Biomedical subjects

M L Wadenberg

Publications and source records attributed to M L Wadenberg.

At least 19 recordsLinked to original sources

PubMed2001

Dopamine D(2) receptor occupancy is a common mechanism underlying animal models of antipsychotics and their clinical effects.

Conditioned avoidance response (CAR) behavior and catalepsy (CAT) are the standard preclinical tests used to predict antipsychotic activity and motor side-effect liability, respectively. Recent data in patients show that striatal dopamine D(2) occupancy predicts antipsychotic response (at 65% D(2) occupancy) and motor side-effects (at greater than 80%). To relate preclinical and clinical findings, this study examined the relationship between striatal D(2) occupancy, CAT and CAR in rats receiving typical and atypical antipsychotics. CAT was observed in animals receiving haloperidol, risperidone and olanzapine, but only at doses that produced a D(2) receptor occupancy > or =85%. The D(2) occupancy of quetiapine did not cross the 85% threshold (up to 100 mg/kg) and it did not show catalepsy. All drugs were effective in the CAR model at a lower level of D(2) occupancy than was required for catalepsy. We suggest that the CAR and CAT models may have displayed high predictive accuracy because they share with the clinical condition a common underlying mechanism: dopamine D(2) occupancy. The implications of this finding for understanding antipsychotic action as well as the continued use of these models in drug discovery is discussed.

Animals↗

PubMed2000

Dopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats.

RATIONALE: Human positron emission tomography (PET) shows that striatal dopamine D2 receptor occupancy predicts extrapyramidal side effects (EPS). Patients showed a clinical response with > or = 65% D2 occupancy, but EPS only when D2 occupancy >78%. Catalepsy and the selective suppression of conditioned avoidance response (CAR) are often used as animal models to predict EPS and antipsychotic effect, respectively. However, the quantitative relationship between striatal D2 occupancy and effects in these models is not known. OBJECTIVES: The present study intended to investigate the relationship between animal catalepsy, suppression of CAR, and D2 receptor blockade using a method of evaluating D2 receptor occupancy similar in principle to that used in patients. METHODS: In vivo binding of [11C]-raclopride and [3H]-raclopride was compared. Doses of cold raclopride were chosen to provide a D2 occupancy from 0 to 95%. The relationship between dose/time course of catalepsy and D2 occupancy was assessed. Effects of raclopride on conditioned avoidance response (CAR) behavior were tested. RESULTS: In vivo binding of [11C]-raclopride compared to [3H]-raclopride was virtually the same. Using [3H]-raclopride, cold raclopride (0.01-0.2 mg/kg) produced 16-77% D2 receptor occupancy and no catalepsy. Raclopride (0.5-2 mg/kg) produced 83-95% D2 occupancy and significant catalepsy. Raclopride (2 mg/kg) produced on average 95% and 87% D2 receptor occupancy 1 and 2 h after administration, respectively, and maximum catalepsy. D2 occupancy at 4, 8 and 24 h was on average 58%, 46%, and 4%, respectively. No catalepsy was observed. Raclopride (0.2 mg/kg), estimated at 70-75% D2 occupancy, produced suppression of CAR. CONCLUSIONS: In vivo D2 occupancy measurements in rats using [3H]-raclopride is analogous to using [11C]-raclopride in human PET scanning. Suppression of CAR occurred at a D2 occupancy of around 70-75%, and catalepsy at D2 occupancy >80%. Results closely resembled human studies where 65-70% D2 occupancy was required for antipsychotic response, while > or = 80% D2 occupancy led to EPS. Brain mechanisms involved in mediation of catalepsy in rats and EPS in humans might indeed be similar. Both suppression of CAR in rats and antipsychotic response in humans might share an underlying construct, i.e. the need for around 70% D2 receptor blockade.

Animals↗

PubMed2000

Enhancement of antipsychotic-like effects by combined treatment with the alpha1-adrenoceptor antagonist prazosin and the dopamine D2 receptor antagonist raclopride in rats.

