PD 158771, a potential antipsychotic agent with D2/D3 partial agonist and 5-HT(1A) agonist actions. II. Preclinical behavioral effects.

PD 158771 has been described in receptor binding and biochemical tests as a partial agonist at dopamine (DA) D2 and D3 receptors as well as an agonist at serotonin (5-HT)(1A) receptors. The present studies describe the profile of PD 158771 in rodent and primate behavioral tests. PD 158771 reduced spontaneous locomotor activity in mice (ED(50)=0.38 mg/kg, i.p.) and rats (ED(50) = 1.2 mg/kg, i.p. and 0.16 mg/kg, s.c.), and reduced amphetamine-stimulated locomotion in mice (ED(50) = 0.13 mg/kg, i.p.). At relatively higher doses up to 3 mg/kg, s.c. in rats, PD 158771 did not produce locomotor stimulation or induce stereotypy, indicating a lack of postsynaptic DA agonist activity. PD 158771 reduced apomorphine stimulated locomotion in rats at a dose 4.6-fold greater than those that reduced spontaneous locomotor activity, indicating weak postsynaptic DA antagonist actions; results consistent with a partial agonist profile. PD 158771 produced anxiolytic-like effects in the water-lick (Vogel) conflict test, effects possibly due to the 5-HT(1A) activity. However, PD 158771 was inactive in the water wheel behavioral despair model in rats, indicating lack of antidepressant properties. Similar to known antipsychotics, PD 158771 produced a potent and long-lasting inhibition of conditioned avoidance responding in squirrel monkeys. In contrast to standard antipsychotics, and similar to clozapine, PD 158771 did not cause catalepsy in rats at a dose 20-fold higher than the ED(50) dose for locomotor inhibition. PD 158771 also had a somewhat lower liability than haloperidol to produce extrapyramidal dysfunction in squirrel and cebus monkeys sensitized to the dystonic effects of haloperidol. The data indicate that PD 158771 is a DA partial agonist with weak intrinsic activity that selectively activates brain DA autoreceptors. PD 158771 produced behavioral effects consistent with potential antipsychotic and anxiolytic efficacy, and has an improved profile in the extrapyramidal side effect model when compared to certain currently available antipsychotic agents.

Reversal of haloperidol-induced extrapyramidal side effects in cebus monkeys by 8-hydroxy-2-(di-n-propylamino)tetralin and its enantiomers.

(+/-)-8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), (+)-8-OH-DPAT, and (-)-8-OH-DPAT produced dose-related reversals of haloperidol-induced extrapyramidal side effects (EPS) in cebus monkeys, with all compounds producing similar almost complete reversals at 0.1 mg/kg i.m. These compounds were more potent than apomorphine, which reversed haloperidol-induced EPS at 0.3, but not 0.1, mg/kg i.m. The data indicate that the reversal of haloperidol-induced EPS by (+/-)-8-OH-DPAT and its enantiomers is mediated via effects at 5-HT1A receptors, not dopamine D2 receptors. Thus, inclusion of 5-HT1A agonist activity in novel antipsychotics may reduce EPS liability.

Modulation of dopamine neuronal activity by glutamate receptor subtypes.

In vitro and in vivo electrophysiological studies have been used to assess the effects of glutamate, as well as specific agonists and antagonists for ionotropic, N-methyl-D-aspartate (NMDA), (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate, and metabotropic subtypes of the glutamate receptor, on the neuronal firing activity of midbrain, substantia nigra zona compacta (A9) and ventral tegmental area (A10), dopamine neurons. In in vitro experiments, agonists for all glutamate receptor subtypes depolarize the membrane and increase firing rate. In in vivo experiments, iontophoretic application of these agonists increases the firing rate and induces burst-firing. Studies with subtype selective antagonists suggest that a tonic glutamate tone, acting via NMDA receptors, may modulate the firing activity of some dopamine neurons. Glutamatergic afferents from the subthalamus, pedunculopontine nucleus and frontal cortex can modulate the firing activity of dopamine neurons. The role(s) of the different glutamate receptor subtypes and pathways in mediating the physiological and pathological effects on dopamine systems is an area for further investigation.

