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Major depressive disorder (MDD) is a major health concern in which approximately 30% of patients do not response to currently approved antidepressant medications and are classified as treatment-resistant patients. The noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine produces both rapid (<24 hr) and sustained (up to several weeks) antidepressant effects in treatmentresistant patients following acute or repeated i.v. infusions of ketamine (0.5 mg·kg −1 ), a finding that has been replicated across several clinical studies. Ketamine also has demonstrated abuse liability among illicit drug users and concerns regarding the possible neurotoxic, and psychotomimetic effects have limited ketamine's clinical use (see Hillhouse & Porter, 2015). These concerns have led to the development and evaluation of ketamine's isomers and their biologically active metabolites to assess safety concerns (i.e., reduced abuse concern), and to elucidate ketamine's mechanism of action.The recent paper by Zanos, Highland, Liu, et al. (2019) aims to fill these gaps in understanding ketamine's therapeutic potential by first examining if ketamine-associated abuse liability can be reduced. The (S)-ketamine enantiomer has higher affinity for NMDA receptors and is thought to be more responsible for the abuse-related effects of ketamine, in that preclinical data have found that (S)-ketamine produces antidepressant-like effects and abuse-related effects at comparable doses. For example, while (S)-ketamine produces antidepressantlike effects across several behavioral models at 10 mg·kg −1 ; (S)-ketamine also produces conditioned place preference (CPP), increases locomotor activity (LMA), and disrupts the startle reflex at 10 mg·kg −1 (Yang et al., 2015;Yang et al., 2017;Zanos et al., 2016;Zhang, Li, & Hashimoto, 2014). Conversely, (R)-ketamine appears to have reduced abuse liability as it failed to produce CPP, increased LMA, or disruption of the startle reflex response, although it should be noted that a limited dose range (10-20 mg·kg −1 ) was tested (Yang et al., 2015). Furthermore, results indicated that (R)-ketamine produces more potent and longer acting antidepressant-like effects, producing antidepressant-like effects as low as 5 mg·kg −1 (Zanos et al., 2016; Zanos, Highland, Liu, et al., 2019). The present study (Zanos, Highland, Liu, et al., 2019) builds upon these findings by demonstrating that (R)-ketamine produces abuse-related effects at doses four to 18 times higher than the antidepressant dose (5 mg·kg −1 ), including hyperactivity (40 mg·kg −1 ), CPP (40 mg·kg −1 ), motor impairments (20-40 mg·kg −1 ), and disrupted started reflex (90 mg·kg −1 ). In sum, the (R)-and (S)-ketamine enantiomers produce both antidepressantlike and abuse-related effects; however, the therapeutic window (i.e., antidepressant-like effects vs. abuse liability) is larger, and the antidepressant-like effects are sustained for longer periods of time for (R)ketamine, compared to (S)-ketamine. Taken together, with evidence which indic...

Preclinical Research Neurotensin is a nonbrain penetrant neuropeptide neurotransmitter that alters dopaminergic and serotonergic neurotransmission. Previous animal behavioral studies have demonstrated that intra-ventral tegmental administration of neurotensin and system administration of the selective neurotensin NTS receptor agonist, PD149163 produce antidepressant-like effects in a forced swim test and a differential reinforcement of low rate task, respectively. The present study sought to expand upon these past findings by assessing systemic administration of PD149163 in a forced swim test, a primary antidepressant preclinical screening model, in mice. The tricyclic antidepressant drug imipramine was tested for comparison, and both compounds were also assessed in an open field test. Both PD149163 and imipramine reduced time spent immobile, an antidepressant-like effect, in the forced swim test. The highest dose of each compound significantly reduced locomotor activity. These findings provide further evidence for the putative antidepressant effects for PD149163 and suggest that NTS receptor activation may be a novel pharmacologic strategy for antidepressant drug development. Drug Dev Res 78 : 196-202, 2017. © 2017 Wiley Periodicals, Inc.

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