The anxiolytic-like profile of the nociceptin receptor agonist, endo-8-[bis(2-chlorophenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octane-3-carboxamide (SCH 655842): comparison of efficacy and side effects across rodent species.

The endogenous opioid-like peptide, nociceptin, produces anxiolytic-like effects that are mediated via the nociceptin (NOP) receptor. Similarly, synthetic, non-peptide NOP agonists produce robust anxiolytic-like effects although these effects are limited by marked side effects. In the present studies, the effects of a novel NOP receptor agonist, SCH 655842, were examined in rodent models sensitive to anxiolytic drugs and tests measuring potential adverse affects. Oral administration of SCH 655842 produced robust, anxiolytic-like effects in three species, i.e., rat, guinea pig, and mouse. Specifically, SCH 655842 was effective in rat conditioned lick suppression (3-10 mg/kg) and fear-potentiated startle (3-10 mg/kg) tests, a guinea pig pup vocalization test (1-3 mg/kg), as well as in mouse Geller-Seifter (30 mg/kg) and marble burying (30 mg/kg) tests. The anxiolytic-like effect of SCH 655842 in the conditioned lick suppression test was attenuated by the NOP antagonist, J-113397. In mice, SCH 655842 reduced locomotor activity and body temperature at doses similar to the anxiolytic-like dose and these effects were absent in NOP receptor knockout mice. In rats, SCH 655842 did not produce adverse behavioral effects up to doses of 70-100 mg/kg. Pharmacokinetic studies in the rat confirmed dose-related increases in plasma and brain levels of SCH 655842 across a wide oral dose range. Taken together, SCH 655842 may represent a NOP receptor agonist with improved tolerability compared to other members of this class although further studies are necessary to establish whether this extends to higher species.

Characterization of the selective mGluR1 antagonist, JNJ16259685, in rodent models of movement and coordination.

Metabotropic glutamate receptor 1 (mGluR1) antagonists interfere with learning and memory; however, their role in motor function is not well elucidated despite their abundance in brain areas implicated in the control of movement. Here, the effects of mGluR1 antagonism on movement, coordination, and motor learning were investigated. JNJ16259685, a selective mGluR1 antagonist (negative allosteric modulator), was tested in assays of motor skill, and motor learning in rats and mice. JNJ16259685 produced very minimal effects on locomotor activity and posture up to a dose of 30 mg/kg. Motor skill was unaffected for well-learned tasks (up to 30 mg/kg) in rats, but impaired in mice. Both rats and mice rats were profoundly impaired (0.3 mg/kg) in the acquisition of a novel motor skill (rotarod). These results implicate the mGluR1 receptor in the acquisition of novel motor skills. JNJ16259685 dramatically reduced rearing behavior, exploration of a novel environment and lever pressing for a food reward (rat: 0.3 mg/kg; mouse: 1 mg/kg). JNJ16259685 (30 mg/kg) had no effect on reflexive startle responses to loud auditory stimuli or foot shock in mice. Previous groups have proposed that mGluR1 antagonists induce a general reduction in motivation. The effects seen here to reduce exploration and reward are consistent with that hypothesis. Pharmacological inhibition of the mGluR1 receptor has a modest effect on motor function but blocks motor learning and may reduce motivation to perform simple behaviors.

Duration of ultrasonic vocalizations in the isolated rat pup as a behavioral measure: sensitivity to anxiolytic and antidepressant drugs.

Neo-natal rats emit ultrasonic vocalizations (USVs) when isolated from their mothers and littermates. Clinically effective anxiolytics reliably reduce USVs, making this behavior a useful animal model of the anxiolytic potential of novel pharmacological approaches to the treatment of anxiety. Here, we assess the hypothesis that USV duration (total time spent vocalizing) is a more sensitive measure of anxiolytic and antidepressant efficacy than USV number by testing established and putative anxiolytics in this model. Negative geotaxis and righting reflex latency were measured to assess sedating properties. The benzodiazepines, CDP (1-10 mg/kg) and diazepam (0.3-3 mg/kg), the 5HT(1A) partial agonist, buspirone (0.3-3 mg/kg), and the mGluR5 antagonist, MTEP (1-30 mg/kg), reduced USV duration at lower doses and to a greater magnitude than USV number. The benzodiazepines, unlike buspirone and MTEP, produced measurable sedation, but it was dissociable from reductions in USV duration. The SSRI antidepressants, fluoxetine (1-30 mg/kg) and citalopram (0.3-30 mg/kg), reduced USV duration more than number with no measurable effect on sedation. The tricyclic antidepressants, imipramine (1-10 mg/kg) and amitriptyline (1-30 mg/kg), had no effect dissociable from sedation. These data support USV duration as a more sensitive and useful measure than USV number in the isolated rat pup model.

The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles.

RATIONALE: Modulation of metabotropic glutamate receptor (mGluR) subtypes represents a novel approach for the treatment of neurological and psychiatric disorders. OBJECTIVES: This study was conducted to investigate the role of the mGluR5 and mGluR1 subtypes in the modulation of pain and anxiety. METHODS: The mGluR5 antagonists, 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), and the mGluR1 antagonist, (4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine HCl (LY456236), were tested in models of pain [mouse formalin test, rat spinal nerve ligation (SNL)] and anxiety [Vogel conflict, conditioned lick suppression (CLS)], and their efficacious effects were compared to any associated side effects. RESULTS: The systemic administration of MPEP, MTEP, and LY456236 reduced hyperalgesia induced by formalin and mechanical allodynia following SNL. However, only LY456236 completely reversed the allodynia. In the anxiety models, MPEP (3--30 mg/kg), MTEP (3--10 mg/kg), and LY456236 (10--30 mg/kg) produced anxiolytic-like effects similar to the benzodiazepine, chlordiazepoxide (CDP, 6 mg/kg). However, only MPEP and MTEP were able to produce a level of anxiolysis comparable to CDP. In a series of tests examining potential side effects, MPEP and MTEP reduced body temperature and locomotor activity and impaired operant responding for food and rotarod performance at doses of 3--30 and 1--30 mg/kg, respectively. LY456236 reduced operant responding at 30 mg/kg. CONCLUSION: Both mGluR5 and mGluR1 antagonists are effective in models of pain and anxiety. However, an mGluR1 antagonist was more efficacious than the two mGluR5 antagonists in the pain models, which, conversely, appeared more efficacious in the anxiety models. These findings support the potential utility of mGluR5 and mGluR1 antagonists for both the treatment of chronic pain and as novel anxiolytics.