The novel use of vascular access ports for intravenous self-administration and blood withdrawal studies in squirrel monkeys.

An important experimental challenge in research with squirrel monkeys (Saimiri scureus) is the development of a reliable closed intravenous system for long term drug self-administration studies and the collection of multiple timed blood samples. A surgical procedure using a vascular access port (VAP) system was developed to provide easy access for venous samples or drug infusions. Daily experiments in chaired monkeys were simple and reliable for durations of up to 6 h. The quantitative performance of the VAP system was evaluated by the number of days until port failure for self-administration studies and the number of days during which blood samples could be collected beyond an initial time of 91 days. The mean best performance for VAP system functional time for self-administration studies was 437 +/- 73 and the mean worst performance was 281 +/- 79. The mean best performance for blood withdrawal functional time was 362 +/- 81 and the mean worst performance was 332 +/- 85. The qualitative performance of the VAP system is described including complications that developed during the procedure; corresponding suggestions for corrective actions are discussed. Enhancements to increase port performance are also recommended.

Metabotropic glutamate receptor-mediated inhibition and excitation of substantia nigra dopamine neurons.

Microiontophoretic drug application and extracellular recording techniques were used to evaluate the effects of the selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate(1S,3R-ACPD) on dopamine (DA) neurons in the substantia nigra zona compacta (SNZC) of chloral hydrate-anesthetized rats. 1S,3R-ACPD had a biphasic effect on the firing rate of DA cells, initially decreasing, then increasing the firing rate. 1S,3R-ACPD also increased the burst-firing activity of DA neurons. Application of the ionotropic receptor (iGluR) agonists (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartate (NMDA) increased the firing rates of neurons which had responded to 1S,3R-ACPD, indicating that mGluRs and iGluRs reside on the same neurons. The initial inhibitory period was not antagonized by systemic haloperidol or iontophoretic bicuculline, indicating a lack of DA or gamma-amino-n-butyric acid (GABA) involvement in this effect. Combined application of the AMPA antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), and the NMDA antagonist, (I)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphoric acid (CPP), at currents which antagonized AMPA and NMDA, did not antagonize either the inhibitory or excitatory effects of 1S,3R-ACPD. Application of the metabotropic antagonist (S)-4-carboxy-phenylglycine antagonized both the inhibitory and excitatory effects of 1S,3R-ACPD. These results indicate that mGluRs may play a role in the modulation of dopaminergic activity in the SNZC.

Pharmacokinetics and pharmacodynamics of an investigational antipsychotic agent, CI-1007, in rats and monkeys.

PURPOSE: To study the pharmacokinetics (PK) and pharmacodynamics (PD) of an investigational antipsychotic agent, CI-1007, in rats and monkeys. METHODS: CI-1007 and a pharmacologically active metabolite, PD 147693 (M1), were evaluated in animal antipsychotic tests (inhibition of dopamine neuron firing and spontaneous locomotor activity in rats, and inhibition of continuous avoidance in monkeys). Plasma concentrations of CI-1007 and M1 were determined using validated HPLC assays. Log-linear and link models were used for PK/PD analysis. RESULTS: CI-1007 and M1 have shown similar effects on dopamine neuron firing (2.5 mg/kg i.p.), and produced dose-related effects on spontaneous locomotor activity in rats (0.3-30 mg/kg p.o.) and on continuous avoidance in monkeys (0.6-1.2 mg/kg p.o.). After pharmacologically active CI-1007 doses, mean plasma CI-1007 Cmax increased from 19 to 200 ng/ml in Sprague-Dawley rats at doses of 3-30 mg/ kg, and from 8.1 to 34 ng/ml in squirrel monkeys at doses of 0.6-1.2 mg/kg, but corresponding plasma M1 Cmax values were near or below the limit of quantitation (5 ng/ml). CI-1007 EC50 was 31.1 ng/ml in rats, calculated from a long-linear regression. In monkeys, CI-1007 ECe50, gamma, and Keo at 0.6 and 1.2 mg/kg were 4.8 and 4.5 ng/ml, 1.9 and 2.0, and 0.47 and 0.48 hr-1, respectively, calculated by the link model. CONCLUSIONS: CI-1007 has shown dose-related pharmacokinetics and pharmacodynamics in rats and monkeys. Although M1 produces antipsychotic-like effects similar to CI-1007, the contribution of M1 to the activity of the parent drug may not be significant in rats and monkeys as based on plasma levels. CI-1007 plasma concentration correlates log-linearly with inhibition effect from the rat locomotor study. The counter-clockwise hysteresis relationship of CI-1007 plasma concentration and inhibition effect from the monkey avoidance test was described by a link model, and the resulting Ce (concentration in effect compartment) versus effect profile exhibits a sigmoidal curve.

