     

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     

Pharmacokinetics of sertindole and its metabolite dehydrosertindole in rats and characterization of their comparative pharmacodynamics based on in vivo D2 receptor occupancy and behavioural conditioned avoidance response

The objectives of this study were to characterize the pharmacokinetics of sertindole and its active metabolite dehydrosertindole in rats and to evaluate the central modulatory and behavioural pharmacodynamics including a competitive interaction model between the compounds. Following oral administration of sertindole or dehydrosertindole, the plasma concentration–time courses were determined in conjunction with striatal dopamine D₂ receptor binding. In addition, the behavioural effects were recorded in the conditioned avoidance response (CAR) paradigm. A one‐compartment model with Michaelis‐Menten elimination best described the pharmacokinetics of sertindole. Formation of dehydrosertindole was incorporated into the pharmacokinetic model and exhibited first‐order elimination. PK/PD modelling after administration of dehydrosertindole resulted in potency estimates of 165 and 424 ng/ml for D₂‐occupancy (Kd) and CAR measurements (EC₅₀), respectively. The pharmacokinetics of the parent–metabolite system was integrated into a competitive pharmacodynamic E_max model in order to quantitate the potency of sertindole with the pharmacodynamic parameters of the metabolite taken into account. Based on this approach, effect compartment concentrations of sertindole needed to attain 50% occupancy and half‐maximal effect in the CAR paradigm were 133 and 338 ng/ml, respectively. The corresponding potency‐estimates obtained after conventional modelling of the sertindole data without accounting for the metabolite amounted to 102 and 345 ng/ml. Based on competitive PK/PD analysis of the parent–metabolite interaction, the relative contribution of dehydrosertindole to the overall pharmacological effect after sertindole administration in rats appeared to be of minor significance. This could mainly be ascribed to the relatively low extent of bioconversion of sertindole into dehydrosertindole in this species. Copyright © 2009 John Wiley & Sons, Ltd.     

Drug-induced suppression of conditioned hyperthermic and conditioned avoidance behavior response in rats

The influence of different drugs on conditioned avoidance behavior and hyperthermia induced by the conditioning situation in rats has been investigated.A specific blocking of conditioned avoidance responses was observed with neuroleptic drugs, but, except for chlorpromazine and thioridazine, they did not affect the conditioned temperature rise.Benzodiazepine derivatives and meprobamate consistently suppressed the hyperthermia at doses which did not impair conditioned avoidance behavior.Among other psychoactive drugs only imipramine (10 mg/kg i.p.) and desipramine (5 mg/kg i.p.) have shown an inhibitory effect on hyperthermia. The conditioned behavioral response was not influenced.Phentolamine at higher doses slightly suppressed the temperature rise. Morphine and aspirin were inactive regarding both parameters tested.     

Effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) after repeated administration on a conditioned avoidance response (CAR) in the rat

8-OH-DPAT, a selective 5-HT_1A agonist, has variously been found to impair, have no effect on or enhance the conditioned avoidance response (CAR). Procedural differences may account for the difference in results. In the first experiment in the present study rats were trained in the two-way active avoidance procedure to a criterion of 65% avoidance. Separate groups of rats were treated with 0.01, 0.1 or 1.0 mg/kg 8-OH-DPAT SC once per day for 14 days. The rats were tested in the CAR each day 5 min after treatment, using a 10 s light and tone conditioned stimulus and five 0.2 mA/0.5 s electric shocks. On the first day the doses of 0.1 and 1.0 mg/kg impaired avoidance, but by the end of training these two doses increased avoidance. This change in effect was accompanied by a 15-fold increase in the number of trials in which the subject crossed during a 10 s period of the ITI, which in turn led to a significant impairment in the discrimination ratio. The results of this experiment show that with repeated treatment 8-OH-DPAT changes from being antipsychotic like to being stimulant-like. The latter effect produces an improvement in avoidance, probably due to a non-specific increase in activity. In the second experiment, the rats were divided into groups based upon the undrugged performance. The avoidance-enhancing effect of 8-OH-DPAT was greater in magnitude in a group of poor performers, but was qualitatively similar in good performers. In the second stage of the experiment, gradual withdrawal from the drug was compared with sudden withdrawal. In the gradual withdrawal group, a reduction in the dose from 0.085 mg/kg to 0.01 mg/kg resulted in a gradual disappearance of the enhanced activity. There was an almost linear relationship between performance and the log dose of the drug, suggesting that the increase in activity seen after repeated administration of 8-OH-DPAT is directly related to the acute level of drug administered. This effect was evident in both good and poor performers. On the basis of these results it is suggested that many, but not all, antidepressant-like effects of 8-OH-DPAT may result from changes in activity.     