Blockade of central alpha1-adrenoceptors has been implicated as a possible factor contributing to the atypical antipsychotic profile of clozapine. Thus, in the present study we examined the effects of concomitant alpha1-adrenoceptor and dopamine D2 receptor blockade on conditioned avoidance response performance, as an index of antipsychotic-like activity, and on the induction of catalepsy, as a test for extrapyramidal side effect liability, in rats. It was found that pretreatment with the alpha1-adrenoceptor antagonist prazosin (0.2mg kg(-1) s.c.) caused an enhancement of a suppression of conditioned avoidance response in the presence of the dopamine D2 receptor antagonist raclopride (0.05-0.20 mg kg(-1) s.c.). The effect was most prominent at a subthreshold dose of raclopride (0.05 mg kg(-1)). At these doses, prazosin or raclopride by themselves, or in combination, did not produce catalepsy. In addition, pretreatment with prazosin (0.2mgkg(-1) s.c.) did not alter the catalepsy produced by a higher dose of raclopride (1.0 mg kg(-1) s.c.). It is suggested that, in the presence of low dopamine D2 receptor occupancy, additional alpha1-adrenoceptor blockade might improve antipsychotic efficacy, and thereby improve the therapeutic window with regard to parkinsonism.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2000

Are animal studies of antipsychotics appropriately dosed? Lessons from the bedside to the bench.

Animal models are crucial for understanding the mechanism of action of antipsychotics. However, the dose of an antipsychotic in animal studies is often arbitrarily chosen, with haloperidol 1 mg/kg being a rather common standard. Recent clinical positron emission tomography (PET) studies in patients show all antipsychotics to block dopamine D2 receptors, and most are effective at doses that lead to 60% to 80% D2 occupancy. When occupancy exceeds 80%, the incidence of side effects rises sharply. To use this "bedside" information to inform the "bench," we measured D2 occupancy in rats using a method similar in principle to the [11C]-raclopride PET method in humans. We found that: 1) as in humans, haloperidol is effective in animal models of antipsychotic action when D2 occupancy > 70% and leads to effects in models of extrapyramidal side effects when D2 occupancy is > 80%; 2) very low doses, 0.06 mg/kg/sc, cause acute D2 occupancy of 75%; 3) and even doses that acutely saturate D2 receptors give little D2 occupancy after 24 hours due to the very short half-life of haloperidol in rats (2.5 hours versus 24 hours in humans). We conclude that most previous animal studies of antipsychotics have used doses giving rise to inappropriately high acute D2 occupancy and inappropriately low D2 occupancy between doses. We exemplify how this dosing confounder could lead to inappropriate conclusions. Data from the bedside translated to the bench--using D2 occupancy as a mediating variable--will lead to more valid animal models.

Animals↗

PubMed1999

Clozapine pre-treatment enhances raclopride catalepsy.

The clinical replacement of clozapine by another antipsychotic sometimes causes extrapyramidal signs, including dystonia, to appear suddenly. The present study was done, therefore, to test whether clozapine pre-treatment of rats could affect raclopride-induced catalepsy. Clozapine, at 5 mg/kg, given 2 h before a catalepsy-threshold dose of 0.1 mg/kg raclopride, markedly enhanced raclopride-induced catalepsy in the rats. The results are compatible with earlier in vitro data where pre-exposure of human cloned dopamine D2 receptors to clozapine resulted in an increased potency of raclopride in inhibiting the binding of [3H]clozapine to the receptors. The mechanism of clozapine potentiation of raclopride action may contribute to the clinically observed post-clozapine dystonia.

Animals↗

PubMed1999

Effects of local application of 5-hydroxytryptamine into the dorsal or median raphe nuclei on haloperidol-induced catalepsy in the rat.

