No abstract

Prepulse inhibition (PPI) of the acoustic startle reflex is a sensorimotor gating process known to be deficient in a number of neurologic and psychiatric conditions, including schizophrenia. Multiple lines of evidence have indicated that the dopaminergic and muscarinic cholinergic systems play an important role in modulating PPI. Moreover, interactions between the dopaminergic and muscarinic cholinergic systems are well known; however, little is known about potential interactions between the two systems in modulating PPI. Therefore, the purpose of the present studies was to determine whether interactions occur between the muscarinic cholinergic and dopaminergic systems in modulating PPI. The efficacy of muscarinic cholinergic receptor agonists in reversing the disruption of PPI induced by apomorphine, a D1/D2 dopamine receptor agonist, was evaluated in male Sprague-Dawley rats. The M1/M4-preferring muscarinic agonist xanomeline and the M2/M4-preferring agonistoctane oxalate] reversed the apomorphineinduced disruption of PPI in a manner similar to that produced by the D2-like dopamine receptor antagonists haloperidol and olanzapine. The muscarinic agonists oxotremorine, RS86, pilocarpine, milameline, and sabcomeline also reversed the apomorphine-induced disruption of PPI. Moreover, the muscarinic antagonist scopolamine also disrupted PPI, and the D2-like receptor antagonist haloperidol, but not the D1-like receptor antagonist SCH23390 [R-(ϩ)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine], reversed the scopolamine-induced disruption. In addition, xanomeline produced a significant reversal of the disruption in PPI produced by scopolamine. Collectively, the present findings demonstrate that a functional interaction occurs between the muscarinic cholinergic and dopaminergic systems in modulating PPI and that muscarinic cholinergic agonists may be effective in the treatment of the PPI and other cognitive impairments observed in schizophrenia.Prepulse inhibition (PPI) of the acoustic startle reflex is one of the best-characterized models used to evaluate sensory information-processing deficits observed in a number of neurologic and psychiatric conditions, including schizophrenia (Braff et al., 1992). PPI theoretically represents a mechanism for the gating or filtering out of irrelevant or distracting stimuli and is operationally defined as the reduction in startle response produced by a low-intensity stimulus presented before a high-intensity, startle-inducing stimulus (Graham, 1975). The role of various neurotransmitter systems in modulating PPI (Geyer et al., 2001) has been reviewed, and multiple lines of evidence have indicated that D2 dopamine receptors are critical for modulating PPI in rats (Peng et al., 1990;Swerdlow et al., 1994). In addition, a synergistic interaction between D1 and D2 dopamine receptors in mediating PPI also exists (Wan et al., 1996). For example, administration of the mixed D1/D2 dopamine receptor agonist apomorphine, the selective D2 dopamine receptor agon...

No abstract

No abstract

Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP (Transient Receptor Potential) super-family. It is a relatively underexplored member of the thermo-TRP sub-family (Figure 1), however, genetic mutations and use of gene knock-outs and selective pharmacological tools are helping to provide insights into its role and therapeutic potential. TRPV3 is highly expressed in skin, where it is implicated in skin physiology and pathophysiology, thermo-sensing and nociception. Gain of function TRPV3 mutations in rodent and man have enabled the role of TRPV3 in skin health and disease to be particularly well defined. Pre-clinical studies provide some rationale to support development of TRPV3 antagonists for therapeutic application for the treatment of inflammatory skin conditions, itch and pain. However, to date, only one compound directed towards block of the TRPV3 receptor (GRC15300) has progressed into clinical trials. Currently, there are no known clinical trials in progress employing a TRPV3 antagonist.

No abstract

No abstract

A major purpose of the present studies was to determine the effects of varying the relative frequency, or bias, of stimulus presentation at different locations in a five-choice serial reaction time attention task. Training sessions were conducted in which the stimulus duration was held constant at 2 s and, initially, stimuli were presented with equal probability above each of the levers. During testing sessions, however, stimulus duration was either 0.2 or 2 s, and the frequency of presentation was varied among no bias, a middle bias, a left bias or a right bias condition. The training conditions were then changed such that the frequency of presentation was always a left bias, and test sessions were again conducted with no, middle, left or right bias. In the presence of the 0.2-s, but not the 2.0-s, stimulus, the percentage of correct responding on each of the choice levers during test sessions varied directly with the bias conditions in that the percentage of correct responding was highest at the most frequently presented location and lowest at the least frequently presented location. In addition, scopolamine, but not metscopolamine, increased omissions while also increasing anticipatory responses in rats trained under left-bias conditions and tested under right-bias conditions. The present findings suggest that varying the frequency of stimulus location can provide additional measures of attention in the five-choice serial reaction time task.