The relationship between dopamine D2 receptor occupancy and the vacuous chewing movement syndrome in rats

Abstract Rationale. A dose–response relationship between dopamine D₂ occupancy and acute extrapyramidal symptoms (EPS) has been well established. However, the link with the induction of tardive dyskinesia (TD) is less clear. Objectives. To ascertain the nature and extent of D₂ receptor occupancy effects on haloperidol-induced vacuous chewing movements (VCMs) in a rat model of TD. Methods. Groups of eight rats received haloperidol decanoate injections corresponding to daily doses of 0, 0.08, 0.17, 0.33, or 1 mg/kg for 10–12 weeks. VCMs were measured on a weekly basis and D₂ occupancy levels were measured in vivo using [³H]-raclopride at the end of the experiment. Results. Final VCM scores were significantly different between haloperidol doses (P=0.001). Moderate but significant correlations were found between dose and average VCM scores (r=0.69, P<0.001) and between D₂ occupancy and average VCM scores (r=0.65, P<0.001). The rats that developed the VCM syndrome (≥8 VCMs) had higher occupancies than rats that did not. Of the rats with an occupancy above 70%, 63% developed VCMs, compared with 37% of the rats with D₂ occupancy below that. Conclusions. These results indicate that chronic haloperidol induces VCMs in a dose-dependent manner, with doses leading to high D₂ occupancy increasing the likelihood of emergence of the VCM syndrome. While a certain level of D₂ occupancy may be necessary for inducing VCMs, it is not sufficient in and of itself to induce the VCM syndrome. Electronic Publication     

The effects of fenfluramine and fluoxetine on the acquisition of a conditioned avoidance response in rats

This study tested a behavior-suppressing punishment system and how its activity may be altered by agents known to interrupt or enhance serotonergic (5-HT) transmission. Holtzman male albino rats were tested for shuttle box avoidance acquisition and intertrial responding either 1 or 8 h following daily injections of fenfluramine (FEN) or fluoxetine (FXT). When the drug-test interval was 1 h, a time when both drugs are presumably potentiating 5-HT activity, avoidance acquisition and intertrial responding were impaired. When testing occurred 8 h after drug treatment, a time when 5-HT levels are unaltered by FXT and are maximally reduced by FEN, these drugs had no effect on avoidance acquisition, but FEN produced an increase in intertrial responses whereas FXT did not. These results support the proposal of an inhibitory 5-HT system. Furthermore, these data demonstrate that FEN is capable of exerting a biphasic action on intertrial responding and suggest that the time interval between drug administration and behavioural testing is a crucial variable when investigating FEN.     

Dose determination of haloperidol, risperidone and olanzapine using an in vivo dopamine D2-receptor occupancy method in the rat

The purpose of the present study was to determine antipsychotic doses that achieve 80% striatal dopamine D₂-receptor occupancy for haloperidol, risperidone and olanzapine in rats. Wistar rats were treated with normal saline vehicle (controls), haloperidol (0.25 and 0.5 mg/kg/day), risperidone (3, 5 and 6 mg/kg/day) and olanzapine (5 and 10 mg/kg/day) for 7 days via osmotic minipumps. Striatal and cerebellar tissue were collected and in vivo dopamine D₂-receptor occupancies were determined using ³H-raclopride. The doses required to achieve dopamine D₂-receptor occupancy of 80% in 11- and 24-week old rats were: haloperidol 0.25 mg/kg/day, risperidone 5 mg/kg/day and olanzapine 10 mg/kg/day.     

