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DU 127090: A novel partial dopamine agonist with antipsychotic activity high potency but low efficacy at dopamine D2 receptors in vitro
108 DU 127090: A NOVEL PARTIAL DOPAMINE AGONIST WITH ANTIPSYCHOTIC ACTIVITY HIGH POTENCY BUT LOW EFFICACY AT DOPAMINE D 2 RECEPTORS IN VITRO M. B. Hesselink,* B. J. van Vliet, E. R o n k e n , M. Tulp, S. K. L o n g , R. W. Feenstra, C. G. K r u s e Solvay Pharmaceuticals Research Laboratories, Weesp, Netherlands The receptor binding profile and the interaction with the dopamine D 2 receptor of DU127090 (7-[4-([1,1'-biphenyl]-3-ylmethyl)-lpiperazinyl]-2(3H)-benzoxazolone, monomethanesulphonate), a novel putative antipsychotic agent, was investigated in a number of in vitro test systems. DU127090 has high affinity for hD 2 receptors (pKi 8.5), hD 3 and hD 4 receptors (pKi 9.2 and 8.8 resp). In contrast to all clinically available antipsychotics, DU127090 has high affinity (pKi 8.0) and partial agonist effect at serotonin 5-HT1A receptors (pD 2 7.0, ot 0.7), while it has virtually no affinity for 5-HT2A and 5HT2c, noradrenergic c~l and cz2, muscarinic and histamine receptors. These properties together are expected to confer both antipsychotic, antidepressant and anxiolytic activity to DU127090, in combination with a favorable side-effect profile. Most interestingly, in a functional assay (adenylate cyclase activity in CHO cells expressing hD2L receptors), DUl27090 induced highly potent but incomplete antagonism of the effects of the dopamine agonist quinpirole (pA 2 10.1), showing weak agonist properties (maximum 28 % agonism at 1 pM, when compared to the full agonist quinpirole). Furthermore, DU127090 inhibited dopamine D 2 receptor-sensitive adenylate cyclase activity in rat striatal slices (pD 2 7.9, c~0.6). Finally, in the same preparation, measuring the inhibitory effect on K +induced release of [3H]-dopamine, DU127090 acted as a highly potent antagonist at presynaptic dopamine D 2 receptors (pA 2 9.4). Data in these functional assays fnlly support the partial agonistic properties of DU 127090. Indeed, when endogenous doparnine tonus is low, as in the case of the adenylate cyclase activity assays in CHO cells and in striatal slices, DU127090 induced agonist-like effects. However, when the endogenous dopamine level is high, as a consequence of a depolarising potassium concenU'ation as used in the [3H]DA release assay, DU 127090 acts as a potent antagonist at dopamine D 2 receptors. High potency and low efficacy agonism at dopamine D 2 receptors are suggestive of a unique antipsychotic profile: in brain regions (n. accumbens) where dopaminergic neurotransmission is postulated to be excessive in [~sychotic patients, DU127090 is expected to act as an antagonist thus moderating dopaminergic activity. In contrast, in prefrontal cortex, where the dopaminergic system is believed to be hypoactive, DU127090 may act as a dopamine stabiliser, restoring dopaminergic neurotransmission.
TYROSINE AVAILABILITYAFFECTS ANTIPSYCHOTIC DRUG-INDUCED DOPAMINE RELEASE IN PREFRONTAL CORTEX AND STRIATUM IN V1VO G. E. Jaskiw,* R. B o n g i o v a n n i Mental Health Care Line, Louis Stokes Cleveland VAMC, Brecksville, OH, USA Schizophrenia has been associated with a dysregulation of dopamine (DA) transmission in prefrontal cortex (PFC) and striatum. Antipsychotic drugs may act by affecting dopamine (DA) transmission in those areas. Our purpose was to evaluate how the availability of brain tyrosine affects antipsychotic-drug induced DA release, In vivo
10. Neurochemistry, Animal microdialysis studies were conducted in male Sprague-Dawley rats (200-250gr). A unilateral cannula was inserted into the medial PFC or striatum; 2 d later, a microdialysis probe was lowered; t6 hrs later, microdialysate collection began (1.0~tl/min). Exp 1: Different concentrations of tyrosine were perfused through the probe. Tyrosine 50 - 100gg/ml had no effect on basal MPFC DA levels, but significantly augmented clozapine-induced (10mg/kg IP) MPFC DA release. In striatum, tyrosine 25gg/ml significantly augmented while tyrosine 150gg/ml attenuated haloperidol-induced (1.0mg/kg IP) DA release. Exp 2: Systemic pretreatment with a tyrosine and phenylanine free neutral amino acid mixture (NAA(-)) (lg/kg, given as two IP injections 1 hr apart) lowered dialysate tyrosine levels by approximately 50%. NAA(-) attenuated clozapine-induced (10mg/kg IP) MPFC DA release and haloperidol-induced (0.25mg/kg IP) striatal DA release. Exp 3: NAA(-) pretreatment significantly enhanced haloperidolinduced catalepsy. We conclude that antipsychotic-drug induced DA release in PFC and striatum depend in part, on the levels of available tyrosine. Given that schizophrenia has been associated with a dysregulation of DA transmission, as well as with an abnormality of tyrosine transport across the blood brain barrier, manipulation of brain tyrosine levels may prove useful in the development of new treatments and/or research probes in schizophrenia. Support- Medical Research Service, Department of Veterans Affairs.
