Todd M. Hillhouse

Acute, but not repeated, administration of the neurotensin NTS1 receptor agonist PD149163 decreases conditioned footshock-induced ultrasonic vocalizations in rats.

Neurotensin is an endogenous neuropeptide that has significant interactions with monoamine neurotransmitter systems. To date, neurotensin NTS1 receptor agonists, such as PD149163, have been primarily evaluated for the treatment for schizophrenia, drug addiction, and pain. Recently, PD149163 was found to attenuate fear-potentiated startle in rats, an experimental procedure used for screening anxiolytic drugs. The present study sought to assess these findings through testing PD149163 in a conditioned footshock-induced ultrasonic vocalization (USV) model. Conditioning was conducted in male Wistar rats using chambers equipped with shock grid floors and an ultrasonic vocalization detector. PD149163 and the 5-HT1A receptor partial agonist buspirone produced a statistically significant reduction of 22kHz USV counts. The typical antipsychotic haloperidol also reduced 22kHz USV counts, but did so at cataleptic doses. Ten days of repeated administration of PD149163 abolished the inhibitory effects of PD149163 on 22kHz USVs. These findings further support an anxiolytic profile for PD149163. However, tolerance to these effects may limit the utility of these drugs for the treatment of anxiety.

Ketamine, but not MK-801, produces antidepressant-like effects in rats responding on a differential-reinforcement-of-low-rate operant schedule.

The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to produce rapid and lasting antidepressant effects in treatment-resistant patients with major depressive disorder and in preclinical behavioral assays. The present study sought to extend the preclinical antidepressant-like effects of ketamine using the differential-reinforcement-of-low-rate 72 s operant task in rats, as well as to determine whether the more selective and higher affinity NMDA receptor antagonist MK-801 produced antidepressant-like effects similar to those of ketamine. Ketamine, the NMDA receptor agonist N-methyl-D-aspartic acid, the tricyclic antidepressant imipramine, and the selective serotonin reuptake inhibitor fluoxetine all produced antidepressant-like effects by increasing the number of reinforcers, decreasing the number of responses, and producing a rightward shift in the peak location of the inter-response time distributions. Conversely, MK-801 and the dopamine receptor agonist D-amphetamine produced a psychostimulant-like effect by decreasing the number of reinforcers, increasing the number of responses, and producing a leftward shift in the peak location of the inter-response time distributions. Although a subeffective dose of ketamine attenuated the antidepressant-like effects of NMDA, a subeffective dose of NMDA did not alter the antidepressant-like effects of ketamine. These data indicate that ketamine and MK-801 produced dissociable effects in the differential-reinforcement-of-low-rate 72 s task, and further suggest that the underlying mechanisms responsible for the antidepressant effects of ketamine may be unique to ketamine and not shared by all NMDA receptor antagonists.

Effects of acute and sustained pain manipulations on performance in a visual-signal detection task of attention in rats.

Preclinical Research

Task- and Treatment Length–Dependent Effects of Vortioxetine on Scopolamine-Induced Cognitive Dysfunction and Hippocampal Extracellular Acetylcholine in Rats

Major depressive disorder (MDD) is a common psychiatric disorder that often features impairments in cognitive function, and these cognitive symptoms can be important determinants of functional ability. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in patients with MDD, including attention, processing speed, executive function, and memory. However, the cause of these effects is unclear, and there are several competing theories on the underlying mechanism, notably including regionally-selective downstream enhancement of glutamate neurotransmission and increased acetylcholine (ACh) neurotransmission. The current work sought to evaluate the ACh hypothesis by examining vortioxetine’s ability to reverse scopolamine-induced impairments in rodent tests of memory and attention. Additionally, vortioxetine’s effects on hippocampal extracellular ACh levels were examined alongside studies of vortioxetine’s pharmacokinetic profile. We found that acute vortioxetine reversed scopolamine-induced impairments in social and object recognition memory, but did not alter scopolamine-induced impairments in attention. Acute vortioxetine also induced a modest and short-lived increase in hippocampal ACh levels. However, this short-term effect is at variance with vortioxetine’s moderately long brain half life (5.1 hours). Interestingly, subchronic vortioxetine treatment failed to reverse scopolamine-induced social recognition memory deficits and had no effects on basal hippocampal ACh levels. These data suggest that vortioxetine has some effects on memory that could be mediated through cholinergic neurotransmission, however these effects are modest and only seen under acute dosing conditions. These limitations may argue against cholinergic mechanisms being the primary mediator of vortioxetine′s cognitive effects, which are observed under chronic dosing conditions in patients with MDD.

