Effect of Kv3 channel modulators on auditory temporal resolution in aged Fischer 344 rats.

AUT00063 and AUT00202 are novel pharmaceutical modulators of the Kv3 subfamily of voltage-gated K+ channels. Kv3.1 channels, which control fast firing of many central auditory neurons, have been shown to decline with age and this may contribute to age-related deficits in central auditory processing. In the present study, the effects of the two novel compounds that specifically modulate Kv3 channels on auditory temporal processing were examined in aged (19-25-month-old) and young-adult (3-5 month-old) Fischer 344 rats (F344) using a behavioral gap-prepulse inhibition (gap-PPI) paradigm. The acoustic startle response (ASR) and its inhibition induced by a gap in noise were measured before and after drug administration. Hearing thresholds in tested rats were evaluated by the auditory brainstem response (ABR). Aged F344 rats had significantly higher ABR thresholds, lower amplitudes of ASR, and weaker gap-PPI compared with young-adult rats. No influence of AUT00063 and AUT00202 administration was observed on ABR hearing thresholds in rats of both age groups. AUT00063 and AUT00202 had suppressive effect on ASR of F344 rats that was more pronounced with AUT00063. The degree of suppression depended on the dose and age of the rats. Both compounds significantly improved the gap-PPI performance in gap detection tests in aged rats. These results indicate that AUT00063 and AUT00202 may influence intrinsic firing properties of neurons in the central auditory system of aged animals and have the potential to treat aged-related hearing disorders.

Using interleaved transcranial magnetic stimulation/functional magnetic resonance imaging (fMRI) and dynamic causal modeling to understand the discrete circuit specific changes of medications: lamotrigine and valproic acid changes in motor or prefrontal effective connectivity.

The purpose of this study was to use interleaved transcranial magnetic stimulation/functional magnetic resonance imaging (TMS/fMRI) to investigate the effects of lamotrigine (LTG) and valproic acid (VPA) on effective connectivity within motor and corticolimbic circuits. In this randomized, double-blind, crossover trial, 30 healthy volunteers received either drug or placebo 3.5 h prior to interleaved TMS/fMRI. We utilized dynamic causal modeling (DCM) to assess changes in the endogenous effective connectivity of bidirectional networks in the motor-sensory system and corticolimbic circuit. Results indicate that both LTG and VPA have network-specific effects. When TMS was applied over the motor cortex, both LTG and VPA reduced TMS-specific effective connectivity between primary motor (M1) and pre-motor cortex (PMd), and between M1 and the supplementary area motor (SMA). When TMS was applied over prefrontal cortex, however, LTG alone increased TMS-specific effective connectivity between the left dorsolateral prefrontal cortex(DLPFC) and the anterior cingulate cortex (ACC). In summary, LTG and VPA inhibited effective connectivity in motor circuits, but LTG alone increased effective connectivity in prefrontal circuits. These results suggest that interleaved TMS/fMRI can assess region- and circuit-specific effects of medications or interventions.

Automated patch clamping using the QPatch.

Whole-cell voltage clamp electrophysiology using glass patch pipettes (1) is regarded as the gold standard for measurement of compound activity on ion channels. Despite the high quality of the data generated by this method, in its traditional format, patch clamping has limited use in drug screening due to very low throughput. Over the years, developments in microfabrication have driven the development of planar, multi-aperture technologies that are suitable for parallel, automated patch recording techniques. Here we present detailed methods for two common applications of the planar patch technology using one of the commercially available instruments. The results demonstrate (a) the high quality of whole-cell recordings obtainable from cell lines expressing human Nav1.2 or hERG ion channels, (b) the advantages of the methodology for increasing throughput, and (c) examples of how these assays support ion channel drug discovery.

Lamotrigine and valproic acid have different effects on motorcortical neuronal excitability.

To investigate different cortical effects of lamotrigine and valproic acid, 30 paid healthy adult men were given, in a randomized/blinded fashion on three separate days (separated by a week), either a single dose of lamotrigine 325 mg, or a single dose of valproic acid 1,250 mg, or placebo. Resting motor threshold (RMT), cortical silent period (CSP) and motor evoked potential recruitment curves (RC) were assessed at baseline and 3 h after administration of each medication (or placebo). Lamotrigine caused a significant increase (63.32 vs. 69.25) in the RMT, compared with an insignificant increase following valproic acid (62.50 vs. 63.35), and a decrease (62.60 vs. 62.36) following placebo (F (2,26) = 18.58, P < 0.0001). No significant difference in CSP was found between placebo and drugs (F (2,26) = 0.119, P > 0.05). RCs were significantly suppressed by lamotrigine (t = 2.07, P < 0.05) and enhanced by valproic acid (t = 2.39, P < 0.05). Lamotrigine and valproic acid have different effects on cortical neuronal excitability as demonstrated by TMS.

Lamotrigine prevents ketamine but not amphetamine-induced deficits in prepulse inhibition in mice.

RATIONALE: Lamotrigine, a broad-spectrum anticonvulsant known to block brain sodium channels, is effective in the treatment of persons with bipolar disorder, perhaps by virtue of its ability to reduce glutamate release. Furthermore, lamotrigine decreases the perceptual abnormalities produced by the N-methyl- d-aspartate (NMDA) antagonist ketamine in humans, similar to the effects of the atypical antipsychotic clozapine. Acutely manic bipolar patients, like persons with schizophrenia, Tourette's, and obsessive compulsive disorder, exhibit decreases in sensorimotor gating, as measured by prepulse inhibition of the startle response (PPI). OBJECTIVE: We assessed the ability of lamotrigine to reduce the PPI-disruptive effects of ketamine and the dopaminergic agent amphetamine in two inbred mouse strains, C57BL/6J and 129SvPasIco. METHODS: Mice were tested in a standard PPI paradigm after administration of lamotrigine (0, 6.7, 13, or 27 mg/kg) or a combination of lamotrigine (27 mg/kg) and either d-amphetamine (10 mg/kg) or ketamine (100 mg/kg). RESULTS: In the 129SvPasIco mice, lamotrigine reversed the ketamine-induced PPI deficit, without altering PPI in control mice. In C57BL/6J mice, however, 27 mg/kg lamotrigine generally increased PPI in both control and ketamine-treated mice. Lamotrigine did not ameliorate the amphetamine-induced PPI deficit in either strain. CONCLUSIONS: In conclusion, lamotrigine can increase PPI on its own and prevent ketamine-induced, but not amphetamine-induced, disruptions of PPI. These results suggest that lamotrigine may exert its effects on PPI through the glutamatergic system.