CI-1007, a dopamine partial agonist and potential antipsychotic agent. II. Neurophysiological and behavioral effects.

CI-1007 has been described in receptor binding and biochemical tests as a dopamine (DA) partial agonist that exhibits DA autoreceptor agonist effects. The present studies describe the profile of CI-1007 in electrophysiological and behavioral tests. CI-1007 inhibited the firing of substantia nigra DA neurons with intrinsic DA agonist activity that was less than that of the full agonists apomorphine and talipexole but greater than that of the weak partial agonist SDZ 208-912. CI-1007 was more potent after intracerebroventricular versus intraperitoneal injection in inhibiting spontaneous locomotor activity in mice, indicating a central site of action. In rats, CI-1007 inhibited locomotor activity after i.v. and p.o. injection, but did not produce locomotor stimulation or induce stereotypy, indicating a lack of postsynaptic DA agonist activity. The relative potencies of CI-1007 for inhibiting apomorphine-stimulated behaviors versus spontaneous locomotor activity in rodents indicated weak postsynaptic DA antagonist actions, consistent with a partial agonist profile. Similar to known antipsychotics, CI-1007 potently inhibited Sidman avoidance responding in squirrel monkeys, but, in contrast to most available antipsychotics, CI-1007 caused only mild extrapyramidal dysfunction in squirrel and cebus monkeys sensitized to the dystonic effects of haloperidol. These data indicate that CI-1007 is a DA partial agonist of moderate intrinsic activity that activates brain DA autoreceptors, produces behavioral effects predictive of antipsychotic efficacy and has a low liability for induction of extrapyramidal side effects.

Evidence for N-methyl-D-aspartate and AMPA subtypes of the glutamate receptor on substantia nigra dopamine neurons: possible preferential role for N-methyl-D-aspartate receptors.

The present studies utilized extracellular single-unit recordings in chloral hydrate-anesthetized rats to evaluate the contribution of N-methyl-D-aspartate (NMDA) and (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) subtypes of glutamate receptors to the excitatory effects of glutamate on substantia nigra dopamine neurons. Iontophoretic administration of NMDA, AMPA and glutamate increased the firing rate and amount of burst-firing of dopamine neurons. Iontophoretic application of the NMDA antagonist (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid (CPP) inhibited the excitatory effect of NMDA and glutamate, but not that of AMPA. Iontophoretic application of the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)-quinoxaline (NBQX), inhibited the excitatory effect of AMPA and glutamate, but not that of NMDA. CPP produced a greater antagonism of the glutamate excitation than did NBQX. In addition, CPP, but not NBQX, reduced the firing rate and burst-firing of a subpopulation of DA neurons. These data indicate that both NMDA and AMPA receptors are present on substantia nigra dopamine neurons and suggest that NMDA receptors may be more sensitive than AMPA receptors to endogenous glutamate and that a tonic glutamate tone, acting via NMDA receptor stimulation, may modulate the firing rate and burst-firing activity of some dopamine neurons.

Pharmacological profile of the dopamine partial agonist, (+/-)-PD 128483 and its enantiomers.