The effects of local application of the endogenous brain neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) into the dorsal (DR) or median (MR) raphe nuclei on haloperidol-induced catalepsy (CAT) in rats were studied. Local application of 5-HT (40 microg, -10 min) into the DR or MR, respectively, produced a significant reversal of haloperidol-induced CAT. Lower doses (5 or 25 microg) of 5-HT were ineffective. Compared to previous studies using the selective 5-HT1A receptor agonist 8-OH-DPAT, the non-selective endogenous serotonin receptor agonist 5-HT was significantly less potent in this paradigm. Furthermore, the observed anticataleptic effect of 5-HT was seen following injections into both DR or MR nuclei. The reversal of CAT by local application of 5-HT (40 microg) into the DR was significant also at 70 min after 5-HT administration, with the same tendency for 5-HT injections into the MR. At this time interval, other serotonergic behavioral symptoms like head twitches and wet-dog shakes also emerged. The early reversal of CAT by local 5-HT administration into the MR is in all probability mediated via stimulation of 5-HT1A autoreceptors on raphe serotonergic cell bodies. The reversal of CAT following 5-HT injections into the DR might alternatively be mediated via functional mechanisms other than stimulation of 5-HT1A autoreceptors. The anticataleptic effects observed at the later observation time could be due to stimulation of postsynaptic 5-HT2 receptors following diffusion of 5-HT into 5-HT2 receptor rich areas of the brain.

Animals↗

PubMed1999

The conditioned avoidance response test re-evaluated: is it a sensitive test for the detection of potentially atypical antipsychotics?

The present review discusses the history and paradigm of the conditioned avoidance response (CAR) in rats for the detection of potential antipsychotic activity of drugs. In addition, the role of dopamine (DA) D2, serotonin (5-HT)2A/2C, alpha1, 5-HT1A, DA D4, muscarinic and glutamate receptors in the suppression of CAR induced by various classes of drugs is evaluated. Finally, data investigating brain sites of action for the mediation of CAR behavior is discussed. It is concluded that the CAR test, originally found to be sensitive for the detection of antipsychotic drugs with high affinity as antagonists for brain dopamine receptors, is also sensitive for the detection of potentially antipsychotic compounds acting primarily via neurotransmitter receptors other than the DA D2 receptor. Furthermore, the review confirms the importance of the nucleus accumbens(shell) in the mediation of effects on CAR produced by traditional, as well as atypical antipsychotic drugs.

Animals↗

PubMed1998

Enhancement of antipsychoticlike properties of raclopride in rats using the selective serotonin2A receptor antagonist MDL 100,907.

BACKGROUND: Selective suppression of conditioned avoidance response (CAR) is a standard animal screening test for predicting antipsychotic effect. Ability to suppress CAR is presumed to be due to antagonism at dopamine receptors, a property shared by all known antipsychotics. METHODS: Using CAR behavior, in a conventional shuttle-box paradigm, as an index for antipsychotic efficacy, the effects of the selective serotonin2A receptor antagonist MDL 100,907 alone, and in combination with the dopamine D2 receptor antagonist raclopride, were studied in adult male Sprague-Dawley rats. Nonparametric procedures were employed for statistical evaluation. RESULTS: MDL 100,907 (0.1-1.5 mg/kg, SC) alone did not suppress CAR in a manner predictive of antipsychotic activity; however, in the presence of an ED50 (0.14 mg/kg, SC) dose of raclopride, MDL 100,907 enhanced and prolonged the suppression of CAR. In the presence of a subthreshold (0.05 mg/kg, SC) dose of raclopride, MDL 100,907 induced a suppression of CAR. CONCLUSIONS: The results suggest that treatment with a selective serotonin2A receptor antagonist alone may not produce a robust antipsychotic effect; however, a selective serotonin2A receptor antagonist in the presence of a minimal dopamine D2 receptor blocking action could potentially be an adjunctive therapy resulting in improved antipsychotic efficacy and fewer extrapyramidal symptoms.

Animals↗

PubMed1997

A novel computer-controlled conditioned avoidance apparatus for rats.

Described and evaluated here is a newly designed apparatus for the assessment of conditioned avoidance response (CAR) performance in rats. The system is computer-assisted using a design and system control development package based on the virtual instrument concept (LabView). The program, which allows for significant flexibility, greatly facilitated and simplified the process of timing and data acquisition. The apparatus was found effective and appropriately designed for CAR performance training, as well as for a reliable assessment of the effects of antipsychotic and potentially antipsychotic compounds on CAR in rats. The design presents a new, effective, and inexpensive option for laboratories involved in animal behavioral research.

