Animal models of depression: challenges from a drug development perspective.

Clinically effective antidepressant drugs have been available for many years but our understanding of how these drugs bring about their therapeutic effects, and how to develop more diverse, better treatments has progressed little. At a time when informed choices need to be taken early on in drug development programs in order to exploit the opportunities for innovation created through genomics, this article considers the strengths and weaknesses of behavioral pharmacology assays and their various roles in the drug discovery process. In the past, a widespread lack of confidence in animal models of depression, combined with the high failure rate of clinical trials and escalating costs of drug development, has stifled a more entrepreneurial approach to drug discovery. In order to encourage greater confidence in discovery programs, the gap between exploratory preclinical and clinical studies needs to be bridged. Functional pharmacology markers need to be developed in patient populations, and in normal volunteers and preclinical species, so that selection of new drug targets can be made with greater confidence at earlier stages of discovery programs. The use of functional brain imaging to quantify drug actions in the human CNS is developing rapidly and may provide powerful new techniques to filter active new drugs of the future from those that are less promising.

P-Glycoprotein efflux reduces the brain concentration of the substance P (NK1 receptor) antagonists SR140333 and GR205171: a comparative study using mdr1a-/- and mdr1a+/+ mice.

Investigation of the antidepressant-like actions of substance P (NK1 receptor) antagonists has been hindered by the few available compounds that bind with high affinity to the rat and mouse NK1 receptor, as these are the most commonly used preclinical species. The best available compounds for such studies are SR140333 and GR205171. However, SR140333 does not penetrate the central nervous system (CNS) after systemic administration, and GR205171 is active only at high doses, where unspecific pharmacological effects occur, so that changes in behaviour cannot be attributed to selective NK1 receptor blockade. These compounds may be substrates for P-glycoprotein (P-gp) and hence are actively excluded from the brain. The present studies used mdr1a-/- mice, a spontaneously occurring mutant that is deficient in P-gp, to examine the CNS penetration of SR140333 and GR205171. Following systemic administration of SR140333 and GR205171 (0.01-10 mg/kg i.v.), considerably higher drug concentrations were achieved in the brains of mdr1a-/- than in mdr1a+/+ mice, and this corresponded with a greater ability to inhibit NK1-agonist-induced behaviours in the mdr1a-/- mutants. Moreover, an NK1-receptor-specific inhibition of aggressive behaviour by GR205171 (10 mg/kg) could be demonstrated in mdr1a-/-, but not mdr1a+/+, mice. These findings suggest that P-gp deficient mice may have useful applications in behavioural pharmacology studies, especially when highly brain-penetrant compounds are not yet available.

The substance P (NK1) receptor antagonist L-760735 inhibits fear conditioning in gerbils.

The ability of the substance P (NK(1) receptor) antagonist (SPA) L-760735 to inhibit conditioned fear was assessed in gerbils using a four plate apparatus. Animals that had been treated with diazepam (3 mg/kg) or L-760735 (3 mg/kg) 30 min before a 3 min conditioning session in the apparatus exhibited a release of plate crossings during the retest session approximately 3 h later. Plate crossings were also increased when animals received diazepam or L-760735 30 min before the retest session. In contrast, fluoxetine and venlafaxine (30 mg/kg) did not exhibit anxiolytic-like effects. During the retest session, gerbils drummed their hind feet on the floor; this behaviour was not observed spontaneously in gerbils that were naïve to the apparatus. Foot drumming was abolished by pretreatment with L-760735 or diazepam (3 mg/kg) but was markedly increased following administration of fluoxetine or venlafaxine (30 mg/kg). Foot drumming elicited by aversive conditioning alone or in combination with fluoxetine was abolished by administration of L-760735 and by amygdala lesions involving the basolateral and lateral nuclei, indicating that this behaviour is an alarm signal or fear response mediated via release of substance P in brain circuits involving the amygdala. The observations provide further evidence for an anxiolytic-like profile of SPAs in preclinical assays and demonstrate a clear difference between the actions of SPAs and established antidepressant drugs.

Chronic substance P (NK1) receptor antagonist and conventional antidepressant treatment increases burst firing of monoamine neurones in the locus coeruleus.

The mechanism of action of conventional antidepressants (e.g. imipramine) has been linked to modulation of central monoamine systems. Substance P (NK1) receptor antagonists may have antidepressant and anxiolytic effects in patients with major depressive disorder and high anxiety but, unlike conventional antidepressants, are independent of activity at monoamine reuptake sites, transporters, receptors, or monoamine oxidase. To investigate the possibility that substance P receptor antagonists influence central monoamine systems indirectly, we have compared the effects of chronic administration of imipramine with that of the substance P receptor antagonist L-760735 on the spontaneous firing activity of locus coeruleus neurones. Electrophysiological recordings were made from brain slices prepared from guinea-pigs that had been dosed orally every day for 4 weeks with either L-760735 (3 mg/kg), imipramine (10 mg/kg), or vehicle (water), or naive animals. Chronic, but not acute, treatment with the substance P receptor antagonist L-760735, induced burst firing of neurones in the locus coeruleus. This effect resembles that of the conventional antidepressant imipramine. However, their effects are dissociable since, in contrast to chronic imipramine treatment, chronic L-760735 treatment does not cause functional desensitisation of somatic alpha2 adrenoceptors. The mechanism by which chronic substance P receptor antagonist or conventional antidepressant treatment influences the pattern of firing activity of norepinephrine neurones remains to be elucidated. However, an indirect action in the periphery or distant brain nuclei has been excluded by the use of the in vitro slice preparation, suggesting a local site of action in the locus coeruleus.

Analgesic and toxic effects of ABT-594 resemble epibatidine and nicotine in rats.

The present study directly compared the antinociceptive and toxic effects of the neuronal nicotinic receptor agonist ABT-594 ((R)-5-(2-azetidinylmethoxy)-2-chloropyridine) with (-)-nicotine and (+)-epibatidine. Like (-)-nicotine (0.8 and 1.6 mg/kg s.c.) and (+)-epibatidine (0.005 and 0.01 mg/kg s.c.), ABT-594 (0.05 and 0.1 mg/kg s.c.) increased response latencies in the hot-plate test in rats, indicating that it has antinociceptive activity. In contrast to (-)-nicotine and (+)-epibatidine, ABT-594 did not cause rotarod impairment at antinociceptive doses but did cause hypothermia and life-threatening adverse effects including seizures. ABT-594 (0.01 and 0.1 mg/kg i.v.) also produced a dose-dependent increase in blood pressure resembling that observed with (-)-nicotine (0.03, 0.1 and 0. 03 mg/kg i.v.) and (+)-epibatidine (0.001 and 0.003 mg/kg i.v.). Both the antinociceptive and toxic effects (convulsions and hypertension) were abolished by pretreatment with the brain penetrant neuronal nAChR antagonist mecamylamine (1 mg/kg s.c.; i.v. for cardiovascular studies), demonstrating that these actions of ABT-594 were mediated via activation of neuronal nicotinic receptors. Continuous infusion of ABT-594 (0.2 mg/kg per day s.c.) to rats for 7 days followed by challenge with mecamylamine (1 mg/kg i.p.) induced a nicotine-like abstinence syndrome suggesting that ABT-594 has nicotine-like dependence liability. These findings indicate that the acute safety profile of ABT-594 is not significantly improved over other nicotinic analgesics.