(+/-)-PD 128483, ((+/-)-4,5,5a,6,7,8-hexahydro-6-methylthiazolo[4,5-f]-quinolin+ ++-2-amine, maleate (1:1)), is a racemic compound that is a p.o. active dopamine (DA) partial agonist that has DA autoreceptor agonist effects and displays antipsychoticlike activity in preclinical tests. In in vitro receptor binding assays, (+/-)-PD 128483 and its enantiomers bound selectively to DA D-2 receptors vs. DA D-1 receptors and showed no affinity for adrenergic alpha-1 or serotonin1A receptors, but had affinity for adrenergic alpha-2 receptors. In tests of DA agonist effects, including reversal of the tau-butyrolactone-stimulated increase in brain dopa synthesis in striatum and inhibition of DA neuronal firing, the rank order of efficacy was (+)-PD 128483 > (+/-)-PD 128483 > (-)-PD 128483. (+/-)-PD 128483 and (+)-PD 128483 inhibited, whereas (-)-PD 128483 increased, brain DA synthesis in normal rats. (+/-)-PD 128483 and (-)-PD 128483 inhibited spontaneous locomotion in rats and did not produce locomotor stimulation or stereotypies. In contrast, (+)-PD 128483 inhibited locomotor activity at low doses, but at relatively high doses increased locomotion and induced stereotypy in rats. (-)-PD 128483 consistently inhibited Sidman avoidance responding in squirrel monkeys. (+/-)-PD 128483 inhibited Sidman avoidance responding in one group of monkeys, but had minimal effects in another group. (+)-PD 128483 did not inhibit avoidance responding. In squirrel or cebus monkeys sensitized to the acute dystonic effects of haloperidol, only (-)-PD 128483 induced extrapyramidal dysfunction. These results indicate that (+/-)-PD 128483 is a DA partial agonist which produces DA autoreceptor agonist effects and has a preclinical behavioral profile suggestive of antipsychotic activity.

Comparison of the effects of the cholecystokinin-B receptor antagonist, PD 134308, and the cholecystokinin-A receptor antagonist, L-364,718, on dopamine neuronal activity in the substantia nigra and ventral tegmental area.

Extracellular single-unit recording techniques were used to study the effects of the cholecystokinin-A (CCK-A) antagonist, L-364,718, and the CCK-B antagonist, PD 134308, on DA neuronal activity in chloral hydrate anesthetized rats. Neither L-364,718 (0.1-1.6 mg/kg i.v.) nor PD 134308 (0.1-6.4 mg/kg) altered the basal firing rate of substantia nigra or ventral tegmental area DA neurons. The ability of PD 134308 and L-364,718 to alter the apomorphine-induced inhibition of substantia nigra DA neurons was assessed. Pretreatment with L-364,718 (0.6 or 4.16 mg/kg i.v.) did not shift the apomorphine dose-response curve (0.5-32 micrograms/kg i.v.). In contrast, PD 134308 (0.6 or 6.4 mg/kg i.v.) produced dose-related, significant shifts to the right of the apomorphine dose-response curves. However, these effects were small in comparison to the haloperidol (0.1 mg/kg i.p.)-induced shift of the apomorphine curve. These data suggest that in the substantia nigra there may be a tonic level of CCK release that, through actions on CCK-B receptors, may modulate DA agonist-induced inhibition of DA neuronal activity.

Lack of involvement of haloperidol-sensitive sigma binding sites in modulation of dopamine neuronal activity and induction of dystonias by antipsychotic drugs.

The present studies evaluated previous suggestions that haloperidol-sensitive sigma binding sites are involved in the modulation of dopamine (DA) neuronal activity and in the induction of the dystonic effects of antipsychotic drugs. These issues were addressed by evaluating the effects of compounds that have differing affinities for sigma binding sites, on the firing activity of DA neurons in the substantia nigra in chloral hydrate-anesthetized rats and on the ability to induce extrapyramidal motor dysfunction in squirrel monkeys sensitized to the dystonic effects of haloperidol. The agents studied included haloperidol, DTG (1,3-di-o-tolylguanidine), (+)-pentazocine, (+)-SKF 10,047, BMY 14802, 8-OH-DPAT and sulpiride. There was no relationship between affinity for sigma binding sites and the ability to either alter DA neuronal activity or to induce extrapyramidal motor dysfunction.

