No abstract

NMDA receptor (NMDAR) antagonists, such as phencyclidine, ketamine, or dizocilpine (MK-801) are commonly used in psychiatric drug discovery in order to model several symptoms of schizophrenia, including psychosis and impairments in working memory. In spite of the widespread use of NMDAR antagonists in preclinical and clinical studies, our understanding of the mode of action of these drugs on brain circuits and neuronal networks is still limited. In the present study spontaneous local field potential (LFP), multi- (MUA) and single-unit activity, and evoked potential, including paired-pulse facilitation (PPF) in response to electrical stimulation of the ipsilateral subiculum were carried out in the medial prefrontal cortex (mPFC) in urethane anesthetized rats. Systemic administration of MK-801 (0.05 mg/kg, i.v.) decreased overall MUA, with a diverse effect on single-unit activity, including increased, decreased, or unchanged firing, and in line with our previous findings shifted delta-frequency power of the LFP and disrupted PPF (Kiss et al., 2011). In order to provide further insight to the mechanisms of action of NMDAR antagonists, MK-801 was administered intracranially into the mPFC and mediodorsal nucleus of the thalamus (MD). Microinjections of MK-801, but not physiological saline, localized into the MD evoked changes in both LFP parameters and PPF similar to the effects of systemically administered MK-801. Local microinjection of MK-801 into the mPFC was without effect on these parameters. Our findings indicate that the primary site of the action of systemic administration of NMDAR antagonists is unlikely to be the cortex. We presume that multiple neuronal networks, involving thalamic nuclei contribute to disrupted behavior and cognition following NMDAR blockade.

Kappa opioid receptors (KORs) have been implicated in anxiety and stress, conditions that involve activation of projections from the basolateral amygdala (BLA) to the medial prefrontal cortex (mPFC). Although KORs have been studied in several brain regions, their role on mPFC physiology and on BLA projections to the mPFC remains unclear. Here, we explored whether KORs modify synaptic inputs from the BLA to the mPFC using in vivo electrophysiological recordings with electrical and optogenetic stimulation. Systemic administration of the KOR agonist U69,593 inhibited BLA-evoked synaptic responses in the mPFC without altering hippocampus-evoked responses. IntramPFC U69,593 inhibited electrical and optogenetic BLA-evoked synaptic responses, an effect blocked by the KOR antagonist nor-BNI. Bilateral intra-mPFC injection of the KOR antagonist nor-BNI increased center time in the open field test, suggesting an anxiolytic effect. The data demonstrate that mPFC KORs negatively regulate glutamatergic synaptic transmission in the BLA-mPFC pathway and anxiety-like behavior. These findings provide a framework whereby KOR signaling during stress and anxiety can regulate the flow of emotional state information from the BLA to the mPFC.

No abstract

Background Essential tremor is the most common movement disorder with clear unmet need. Mounting evidence indicates tremor is caused by increased neuronal burst firing and oscillations in cerebello‐thalamo‐cortical circuitry and may be dependent on T‐type calcium channel activity. T‐type calcium channels regulate sigma band electroencephalogram (EEG) power during non‐rapid eye movement sleep, representing a potential biomarker of channel activity. PRAX‐944 is a novel T‐type calcium channel blocker in development for essential tremor. Objectives Using a rat tremor model and sigma‐band EEG power, we assessed pharmacodynamically‐active doses of PRAX‐944 and their translation into clinically tolerated doses in healthy participants, informing dose selection for future efficacy trials. Methods Harmaline‐induced tremor and spontaneous locomotor activity were used to assess PRAX‐944 efficacy and tolerability, respectively, in rats. Sigma‐power was used as a translational biomarker of T‐type calcium channel blockade in rats and, subsequently, in a phase 1 trial assessing pharmacologic activity and tolerability in healthy participants. Results In rats, PRAX‐944 dose‐dependently reduced tremor by 50% and 72% at 1 and 3 mg/kg doses, respectively, without locomotor side effects. These doses also reduced sigma‐power by ~30% to 50% in rats. In healthy participants, sigma‐power was similarly reduced by 34% to 50% at 10 to 100 mg, with no further reduction at 120 mg. All doses were well tolerated. Conclusions In rats, PRAX‐944 reduced sigma‐power at concentrations that reduced tremor without locomotor side effects. In healthy participants, comparable reductions in sigma‐power indicate that robust T‐type calcium channel blockade was achieved at well‐tolerated doses that may hold promise for reducing tremor in patients with essential tremor. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society