Locomotor hyperactivity following treatment was measured using automated photocell cages.
Similar to phencyclidine, 5,7-DHT-induced lesions of the dorsal hippocampus enhanced ketamine-induced hyperlocomotion at all
doses. They also reduced methamphetamine-induced hyperlocomotion at the high dose only and caused a minor, biphasic modulation of responses to cocaine. Locomotor Dabrafenib manufacturer responses to d-amphetamine and MDMA were unchanged by lesions of the dorsal hippocampus. Serotonergic lesions of the ventral hippocampus did not significantly alter locomotor hyperactivity induced by any of the drugs investigated.
These findings further implicate a role for serotonin in the dorsal hippocampus in modulating the behavioral effects of dissociative anesthetics, such as ketamine, with more subtle effects on psychostimulant drugs of abuse. The dorsal hippocampus may be a site of serotonergic dysfunction in aspects of schizophrenia.”
“A
condition of excess activity in the hippocampal formation is observed in the aging brain and in conditions that confer additional risk during aging for Alzheimer’s disease. Compounds that act as positive allosteric modulators at GABA(A) alpha 5 receptors BMS345541 might be useful in targeting this condition because GABA(A) alpha 5 receptors mediate tonic inhibition of principal neurons in the affected network. While agents to improve cognitive function in the past focused on inverse agonists, which are negative allosteric modulators at GABA(A) alpha 5 receptors, research supporting that approach used only young animals and predated current evidence for excessive hippocampal activity in age-related conditions of cognitive impairment. Here, we used two compounds, Compound 44 [6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one] and Compound 6 [methyl 3,5-diphenylpyridazine-4-carboxylate], with functional activity as potentiators of gamma-amino-butyric acid at GABA(A) alpha 5 receptors, to test their ability to improve hippocampal-dependent
memory in aged rats with identified cognitive impairment. Improvement was obtained in aged rats across protocols differing in ADAMTS5 motivational and performance demands and across varying retention intervals. Significant memory improvement occurred after either intracereboventricular infusion with Compound 44 (100 mu g) in a water maze task or systemic administration with Compound 6 (3 mg/kg) in a radial arm maze task. Furthermore, systemic administration improved behavioral performance at dosing shown to provide drug exposure in the brain and in vivo receptor occupancy in the hippocampus. These data suggest a novel approach to improve neural network function in clinical conditions of excess hippocampal activity.
This article is part of a Special Issue entitled ‘Cognitive Enhancers’. (C) 2012 Elsevier Ltd. All rights reserved.