MAO inhibition and the effects of centrally administered LSD,serotonin, and 5-methoxytryptamine on the conditioned avoidance response in rats

Pretreatment with the MAO-inhibitors iproniazid, clorgyline, or deprenyl abolishes the effects of LSD on the conditioned avoidance response (CAR) in rats. The effects of serotonin (5-HT) and 5-methoxytryptamine (5-MT) are greatly potentiated by these substances. Brain levels of LSD are not affected by MAO inhibition whereas levels of 5-HT and 5-MT are significantly elevated. It is postulated that the decreased behavioral response to LSD is the result of MAO inhibitor-induced changes whereas the increased response of 5-HT and 5-MT results from increased brain levels of these compounds.     

Radiosynthesis of a 2‐substituted 4,5‐dihydro‐1H‐[2‐11C] imidazole: the I2 imidazoline receptor ligand [11C] benazoline

Benazoline (2‐naphthalen‐2‐yl‐4,5‐dihydro‐1H‐imidazole) is a selective high‐affinity ligand for the imidazoline I₂ receptor. This compound was labelled with carbon‐11 (T_1/2=20.4 min) at the number two carbon atom of its 2‐imidazoline ring. Cyclotron‐produced [¹¹C]carbon dioxide reacted with 2‐naphthylmagnesium bromide to give 2‐[carboxyl‐¹¹C]naphthoic acid in 60% radiochemical yield. The latter was heated with a mixture of ethylenediamine and its dihydrochloride at 300°C to give [¹¹C]benazoline in 16% overall yield, relative to [¹¹C]carbon dioxide and with a specific radioactivity of 54 GBq/μmol, decay corrected for end of irradiation. The procedure requires about 45 min from end of cyclotron irradiation. This method should be extendable to other imidazolines. Copyright © 2003 John Wiley & Sons, Ltd.     

In vivo occupancy of dopamine D2 receptors by antipsychotic drugs and novel compounds in the mouse striatum and olfactory tubercles

Interaction with dopamine D₂-like receptors plays a major role in the therapeutic effects of antipsychotic drugs. We examined in vivo dopamine D₂ receptor occupancy of various established and potential antipsychotics in mouse striatum and olfactory tubercles 1 h after administration of the compound, using [³H]nemonapride as a ligand. All the compounds reduced in vivo binding of [³H]nemonapride in the striatum. When administered systemically, conventional antipsychotics, D₂ antagonists, nemonapride (ID₅₀: 0.034 mg/kg), eticlopride (0.047), haloperidol (0.11) and raclopride (0.11) potently inhibited [³H]nemonapride binding. The ‘atypical’ antipsychotics, risperidone (0.18), ziprasidone (0.38), aripiprazole (1.6), olanzapine (0.99), and clozapine (11.1) were less potent for occupying D₂-like receptors. New compounds, displaying marked agonism at 5-HT_1A receptors in addition to D₂ receptor affinity, exhibited varying D₂ receptor occupancy: bifeprunox (0.25), SLV313 (0.78), SSR181507 (1.6) and sarizotan (6.7). ID₅₀ values for inhibition of [³H]nemonapride binding in the striatum correlated with those in the olfactory tubercles (r=0.95, P<0.0001). These values also correlated with previously-reported in vitro affinity of the compounds at rat D₂ receptors (r=0.85, P=0.0001) and with inhibition of apomorphine-induced climbing in mice (r=0.79 P=0.0005). In contrast, there was no significant correlation between ID₅₀ values herein and previously-reported ED₅₀ values for catalepsy in mice. These data indicate that: (1) there is no difference in D₂ receptor occupancy in limbic versus striatal regions between most classical and atypical or potential antipsychotics; and (2) high occupancy of D₂ receptors can be dissociated from catalepsy, if the drugs also activate 5-HT_1A receptors. Taken together, these data support the strategy of simultaneously targeting D₂ receptor blockade and 5-HT_1A receptor activation for new antipsychotics.     