C7β-Methyl Analogues of the Orvinols: The Discovery of Kappa Opioid Antagonists with Nociceptin/Orphanin FQ Peptide (NOP) Receptor Partial Agonism and Low, or Zero, Efficacy at Mu Opioid Receptors

Buprenorphine is a successful analgesic and treatment for opioid abuse, with both activities relying on its partial agonist activity at mu opioid receptors. However, there is substantial interest in its activities at the kappa opioid and nociceptin/orphanin FQ peptide receptors. This has led to an interest in developing compounds with a buprenorphine-like pharmacological profile but with lower efficacy at mu opioid receptors. The present article describes aryl ring analogues of buprenorphine in which the standard C20-methyl group has been moved to the C7β position, resulting in ligands with the desired profile. In particular, moving the methyl group has resulted in far more robust kappa opioid antagonist activity than seen in the standard orvinol series. Of the compounds synthesized, a number, including 15a, have a profile of interest for the development of drug abuse relapse prevention therapies or antidepressants and others (e.g., 8c), as analgesics with a reduced side-effect profile.

Effects of the noncompetitive N-methyl-d-aspartate receptor antagonists ketamine and MK-801 on pain-stimulated and pain-depressed behaviour in rats.

Pain is a significant public health concern, and current pharmacological treatments have problematic side effects and limited effectiveness. N‐methyl‐d‐aspartate (NMDA) glutamate receptor antagonists have emerged as one class of candidate treatments for pain because of the significant contribution of glutamate signalling in nociceptive processing.

(S)-amisulpride as a discriminative stimulus in C57BL/6 mice and its comparison to the stimulus effects of typical and atypical antipsychotics

Amisulpride, a substituted benzamide derivative, exerts atypical antipsychotic and antidepressant clinical effects and its (S)-stereoisomer is thought to underlie these actions. In the present study, male C57BL/6 mice were trained to discriminate (S)-amisulpride (10mg/kg, s.c.) from vehicle in a two-lever drug discrimination task for food reward. The (S)-amisulpride stimulus was rapidly acquired and was shown to be dose-related, time dependent (effective between 30 and 120min) and stereoselective: (S)-amisulpride (ED50=1.77mg/kg; 4.2µmol/kg) was about three times more potent than rac-amisulpride (ED50=4.94mg/kg; 13.4µmol/kg) and ten times more potent than (R)-amisulpride (ED50=15.84mg/kg; 42.9µmol/kg). In tests of stimulus generalization, the (S)-amisulpride stimulus generalized completely to sulpiride (ED50=12.67mg/kg; 37.1µmol/kg), a benzamide analog that also is purported to be an atypical antipsychotic, but did not fully generalize to the typical antipsychotic drug haloperidol (maximum of 45% drug-lever responding) nor to the atypical antipsychotic drugs clozapine (partial substitution of 65% drug-lever responding) or aripiprazole (~30% drug-lever responding). These results demonstrated that (S)-amisulpride appears to exert a unique discriminative stimulus effect that is similar to other benzamides, but which differs from other structural classes of antipsychotic drugs.

Comparison of antidepressant-like and abuse-related effects of phencyclidine in rats

Preclinical Research

Effects of the noncompetitive N-methyl-D-aspartate receptor antagonist ketamine on visual signal detection performance in rats.

The noncompetitive N-methyl-D-aspartate receptor antagonist ketamine produces consistent, rapid, and sustained antidepressant effects in patients suffering from treatment-resistant depression. However, ketamine-induced cognitive impairments remain a major concern. The present study sought to extend the preclinical evaluation of ketamine-induced cognitive impairments by evaluating the dose (1.0–18.0 mg/kg) and time-course (10 min–24 h) of effects of ketamine on sustained attention using a visual signal detection procedure in rats. Overall, ketamine (10.0–18.0 mg/kg) dose-dependently decreased percent hit and correct rejection accuracy. Additionally, these same doses of ketamine increased response latency and trial omissions. In the time-course study, treatment with 18.0 mg/kg ketamine produced the greatest decrease in visual signal detection performance at 10 min, when ketamine decreased percent hit and correct rejection accuracy as well as increased response latency and trial omissions, but returned to saline baseline controls by 100 min. In conclusion, acute ketamine inhibited sustained attention in rats performing a visual signal detection task; however, these effects were short in duration, similar to the short duration (<2 h) of psychotomimetic effects reported in low-dose ketamine treatment in depressed patients.

The quetiapine active metabolite N-desalkylquetiapine and the neurotensin NTS₁ receptor agonist PD149163 exhibit antidepressant-like effects on operant responding in male rats.

Major depressive disorder is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that is apparent after 1 week of treatment, and it is possible that the active metabolite N-desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 suggest antidepressant efficacy, but the effects of a NTS₁ receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of N-desalkylquetiapine, PD14916, quetiapine, the tricyclic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate 72-s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. Raclopride decreased reinforcers and responses. These data suggest that N-desalkylquetiapine likely contributes to quetiapines antidepressant efficacy and identify NTS₁ receptor activation as a potential novel pharmacologic strategy for antidepressant drugs.