GENETIC VASOPRESSIN DEFICIENCY FACILITATES PERFORMANCE OF A LATERALIZED REACTION TIME TASK: ALTERED ATTENTIONAL AND MOTOR PROCESSES J. J e n t s c h Psychology, UCLA, Los Angeles, CA, USA Alterations of neurophysin signaling have been hypothesized to contribute to the pathophysiology of schizophrenia, and recent studies from animal models of vasopressin deficiency have supported this link. Brattleboro rats are a variety of the outbred Long-Evans strain that possess a single nucleotide deletion in the second exon of the arginine vasopressin gene, resulting in the synthesis of an altered protein that does not enter the normal secretory pathway. Rats heterozygous (di/+) for the deletion have a partial vasopressin deficiency and exhibit a variety of behavioral and neurochemical alterations, relative to normal wild-type Long-Evans rats, that provide evidence for a central nervous system function for vasopressin. For example, Feifel and Preibe (2001) recently demonstrated that Brattleboro rats exhibit deficits of sensorimotor gating. Here, we examined the acquisition and performance of a test of visuospatial attention by di/+ Brattleboro rats and their wild-type Long-Evans control counterparts because attentional dysfunction is a critical feature of the neurocognitive dysfunction of schizophrenia. Surprisingly, di/+ rats exhibited superior performance of the task relative to wild-type controls; performance differences included greater accuracy of detection of visual target stimuli, faster overall reaction times and fewer trial omissions. Di/+ rats also exhibited more perseverative approaches to the reinforcer receptacle. These results demonstrate that alterations of vasopressin signaling result in a clear cognitive phenotype, including faster motor initiations, superior stimulus detection accuracy, as well as heightened impulsivity. Though further studies of homozygous Brattleboro rats (that are completely vasopressin deficient) are necessary, these data indicate that heterozygous Brattleboro rat does not model the neurocognitive dysfunction inherent in schizophrenia.
International Congress on Schizophrenia Research 2003
TYROSINE AVAILABILITYAFFECTS ANTIPSYCHOTIC DRUG-INDUCED DOPAMINE RELEASE IN PREFRONTAL CORTEX AND STRIATUM IN V1VO G. E. Jaskiw,* R. B o n g i o v a n n i Mental Health Care Line, Louis Stokes Cleveland VAMC, Brecksville, OH, USA Schizophrenia has been associated with a dysregulation of dopamine (DA) transmission in prefrontal cortex (PFC) and striatum. Antipsychotic drugs may act by affecting dopamine (DA) transmission in those areas. Our purpose was to evaluate how the availability of brain tyrosine affects antipsychotic-drug induced DA release, In vivo
10. Neurochemistry, Animal microdialysis studies were conducted in male Sprague-Dawley rats (200-250gr). A unilateral cannula was inserted into the medial PFC or striatum; 2 d later, a microdialysis probe was lowered; t6 hrs later, microdialysate collection began (1.0~tl/min). Exp 1: Different concentrations of tyrosine were perfused through the probe. Tyrosine 50 - 100gg/ml had no effect on basal MPFC DA levels, but significantly augmented clozapine-induced (10mg/kg IP) MPFC DA release. In striatum, tyrosine 25gg/ml significantly augmented while tyrosine 150gg/ml attenuated haloperidol-induced (1.0mg/kg IP) DA release. Exp 2: Systemic pretreatment with a tyrosine and phenylanine free neutral amino acid mixture (NAA(-)) (lg/kg, given as two IP injections 1 hr apart) lowered dialysate tyrosine levels by approximately 50%. NAA(-) attenuated clozapine-induced (10mg/kg IP) MPFC DA release and haloperidol-induced (0.25mg/kg IP) striatal DA release. Exp 3: NAA(-) pretreatment significantly enhanced haloperidolinduced catalepsy. We conclude that antipsychotic-drug induced DA release in PFC and striatum depend in part, on the levels of available tyrosine. Given that schizophrenia has been associated with a dysregulation of DA transmission, as well as with an abnormality of tyrosine transport across the blood brain barrier, manipulation of brain tyrosine levels may prove useful in the development of new treatments and/or research probes in schizophrenia. Support- Medical Research Service, Department of Veterans Affairs.
GENETIC VASOPRESSIN DEFICIENCY FACILITATES PERFORMANCE OF A LATERALIZED REACTION TIME TASK: ALTERED ATTENTIONAL AND MOTOR PROCESSES J. J e n t s c h Psychology, UCLA, Los Angeles, CA, USA Alterations of neurophysin signaling have been hypothesized to contribute to the pathophysiology of schizophrenia, and recent studies from animal models of vasopressin deficiency have supported this link. Brattleboro rats are a variety of the outbred Long-Evans strain that possess a single nucleotide deletion in the second exon of the arginine vasopressin gene, resulting in the synthesis of an altered protein that does not enter the normal secretory pathway. Rats heterozygous (di/+) for the deletion have a partial vasopressin deficiency and exhibit a variety of behavioral and neurochemical alterations, relative to normal wild-type Long-Evans rats, that provide evidence for a central nervous system function for vasopressin. For example, Feifel and Preibe (2001) recently demonstrated that Brattleboro rats exhibit deficits of sensorimotor gating. Here, we examined the acquisition and performance of a test of visuospatial attention by di/+ Brattleboro rats and their wild-type Long-Evans control counterparts because attentional dysfunction is a critical feature of the neurocognitive dysfunction of schizophrenia. Surprisingly, di/+ rats exhibited superior performance of the task relative to wild-type controls; performance differences included greater accuracy of detection of visual target stimuli, faster overall reaction times and fewer trial omissions. Di/+ rats also exhibited more perseverative approaches to the reinforcer receptacle. These results demonstrate that alterations of vasopressin signaling result in a clear cognitive phenotype, including faster motor initiations, superior stimulus detection accuracy, as well as heightened impulsivity. Though further studies of homozygous Brattleboro rats (that are completely vasopressin deficient) are necessary, these data indicate that heterozygous Brattleboro rat does not model the neurocognitive dysfunction inherent in schizophrenia.
International Congress on Schizophrenia Research 2003