A comparison of the effects of the novel muscarinic receptor agonists L-689,660 and AF102B in tests of reference and working memory

Abstract

Four experiments compared the CNS effects of a novel M1/M3 receptor agonist L-689,660 with those of the M1/M3 muscarinic receptor agonist AF102B. In the mouse tail-flick test of antinociception (TF) the minimum effective doses to increase tail-flick latency (MED) of L-689,660 and AF102B were 0.03 mg/kg and 10.0 mg/kg, respectively. In a rat conditioned-suppression-of-drinking (CSD) test of reference memory, doses of 0.3 and 1.0 mg/kg L-689,660 and a dose of 5.0 mg/kg AF102B reversed a scopolamine-induced deficit in performance (0.6 mg/kg). Although there was a tendency for L-689,660 to reverse the scopolamine-induced (0.4 mg/kg) performance deficit in a rat delayed-matching-to-position (DMTP) test, the difference failed to reach statistical significance. In contrast, a 5.0 mg/kg dose of AF102B potentiated the scopolamine-induced deficit in choice accuracy and the number of trials completed on this task. In a response sensitivity (RS) test, chain-pulling rates were significantly decreased by L-689,660 (MED = 0.03 mg/kg) and by AF102B (MED = 5.0 mg/kg). These results suggest that L-689,660 and AF102B may ameliorate or reverse a scopolamine-induced deficit, but only at doses that also reduce chain-pulling rates on operant schedules of reinforcement.

Animal models of dementia

“…Other compounds have also been investigated in delayed rriatcliing procedures, usually using the stabilized performance phase. Deacon 119911 reported that scopolarnirre-iirdriced deficits in a delayed nonmatching task were attenuated by the cholinornirnctics physostigmine and tacrine, with similar findings being described b y Dawson et al [1994] for the novel rnuscarinic agonists L-689660 arid AF102B. On the other hand, two choliiiergic agonists (arccolinc, physostigmine) did not correct the delay-dependent deficits in aged animals [Dunnett et al, 19881. Cole et al [1994] reported that memory performance in normal young rats and in rats impaired I)y scopolamine was erilianced by acute treatrnciiLs with the 5-FIT,, agonists 8-OH DPAT and ipsapirone at long retention delays, but another group did not confirin these findings with ipsapirone [Jansen and Andrews, 19941.…”

Anxiogenic properties of an inverse agonist selective for α3 subunit‐containing GABAA receptors

“…Although a reduced responding rate in this paradigm has been used to assess the level of sedation produced by benzodiazepine site agonists (Bayley et al ., 1996), the impairments produced by α 3IA and FG 7142 are unlikely to be due to sedation since FG 7142 increases, rather than decreases, attention (Sarter et al ., 2001). Rather, the decreased performance presumably serves as a marker of a lack of well‐being (Dawson et al ., 1994). Consequently, the effects of α 3IA and FG 7142 on reducing chain‐pulling performance may well reflect an anxiogenic state that could manifest itself as a decrease in responding rate (Dawson et al ., 1995).…”

A Proposed Test Battery and Constellations of Specific Behavioral Paradigms to Investigate the Behavioral Phenotypes of Transgenic and Knockout Mice

“…Good reference sources inbrain function. Prepulse inhibition is employed to evalclude major textbooks and review articles (Becker et al, uate sensorimotor gating (Braff and Geyer, 1990;Paylor 1992;Crawley, 1985Crawley, , 1989Crawley et al, in and Crawley, in press). The prepulse inhibition parapress; Iversen and Iversen, 1981;Koob et al, 1989; digm quantitates the normal suppression of a startle Seiden and Balster, 1985;Willner, 1995).…”