Effects of (-)3-PPP on acquisition and retention of a conditioned avoidance response in the rat

The administration of (-)3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) was found to partially, but significantly, suppress the acquisition (4–8 mg/kg IP) and performance (8–16 mg/kg IP) of a conditioned avoidance response (CAR) in male Sprague-Dawley rats. All statistically significant effects were observed within 2 h of injection. Furthermore, using a situation in which the CAR was dependent on a visual successive discrimination, it was shown that discriminative performance was unaffected, and that (-)3-PPP (12.5–25 mg/kg IP) but not (+)3-PPP, suppressed the CAR. When (-)3-PPP (6.25 mg/kg IP) was combined with haloperidol (0.1–0.4 mg/kg IP), additive effects on the CAR performance were observed. Considering these effects, and the doses of (-)3-PPP required to suppress the CAR performance, it is concluded that the effects obtained in the present experiments are primarily due to a blockade of postsynaptic DA receptors.     

D1/D2 dopamine and N-methyl-d-aspartate (NMDA) receptor participation in experimental catalepsy in rats

Mixed D₁/D₂ dopamine (DA) antagonists, perphenazine (5 mg/kg) and haloperidol (2 mg/kg) induced catalepsy in rats. SCH 23390 (1 mg/kg), a D₁ DA antagonist, also produced catalepsy. Co-administration of perphenazine (0.5 mg/kg) and SCH 23390 (0.1 mg/kg), at low doses, produced a marked increase in cataleptic response. B-HT 920, a D₂ agonist, reversed the cataleptogenic effects of perphenazine, haloperidol and SCH 23390. SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy. SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy. Combined administration of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) enhanced the protective effect of B-HT 920 in SCH 23390-treated animals but not in animals treated with haloperidol or perphenazine. MK-801 (0.025–0.5 mg/kg), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reduced the cataleptogenic effects of perphenazine, haloperidol as well as SCH 23390. The anticataleptic action of MK-801 was enhanced by scopolamine (0.1 mg/kg) but not by bromocriptine (1 mg/kg) or clonidine (0.05 mg/kg) in perphenazine-treated rats. Unlike B-HT 920 (0.1 mg/kg), SKF 38393 (5 mg/kg) potentiated the anticataleptic effect of MK-801 (0.01 mg/kg) against SCH 23390-induced catalepsy. The above data suggests D₁/D₂ interdependence in catalepsy and a modulatory role of D₁ and D₂ DA receptor stimulation on the anticataleptic effect of MK-801.     

A neurocomputational account of catalepsy sensitization induced by D2 receptor blockade in rats: context dependency,extinction, and renewal

Rationale  Repeated haloperidol treatment in rodents results in a day-to-day intensification of catalepsy (i.e., sensitization). Prior experiments suggest that this sensitization is context-dependent and resistant to extinction training. Objectives  The aim of this study was to provide a neurobiological mechanistic explanation for these findings. Materials and methods  We use a neurocomputational model of the basal ganglia and simulate two alternative models based on the reward prediction error and novelty hypotheses of dopamine function. We also conducted a behavioral rat experiment to adjudicate between these models. Twenty male Sprague–Dawley rats were challenged with 0.25 mg/kg haloperidol across multiple days and were subsequently tested in either a familiar or novel context. Results  Simulation results show that catalepsy sensitization, and its context dependency, can be explained by “NoGo” learning via simulated D2 receptor antagonism in striatopallidal neurons, leading to increasingly slowed response latencies. The model further exhibits a non-extinguishable component of catalepsy sensitization due to latent NoGo representations that are prevented from being expressed, and therefore from being unlearned, during extinction. In the rat experiment, context dependency effects were not dependent on the novelty of the context, ruling out the novelty model’s account of context dependency. Conclusions  Simulations lend insight into potential complex mechanisms leading to context-dependent catalepsy sensitization, extinction, and renewal. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

Effects of second-generation histamine H1 receptor antagonists on the active avoidance response in rats