Amphetamines↗

PubMed1996

Serotonergic mechanisms in neuroleptic-induced catalepsy in the rat.

The present paper reviews a series of experiments aimed at elucidating the interaction between specific dopamine (DA) and 5-hydroxytryptamine (5-HT) receptors in the mediation of extrapyramidal motor functions in the rat. There is strong evidence to suggest that (1) the catalepsy produced by dopamine D1 or D2 receptor antagonists can be completely antagonized by the administration of 5-HT1A receptor agonists acting at 5-HT autoreceptors in the median raphe nucleus; (2) the catalepsy produced by a dopamine D2 receptor antagonist can be completely antagonized by treatment with a 5-HT2A/C receptor agonist; and (3) the catalepsy produced by blockade of either dopamine D1 or D2 receptors is not affected by the administration of a 5-HT2A/C receptor antagonist. The emerging picture of DA/5-HT receptor interactions in the mediation of extrapyramidal motor functions is of great interest in relation to present efforts to develop new atypical neuroleptics with affinity for brain 5-HT receptor subtypes, and also for the observations that new serotonin selective re-uptake inhibiting antidepressants can produce parkinson-like symptoms in vulnerable individuals.

Animals↗

PubMed1996

Enhancement of antipsychotic-like properties of the dopamine D2 receptor antagonist, raclopride, by the additional treatment with the 5-HT2 receptor blocking agent, ritanserin, in the rat.

The effects of 5-HT2 receptor blockade on the ability of a dopamine (DA) D2 receptor antagonist to produce suppression of conditioned avoidance response (CAR) and to produce catalepsy in rats were examined. It was found that ritanserin (2 mg kg-1 s.c.) enhanced the raclopride (0.1 mg kg-1 s.c.)-induced suppression of CAR without affecting raclopride-induced catalepsy at either maximal (4 mg kg-1 s.c.) or submaximal (0.2 mg kg-1 s.c.) doses. Considering the CAR performance as an index of mesocorticolimbic dopaminergic functions, it is concluded that 5-HT2 receptor blockade confers a limbic profile on the DA D2 receptor antagonist.

Animals↗

PubMed1995

Antagonism by the 5-HT2A/C receptor agonist DOI of raclopride-induced catalepsy in the rat.

It has been shown that the administration of 5-hydroxytryptamine (5-HT)1A receptor agonists will antagonize the catalepsy induced by dopamine D1 or D2 receptor blocking agents. In the present study, administration of the 5-HT2A/C receptor agonist, 1-(2,5-dimethoxy-4-iodo)-2-aminopropane (DOI) (1 mg kg-1 s.c.), counteracted the catalepsy produced by the dopamine D2 receptor antagonist, raclopride (16 mg kg-1 s.c.), but not by the dopamine D1 receptor antagonist (R)-(+)-8-chloro-2,3,4,5-tetra-hydro-3-methyl-5-phenyl-1H-3-benzazepine (SCH 23390) (0.2 mg kg-1 s.c.). The effects of DOI on raclopride-induced catalepsy were fully antagonized by pretreatment with the 5-HT2A/C receptor antagonist, ritanserin (2 mg kg-1 s.c.). The 5-HT precursor, 5-hydroxytryptophan (5-HTP) (6.25-25.0 mg kg-1 i.p.), in combination with the peripheral 5-HTP decarboxylase inhibitor, benserazide (25 mg kg-1 i.p.), and the selective serotonin reuptake inhibitor, zimeldine (10 mg kg-1 s.c.), enhanced the catalepsy produced by a low dose of raclopride (4 mg kg-1 s.c.). It is concluded that stimulation of (postsynaptic) 5-HT2 receptors results in antagonism of the catalepsy induced by treatment with a dopamine D2, but not a D1, receptor antagonist. The fact that 5-HTP, in the presence of benserazide and zimeldine, enhanced raclopride-induced catalepsy suggests the possibility of postsynaptic 5-HT receptors acting in opposition to the 5-HT1 and 5-HT2 receptors, as regards extrapyramidal motor functions in the rat.

