Effects of subanesthetic ketamine and (2R,6R) hydroxynorketamine on working memory and synaptic transmission in the nucleus reuniens in mice.

RATIONALE: Acute cognitive impairment and abuse potential of ketamine incentivizes the search for alternatives to ketamine for clinical management of treatment-resistant depression. Recently, (2R,6R) hydroxynorketamine ((2R,6R)-HNK), a metabolite of ketamine, has shown promise due to its reported lack of ketamine-like reinforcing properties. Nonetheless, the effect of (2R,6R)-HNK on cognition has not been reported. METHOD: Adult male mice were placed in a Y-maze to measure spatial working memory (SWM) 24 h after treatment with either a single or repeated subanesthetic dose of (2R,6R)-HNK or ketamine. To determine the effect of the drug regimens on synaptic mechanisms in neural circuits deemed critical for SWM, we conducted patch-clamp electrophysiological recordings from neurons in the midline thalamic nucleus reuniens (RE) in response to optogenetic stimulation of medial prefrontal cortex (mPFC) inputs in acutely prepared brain slices. RESULTS: Single or repeated treatment with a 10 mg/kg dose of either drug did not impact performance in a Y-maze. However, single administration of a ½-log higher dose (32 mg/kg) of ketamine significantly reduced SWM. The same dose of (2R,6R)-HNK did not produce SWM deficits. Interestingly, repeated administration of either drugs at the 32 mg/kg had no effect on SWM performances. Concomitant to these effects on SWM, only single injection of 32 mg/kg of ketamine was found to increase the mPFC-driven action potential firing activity in the RE neurons. Conversely, both single and repeated administration of the 32 mg/kg dose of (2R,6R)-HNK but not ketamine, increased the input resistance of the RE neurons. CONCLUSION: Our results indicate that acute treatment of ketamine at 32 mg/kg increases mPFC-driven firing activity of RE neurons, and this contributes to the ketamine-mediated cognitive deficit. Secondly, sub-chronic treatment with the same dose of ketamine likely induces tolerance. Although single or repeated administration of the 32 mg/kg dose of (2R,6R)-HNK can alter intrinsic properties of RE neurons, this dose does not produce cognitive deficit or changes in synaptic mechanism in the RE. This article is part of the special Issue on 'Stress, Addiction and Plasticity'.

Nucleus Reuniens Afferents in Hippocampus Modulate CA1 Network Function via Monosynaptic Excitation and Polysynaptic Inhibition.

The thalamic midline nucleus reuniens modulates hippocampal CA1 and subiculum function via dense projections to the stratum lacunosum-moleculare (SLM). Previously, anatomical data has shown that reuniens inputs in the SLM form synapses with dendrites of both CA1 principal cells and inhibitory interneurons. However, the ability of thalamic inputs to excite the CA1 principal cells remains controversial. In addition, nothing is known about the impact of reuniens inputs on diverse subpopulations of interneurons in CA1. Therefore, using whole cell patch-clamp electrophysiology in ex vivo hippocampal slices of wild-type and transgenic mice, we measured synaptic responses in different CA1 neuronal subtypes to optogenetic stimulation of reuniens afferents. Our data shows that reuniens inputs mediate both excitation and inhibition of the CA1 principal cells. However, the optogenetic excitation of the reuniens inputs failed to drive action potential firing in the majority of the principal cells. While the excitatory postsynaptic currents were mediated via direct monosynaptic activation of the CA1 principal cells, the inhibitory postsynaptic currents were generated polysynaptically via activation of local GABAergic interneurons. Moreover, we demonstrate that optogenetic stimulation of reuniens inputs differentially recruit at least two distinct and non-overlapping subpopulations of local GABAergic interneurons in CA1. We show that neurogliaform cells located in SLM, and calretinin-containing interneuron-selective interneurons at the SLM/stratum radiatum border can be excited by stimulation of reuniens inputs. Together, our data demonstrate that optogenetic stimulation of reuniens afferents can mediate excitation, feedforward inhibition, and disinhibition of the postsynaptic CA1 principal cells via multiple direct and indirect mechanisms.

Effects of acute and repeated treatment with serotonin 5-HT2A receptor agonist hallucinogens on intracranial self-stimulation in rats.

The prototype 5-HT2A receptor agonist hallucinogens LSD, mescaline, and psilocybin are classified as Schedule 1 drugs of abuse by the U.S. Drug Enforcement Administration. Accumulating clinical evidence has also suggested that acute or repeated "microdosing" with these drugs may have utility for treatment of some mental health disorders, including drug abuse and depression. The goal of the present study was to evaluate LSD, mescaline, and psilocybin effects on intracranial self-stimulation (ICSS), a procedure that has been used to evaluate abuse-related effects of other classes of abused drugs. Effects of repeated LSD were also examined to evaluate potential changes in its own effects on ICSS or changes in effects produced by the abused psychostimulant methamphetamine or the prodepressant kappa opioid receptor (KOR) agonist U69,593. Male Sprague-Dawley rats were implanted with microelectrodes targeting the medial forebrain bundle and trained to respond under a "frequency-rate" ICSS procedure, in which many drugs of abuse increase (or "facilitate") ICSS. In acute dose-effect and time-course studies, evidence for abuse-related ICSS facilitation was weak and inconsistent; the predominant effect of all 3 drugs was dose- and time-dependent ICSS depression. Repeated LSD treatment failed to alter either its own ICSS depressant effects or the abuse-related effects of methamphetamine; however, repeated LSD did attenuate ICSS depression by U69,593. These results extend those of previous preclinical studies to suggest weak expression of abuse-related effects by 5-HT2A agonist hallucinogens and provide supportive evidence for therapeutic effects of repeated LSD dosing to attenuate KOR-mediated depressant effects but not abuse potential of psychostimulants. (PsycINFO Database Record (c) 2019 APA, all rights reserved).