1. The aim of the present study was to establish a new schedule of active avoidance response in rats to estimate the central effects of second-generation histamine H1 receptor antagonists. 2. With the new schedule, a rat was placed into a dark room. A sliding door was opened after a delay of 5 s and, unless the animal moved into the lit room, an electric shock was delivered for 3 s. With the conventional schedule, the sliding door was opened immediately after the rat was placed into the dark room. 3. Ketotifen, at a dose of 50 mg/kg, showed no significant effect on the retrieval of active avoidance response with the conventional schedule. However, with the new schedule, the drug caused significant inhibition of retrieval of the response, even at a dose of 10 mg/kg. 4. Epinastine showed no significant effect on retrieval of the active avoidance response, even at a dose of 50 mg/kg with the new schedule. 5. Cetirizine, at a dose of 50 mg/kg, caused a significant effect, indicating that cetirizine, at this dose, markedly inhibits memory retrieval. 6. Both olopatadine and loratadine had potent effects; at doses of 20 and 50 mg/kg, respectively, these agents showed significant inhibitory effects on retrieval of the response. 7. In conclusion, we have developed a new schedule of active avoidance response that can be used to estimate the central effects of second-generation histamine H1 receptor antagonists.     

Autoradiographic localisation of D3-dopamine receptors in the human brain using the selective D3-dopamine receptor agonist (+)-[3H]PD 128907

The selective D₃-dopamine receptor agonist 4aR,10bR-(+)-trans-3,4,4a,10b-tetrahydro-4-[N-propyl-2,3-³H]-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol ([³H]PD 128907) was used to visualise D₃-dopamine receptors in whole hemisphere cryosections from post-mortem human brain. [³H]PD 128907 has an 18- to 40-fold selectivity for D₃- over D₂-dopamine receptors as compared to a 7- to 24-fold selectivity of the more commonly used ligand [³H]7-OH-DPAT. [³H]PD 128907 accumulated markedly in the nucleus accumbens and in the ventral parts of caudate nucleus and putamen, with a slightly heterogeneous (patch-matrix like) distribution. The binding in the lateral parts of caudate nucleus and putamen was much less dense. No binding was obtained in any other regions. A very high proportion of [³H]PD 128907 was specifically bound, as judged from the low binding remaining in the presence of the D₂/D₃-dopamine receptor antagonist raclopride. This gives the ligand a potential for the detection of low density D₃-dopamine receptors in the human brain. The binding obtained with [³H]PD 128907 was qualitatively similar to that using [³H]7-OH-DPAT in the presence of GTP. However, [³H]7-OH-DPAT labelled, in contrast to [³H]PD 128907, also D₃-dopamine receptors in neocortex. The new compound [³H]PD 128907 appears to be a suitable radioligand for autoradiographic examination of the D₃-dopamine receptor localisation in the human brain, and should also be useful for pharmacological studies of this receptor subtype. Received: 20 November 1995/Final version: 2 May 1996     

Catalepsy produced by striatal microinjections of the D1 dopamine receptor antagonist SCH 23390 in neonatal rats.

Systemic injection of the D₁ dopamine receptor antagonist SCH 23390 produces catalepsy that is of lesser magnitude in neonatal than in adult rats. The present experiments were conducted in order to determine if SCH 23390 would produce catalepsy in neonatal rats following intrastriatal injection and if the ontogenetic pattern of catalepsy induced by intrastriatal SCH 23390 would be similar to the pattern observed with systemic injections. Rat pups (11 or 28 days of age) were microinjected unilaterally with SCH 23390 (0.2, 1, 5 or 10 μg) and tested for catalepsy using the forepow-on-horizontal-bar test. The results demonstrated that robust catalepsy occurred at both ages following intrastriatal injection and that catalepsy induced by 5 μg SCH 23390 was of lesser magnitude in 11-day-olds than in 28-day-olds. A separate study assessed the distribution of [³H]SCH 23390 (5 μg) following intrastriatal injection in 28-day-olds. Results of the distribution study indicated that [³H]SCH 23390 was localized primarily within the striatum. Taken together, these results suggest that the striatal mechanisms for catalepsy produced by D₁ receptor blockade are present, but not fully mature, in preweanling rat pups.     