5-Hydroxytryptophan↗

PubMed1995

Stimulation of median, but not dorsal, raphe 5-HT1A autoreceptors by the local application of 8-OH-DPAT reverses raclopride-induced catalepsy in the rat.

The local application of 8-OH-DPAT (0.5 or 2.5 micrograms/rat, 10 min) into the median, but not the dorsal, raphe nucleus resulted in a reversal of the catalepsy induced by the DA D2 receptor blocking agent raclopride (16 mg kg-1 s.c., 60 min). The local application of 8-OH-DPAT into serotonergic projection areas of the forebrain (dorso-lateral neostriatum, accumbens core; 0.5 or 2.0 micrograms/side) did not affect raclopride-induced catalepsy. Thus, the 5-HT1A autoreceptor in the median raphe nucleus is an important site of action for the reversal of DA D2 receptor antagonist-induced catalepsy by systemic administration of 5-HT1A receptor agonists, in the rat.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1994

Evidence for specific interactions between 5-HT1A and dopamine D2 receptor mechanisms in the mediation of extrapyramidal motor functions in the rat.

Administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1 mg kg-1 SC) completely antagonised the catalepsy produced by the dopamine (DA) D2 receptor antagonist raclopride (16 mg kg-1 SC). This effect by 8-OH-DPAT was in turn completely antagonised by treatment with the new 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin [(S)-UH-301] (3.5 mg kg-1 SC), but not by the mixed 5-HT1 receptor/beta-adrenoceptor antagonist (-)pindolol (2.0 mg kg-1 SC). The failure by (-)pindolol to antagonise the effects of 8-OH-DPAT on raclopride-induced catalepsy could be due to its beta-receptor-blocking properties, since by themselves both (-)pindolol and the selective beta-adrenoceptor antagonist betaxolol (4 mg kg-1 SC) at least partially antagonised the raclopride-induced catalepsy. The present results provide further support for specific interactions between 5-HT1A and DA D2 receptor mechanisms in the mediation of extrapyramidal motor functions in the rat.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1993

Potency mismatch for behavioral and biochemical effects by dopamine receptor antagonists: implications for the mechanism of action of clozapine.

Clozapine (3.8-60.0 mumol kg-1) did not produce any alterations in DOPA accumulation (following inhibition of cerebral aromatic L-amino acid decarboxylase) in the prefrontal cortex or in three regions of the neostriatum, i.e. the ventral, the dorso-lateral and the posterior regions, in the rat. In contrast, clozapine produced a reduction in the 5-HTP accumulation in all these brain areas, except for the prefrontal cortex. Raclopride (0.08-20.0 mumol kg-1) produced a marked increase in DOPA accumulation in all four brain regions and an increase in 5-HTP accumulation in the dorso-lateral neostriatum (2.5-20.0 mumol kg-1), but not in the other forebrain regions. Treatment with SCH-23390 (0.4-1.6 mumol kg-1) resulted in increased DOPA accumulation in the ventral and posterior parts of the neostriatum. No other changes in the DOPA or 5-HTP accumulation were seen with SCH-23390. Considering the doses of these three compounds needed for suppression of conditioned avoidance behavior and for the induction of cataleptic rigidity, it is concluded that raclopride produces an increased DA synthesis at much lower doses than those needed for behavioral effects. In contrast, the behavioral effects of SCH-23390 or clozapine precedes effects on brain DA synthesis on the dose-effect curve. In fact, the only biochemical effect of clozapine, which was observed in low, yet behaviorally active doses, was a decrease in forebrain 5-HTP accumulation. In conclusion, the present results demonstrate a mismatch, in different directions for raclopride and SCH-23390, as regards to the doses needed to produce effects on brain dopamine synthesis and on behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Supraspinal mediation of dopamine-serotonin interactions in extrapyramidal motor functions in the rat.

