Effects of chlordiazepoxide and FG 7142 on a rat model of diencephalic amnesia as measured by delayed-matching-to-sample performance

Abstract

The intralaminar thalamic nuclei (ILn) have been implicated as a critical site of pathology in amnesia. Lesions of the ILn have been found to produce behavioral effects comparable to benzodiazepine (BDZ) receptor agonists. We compared the effects of chlordiazepoxide (CDP), a BDZ agonist, and FG 7142, a partial inverse agonist at the BDZ receptor, in rats with thalamic lesions and in unlesioned controls. Delayed matching-to sample (DMS) performances were studied during treatment with ascending doses of CDP, counterbalanced trials with 2.5 mg/kg CDP and saline, ascending doses of FG 7142, and (for unlesioned controls only) counterbalanced trials with saline and higher doses of CDP. CDP had effects similar to the ILn lesion, decreasing response speed and percent correct responding in a delay-independent fashion. These effects were additive with the impairments associated with the ILn lesion. The effects of FG 7142 were more complex. At lower doses, it increased response speed without affecting response accuracy. At higher doses, it diminished both the speed and the accuracy of DMS responding. These results support the hypothesis that ILn lesions and BDZ agonists have similar effects on DMS performance. The biphasic effects observed for FG 7142 are consistent with other evidence that low doses of this drug enhance while higher doses impair memory performance. Although DMS accuracy was not improved, the enhancement observed for response speed provides evidence that partial inverse BDZ agonists have potential utility as treatments for cognitive impairments associated with amnesia.

Determination of the Effectiveness of Components of the Herbal Medicine Toki-Shakuyaku-San and Fractions of Angelica acutiloba in Improving the Scopolamine-Induced Impairment of Rat’s Spatial Cognition in Eight-Armed Radial Maze Test

“…FG7142 is a partial inverse agonist of benzodiazepine that could indirectly increase the mnemonic function of cholinergic neurons by reducing the GABA-ergic inhibition. FG7142 has been reported to reverse scopolamineinduced mistakes (35) and to improve memory when injected into the nucleus basalis prior to training in the double Y-maze (36,37) and intralaminar thalamic nuclei in delayed matching-to sample (38). It should be noted that FG7142 improved the memory at 0.01 mg / kg by increasing the CC and decreasing the EC.…”

“…It produced no effect at 0.1 mg / kg, whereas at 1 mg/ kg it decreased the EC without affecting the CC. This result may be attributed to the biphasic property of the effect of FG7142 due to increasing performance at low dose and decreasing it at high dose (38,39).…”

Cognitive Activation by Central Thalamic Stimulation: The Yerkes-Dodson Law Revisited

“…FG-7142 is an inverse benzodiazepine agonist that has an allosteric effect reducing the affinity of GABA A receptors for GABA and thus decreasing the level of inhibition. Previous studies have shown evidence of an inverted-U dose response curve when FG-7142 was administered systematically in rats performing the DMTP task (Cole and Hillman, 1991; Burk et al , 1999). Here similar results were observed for intrathalamic injections (Figure 3).…”