Synthesis of a delta opioid agonist in [2H6], [2H4], [11C], and [14C] labeled forms

In support of a program to develop a treatment for depression, four labeled forms of a delta opioid agonist were prepared. The [²H₄] labeled form was prepared using a relatively straightforward conversion of [²H₄]bromoethanol to [²H₄]N‐methyl‐2‐hydroxyethylamine. The key step in the synthesis of the [²H₆] labeled form involved the Pd‐catalyzed exchange in D₂O of 8‐quinolin‐8‐ol to give [²H₆] 8‐quinolin‐8‐ol. The C‐14 labeled form was synthesized in one step using [¹⁴C]carbonylation, and the C‐11 labeled form was prepared in two steps from ¹¹CH₃I. Copyright © 2011 John Wiley & Sons, Ltd.     

The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats

Rationale Cannabinoid type 1 (CB₁) receptor antagonists are reportedly effective in reducing food intake both preclinically and clinically. This may be due in part to their effects on monoamine release in the brain. The level of central CB₁ receptor occupancy underlying these neurobiological effects is unclear. Objectives We explored the relationship between in vivo CB₁ receptor occupancy in the frontal cortex and changes in both monoamine release in the medial prefrontal cortex (mPFC) and feeding behavior in rats in response to two orally administered CB₁ receptor antagonists presently in clinical trials, SR141716A (rimonabant) and SLV319. Methods CB₁ receptor occupancy was measured using [³H] SR141716A, and these occupancies were related to potencies to mediate increases in dopamine (DA) and norepinephrine (NE) release measured with microdialysis and decreases in consumption of a highly palatable diet (HP). Results High receptor occupancy levels (>65%) were required to detect increases in monoamine release that were achieved with 3 and 10 mg/kg of SR141716A and 10 mg/kg of SLV319 for DA and 10 mg/kg of SR141716A for NE. Decreases in HP consumption were seen at occupancies higher than 65% for SR141716A that were achieved with 3 and 10 mg/kg. In contrast, decreases in HP consumption were seen at relatively low CB₁ receptor occupancies (11%) for SLV319. Conclusions The occupancy method described here is an effective tool for interrelating central CB₁ receptor occupancy with neurobiological actions of CB₁ receptor antagonists and for furthering our understanding of the role of CB₁ receptors in central nervous system physiology and pathology.     

Predicting the dopamine D2 receptor occupancy of ropinirole in rats using positron emission tomography and pharmacokinetic–pharmacodynamic modeling

1. The purpose of this study was to measure dopamine D_2/3 receptor occupancy (RO) as a marker of the clinical efficacy of ropinirole in rats via positron emission tomography (PET) using ¹⁸F-fallypride as the radiotracer and to explore the relationship between dopamine RO and the plasma concentration of ropinirole via pharmacokinetic–pharmacodynamic modeling.

2. Plasma was collected from 16 rats treated with one of four doses of ropinirole. For the time-dependent study, the data of 16 rats in the 15?mg/kg dose group at four time points were averaged, and another 24 rats were divided into three dose groups (5?mg/kg, 30?mg/kg and 60?mg/kg) for the dose-dependent study; the animals were assessed via ¹⁸F-fallypride PET scans. The correlation between dopamine RO and the ropinirole plasma concentration was investigated, and a pharmacokinetic–pharmacodynamic (PK–PD) model was established with WinNonlin 6.3 software. Both the plasma concentration and the binding potential changed in a time- and dose-dependent manner, and the plasma concentration that induces 50% RO (EC₅₀) as calculated by the PK–PD model was 1391?ng/mL.

3. ¹⁸F-fallypride appeared to be a suitable radiotracer for ropinirole imaging, and its binding to the dopamine D₂ receptor has time- and concentration-dependent characteristics. A theory-based PK–PD model was developed to describe the relationship between the plasma ropinirole concentration and RO, providing a methodological foundation for noninvasive and in vivo clinical evaluations of ropinirole treatment.