The effects of intracerebroventricularly (i.c.v.) or intrathecally (i.t.) administrated 8-OH-DPAT on catalepsy, induced by the specific DA D2 antagonist raclopride (16 mg kg-1 s.c.), were studied in rats. It was found that 8-OH-DPAT (0.5 or 2.0 micrograms kg-1) injected by the i.c.v. route produced a statistically significant of raclopride-induced catalepsy at both doses. In contrast, 8-OH-DPAT (0.2 or 2.0 micrograms kg-1) given by the i.t. route had no statistically significant effect on the raclopride-induced catalepsy. These results suggest that the antagonistic effect of 8-OH-DPAT on catalepsy, induced by DA blocking agents, is primarily mediated at the supraspinal level.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

Antagonism by 8-OH-DPAT, but not ritanserin, of catalepsy induced by SCH 23390 in the rat.

In the present experiments, it was shown that the catalepsy induced by the dopamine D1 antagonist SCH 23390 (0.2 mg kg-1 sc), was completely antagonised by the administration of 8-OH-DPAT (0.1 mg kg-1 sc) for the duration of the effect of SCH 23390 (approx. 120 min). Neither the catalepsy induced by raclopride (16 mg kg-1 sc) nor that induced by SCH 23390 (0.2 mg kg-1 sc) could be antagonised by treatment with the 5-HT2 receptor antagonist ritanserin (0.13-2.0 mg kg-1 sc). Administration of SCH 23390 (0.0125-0.2 mg kg-1 sc) produced a significant suppression of avoidance behavior at all doses, and also produced a significant decrease in the number of intertrial crosses. At the higher doses, 0.05 and 0.2 mg kg-1 sc, there were also escape failures. In contrast to the finding in our previous report that raclopride and 8-OH-DPAT in a synergistic manner produce a suppression of conditioned avoidance behavior, no such interaction was found between 8-OH-DPAT (0.1 mg kg-1 sc) and SCH 23390 (6 micrograms kg-1 sc) in the present study.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1991

Antipsychotic-like profile of combined treatment with raclopride and 8-OH-DPAT in the rat: enhancement of antipsychotic-like effects without catalepsy.

The administration of the 5-HT1A agonist 8-OH-DPAT, 0.1 mg kg-1 sc-20 min, produced a moderate suppression of conditioned avoidance behavior (60% of controls) in the rat. This effect, however, was not seen after administration of higher doses, 0.4 and 1.6 mg kg-1 sc. The number of intertrial crosses were not affected by the lower dose but significantly increased by administration of the two higher doses of 8-OH-DPAT. The dopamine D2 receptor blocking agent raclopride, 0.05 mg kg-1, by itself did not suppress the avoidance behavior, but in combination with 8-OH-DPAT produced suppression of avoidance behavior (30% of controls) as well as intertrial crosses. Open field locomotor activity was suppressed by raclopride, 0.1 mg kg-1 sc, or by 8-OH-DPAT, 0.1 mg kg-1 sc. The combined treatment produced a further suppression of locomotor activity and a marked increase in "immobility" (stationary movements). Treadmill locomotion, however, was not affected by either compound by itself, whereas the combined treatment impaired treadmill performance. Suppression of treadmill performance by a higher dose of raclopride, 0.4 mg kg-1 sc, was not altered by the additional treatment with 8-OH-DPAT, 0.1 mg kg-1. In contrast to the additive effects of 8-OH-DPAT and raclopride on conditioned avoidance behavior, open field locomotion and treadmill performance, the catalepsy produced by raclopride, 16 mg kg-1 was completely antagonised by treatment with 8-OH-DPAT 0.1 mg kg-1. Taken together, the present findings demonstrate strong interactions between a 5-HT agonist and a DA D2 antagonist on some critical tests for antipsychotic-like actions and extrapyramidal motor effects in rats, and suggest new possibilities in the search for new antipsychotic drugs with higher clinical efficacy and less extrapyramidal side effects.

8-Hydroxy-2-(di-n-propylamino)tetralin↗