Ulotaront, a novel TAAR1 agonist with 5-HT1A agonist activity, lacks abuse liability and attenuates cocaine cue-induced relapse in rats.

Background: Ulotaront (SEP-363856) is a trace amine-associated receptor 1 (TAAR1) agonist with 5-hydroxytryptamine type 1A (5-HT1A) agonist activity that is currently in Phase 3 clinical development for the treatment of schizophrenia. Unlike available antipsychotics, the efficacy of ulotaront is not mediated by blockade of dopamine D2 or serotonin 5-HT2A receptors. In a short-term randomized clinical trial, ulotaront has demonstrated significant efficacy in the treatment of adults with an acute exacerbation of schizophrenia.

Structural, kinetic, and pharmacodynamic mechanisms of D-amino acid oxidase inhibition by small molecules.

We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (Kd ≈ 2-4 μM). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (Kd ≈ 100-200 nM) and slow release kinetics (k < 0.

Pharmacodynamic effects of a D-amino acid oxidase inhibitor indicate a spinal site of action in rat models of neuropathic pain.

Inhibition of d-amino acid oxidase (DAAO) activity is a potential target for the treatment of chronic pain. Here we characterized the effects of systemic administration of the DAAO inhibitor 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN) in rat models of neuropathic and inflammatory pain. Oral administration of SUN dose dependently attenuated tactile allodynia induced by ligation of the L5 spinal nerve (SNL) and similarly reversed thermal hyperalgesia produced by chronic constriction injury.

Effect of gonadectomy and gonadal hormone replacement on cocaine self-administration in female and male rats.

Both sex and gonadal steroid hormones may influence the abuse-related behavioral effects of cocaine under some conditions, but there is considerable inconsistency in the literature. In the present study, rats were trained under a fixed ratio (FR) 5 schedule of food presentation and were then allowed to self-administer cocaine (1.0 mg/kg/injection) until behavior stabilized.

Effects of mixed-action kappa/mu opioids on cocaine self-administration and cocaine discrimination by rhesus monkeys.

kappa-Opioid agonists may functionally antagonize some behavioral effects of cocaine, but the role of mixed kappa/mu receptor activity is unclear. The effects of three mixed kappa/mu agonists (MCL-101, (-)cyclorphan, and Mr2034) and one kappa-selective agonist (enadoline) on cocaine self-administration and cocaine discrimination were compared in rhesus monkeys. Acute treatment with all kappa agonists dose dependently reduced cocaine-maintained responding and produced a downward shift in the cocaine self-administration dose-effect curve (0.

Comparison of plasma cocaine levels during a "binge" pattern of cocaine administration in male and female rhesus monkeys.

Rationale: Cocaine is often abused in a "binge" pattern, but little is known about changes in plasma cocaine concentrations or cocaine pharmacokinetics during administration of multiple cocaine doses. Moreover, the extent to which gender may influence plasma cocaine levels during a cocaine binge has not been studied in rhesus monkeys.

Objectives: To compare the effects of repeated injections of the same dose of cocaine (0.

Antagonism of the antinociceptive and discriminative stimulus effects of heroin and morphine by 3-methoxynaltrexone and naltrexone in rhesus monkeys.

It has been suggested that heroin and morphine may act on different opioid receptor populations in rodents. In support of this hypothesis, the opioid antagonist 3-methoxynaltrexone was reported to be more potent as an antagonist of the antinociceptive effects of heroin than of morphine in mice and rats. To assess the generality of this finding across species and experimental endpoints, the present study compared the potencies of naltrexone and 3-methoxynaltrexone as antagonists of heroin and morphine in two behavioral assays in rhesus monkeys.

The effects of heroin on prolactin levels in male rhesus monkeys: use of cumulative-dosing procedures.

There is considerable evidence that mu opioid receptors are involved in the regulation of anterior pituitary function. For example, in nonhuman primates and humans, mu agonists generally increase prolactin (PRL) levels. In contrast, mu antagonists decrease or have no effect on PRL levels.