No abstract

This study examined the abilities of 5-hydroxytryptamine (5-HT) agonists with varying selectivity for different subtypes of 5-HT receptors to produce antidepressant-like behavioral effects in the forced swim test in rats. The 5-HT1A agonists 8-OH-DPAT (0.125-1.0 mg/kg, SC) and tandospirone (SM-3997) (5-20 mg/kg, SC) both produced dose-related decreases in immobility time following subchronic treatment in rats. These effects were similar to those of the tricyclic antidepressants imipramine (5-15 mg/kg) and desipramine (5-15 mg/kg). In addition, the 5-HT1A agonists, buspirone (20 mg/kg), gepirone (20 mg/kg) and ipsapirone (10 and 20 mg/kg) demonstrated antidepressant-like effects. Other groups of rats treated subchronically with each of the 5-HT1A agonists or antidepressants showed no increase in locomotor activity, so that general changes in activity could not account for the reduction of immobility time in the forced swim test. 5-HT agonists selective for other receptor subtypes, such as the 5-HT1B/1C agonist m-CPP (5 mg/kg) and the 5-HT2/1C agonist DOB (1 mg/kg), were not effective in this behavioral test. The benzodiazepine diazepam (5 mg/kg) also failed to reduce immobility time, suggesting that anxiolytic properties of 5-HT1A agonists did not mediate this behavioral effect. A common metabolite of some of the 5-HT1A agonists, 1-PP, was ineffective in reducing immobility time. The stimulant d-amphetamine (2 mg/kg) significantly reduced immobility time but also significantly increased locomotor activity.(ABSTRACT TRUNCATED AT 250 WORDS)

This study examined whether the antidepressant-like effect of serotonin (5-HT)1A receptor agonists in the forced swim test (FST) is mediated by 5-HT1A receptors. The 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and buspirone decreased immobility in the FST. The effect of 8-OH-DPAT was blocked by the 5-HT1A receptor antagonists NAN 190, BMY 7378 and pindolol. The effect of buspirone was blocked by NAN 190 and pindolol. The antagonists produced no effects on their own. The norepinephrine (NE) uptake inhibitor desipramine (DMI) also reduced immobility, and this was also blocked by NAN 190, BMY 7378 and pindolol. The alpha 1, beta 1 and beta 2 adrenergic antagonists prazosin, betaxolol and ICI 118,551 did not block either 8-OH-DPAT or DMI, and produced no effects on their own. These results provide evidence that the antidepressant-like effects of 5-HT1A receptor agonists in the FST are mediated through 5-HT1A receptors, probably located postsynaptically. The finding that the 5-HT1A receptor antagonists blocked the effect of DMI suggests that the NE and 5-HT systems interact in the FST.

Pregnan steroids have been shown to possess anesthetic, hypnotic, anticonvulsant and anxiolytic properties. In this study, two endogenous neuroactive steroid isomers, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) and 3 alpha-hydroxy-5 beta-pregnan-20-one 3 alpha,5 beta-P), were studied for differences in their pharmacological properties using behavioral assays. 3 alpha,5 alpha-P and 3 alpha,5 beta-P were similar in their potencies and efficacies in blocking pentylenetetrazol-induced seizures in mice (ED50: 3 alpha, 5 alpha-P = 2.8 mg/kg and 3 alpha,5 beta-P = 3.0 mg/kg). Similarly, both neuroactive steroids produced roto-rod deficits within the same range of potency (TD50: 3 alpha,5 alpha-P = 18.8 mg/kg and 3 alpha,5 beta-P = 21.2 mg/kg). However, in animal models of anxiety, subtle differences were observed between the two isomers. In both the light/dark transition test and elevated plus-maze, 3 alpha,5 beta-P was more efficacious than 3 alpha,5 alpha-P, though both compounds had similar potencies. In the Geller-Seifter test, 3 alpha,5 beta-P was more potent and efficacious than 3 alpha,5 alpha-P. Neither compound had significant effects on unpunished responding within the dose range tested. Both compounds produced similar biphasic curves in the locomotor test. All together, the data indicate that 3 alpha,5 alpha-P and 3 alpha,5 beta-P have similar anticonvulsant activity, but the 5 beta-isomer possesses more potent and efficacious anxiolytic properties than the 5 alpha-isomer.

Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress. The objectives of the present study were to assess the safety, tolerability, and pharmacokinetics of arimoclomol in ALS. Eighty-four participants with ALS received arimoclomol at one of three oral doses (25, 50, or 100 mg three times daily) or placebo. The primary outcome measure was safety and tolerability. A subset of 44 participants provided serum and cerebrospinal fluid (CSF) samples for pharmacokinetic analysis. Participants who completed 12 weeks of treatment could enroll in a 6-month open-label study. Arimoclomol at doses up to 300 mg/day was well tolerated and safe. Arimoclomol resulted in dose-linear pharmacologic exposures and the half-life did not change with continued treatment. Arimoclomol CSF levels increased with dose. Arimoclomol was shown to be safe, and it crosses the blood-brain barrier. Serum pharmacokinetic profiles support dosing of three times per day. An efficacy study in ALS is planned.