CI-943, a potential antipsychotic agent. III. Evaluation of effects on dopamine neuronal activity.

CI-943 (8-ethyl-7,8-dihydro-1,3,5-trimethyl-1H-imidazo[1,2- c]pyrazolo[3,4-e]pyrimidine) has been identified as a novel potential antipsychotic agent that does not bind to dopamine (DA) receptors. In the present studies, the effects of acute and chronic administration of CI-943 on the electrophysiological activity of A9 and A10 DA neurons were assessed and compared to the effects of DA antagonist antipsychotic drugs. Acute administration of CI-943 did not increase the base-line firing rate (10-20 mg/kg i.p.), did not increase the number of spontaneously active DA neurons (40 mg/kg p.o.) and did not antagonize the effects of apomorphine or amphetamine on A9 or A10 DA neurons (20-40 mg/kg i.p.). A high dose of CI-943 (40 mg/kg i.p.) decreased the firing rate of A9 and A10 DA neurons, an effect that was not antagonized by haloperidol. In contrast, haloperidol increased the base-line firing rate (0.5 mg/kg i.p.), increased the number of spontaneously active DA neurons (0.5 mg/kg p.o.) and antagonized the effects of apomorphine and d-amphetamine on A9 and A10 DA neurons (0.1 mg/kg i.p.). Repeated (21 days) administration of CI-943 (36 mg/kg/day p.o.) did not alter the number of spontaneously active A9 DA neurons but increased the number of active A10 DA neurons. In contrast, repeated administration of haloperidol (0.4 mg/kg/day p.o.) decreased the number of spontaneously active DA neurons in A9 and A10, whereas repeated administration of clozapine (19 mg/kg/day p.o.) decreased the number of active A10 DA neurons but increased the number of active A9 DA neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intraperitoneal administration of apomorphine and the isomers of 3-(1-propyl-3-piperidinyl)phenol on the firing activity of substantia nigra dopamine neurons: comparison of agonist efficacies and development of acute tolerance.

The effects of intraperitoneal administration of apomorphine, (+)-3-PPP, and (-)-3-PPP on slow-(less than 4 spikes/sec) and fast-(greater than 4 spikes/sec) firing dopaminergic neurons in the substantia nigra zona compacta of rats anesthetized with chloral hydrate were assessed. All compounds completely inhibited slow-firing dopaminergic neurons. When a dose-response was determined by administering each dose in a single bolus injection, apomorphine and (+)-3-PPP produced dose-related inhibitions of fast-firing dopaminergic neurons, with the largest dose of each compound completely inhibiting nearly all cells tested. In contrast, (-)-3-PPP only partially inhibited (50%) fast-firing dopaminergic neurons. Thus, on fast-firing neurons, (-)-3-PPP had the profile of a partial agonist, while apomorphine and (+)-3-PPP demonstrated greater efficacy than (-)-3-PPP. Pretreatment while doses of apomorphine, (+)-3-PPP, or (-)-3-PPP that partially inhibited the activity of dopaminergic neurons antagonized the complete inhibitory effects of a dose of apomorphine that normally produced complete inhibition of neuronal firing. In addition, pretreatment with doses of (+)-3-PPP that partially inhibited the activity of cells antagonized the complete inhibitory effects of a dose of (+)-3-PPP that, normally produced complete inhibition of neuronal firing. From the antagonism studies alone, it was not clear if tachyphylaxis or partial agonist activity accounted for the observed antagonisms. However, since apomorphine and (+)-3-PPP completely inhibited the activity of fast-firing DA neurons, it is proposed that they antagonize by inducing a dose- and time-dependent tachyphylaxis. In contrast, (-)-3-PPP is proposed to antagonize by virtue of its partial agonist activity.