Relative potency and effectiveness of flunitrazepam, ethanol, and beta-CCE for disrupting the acquisition and retention of response sequences in rats

Abstract

Despite the knowledge that GABA A modulators can affect learning and memory, their capacity for disrupting each of these complex processes is rarely compared, and often mistakenly assumed to occur with identical potency. For these reasons, the effects of flunitrazepam (0.056-3.2 mg/kg), ethanol (0.25-1.5 g/kg), and β-CCE (ethyl-β-carboline-3-carboxylate; 1-17.8 mg/kg) were compared in groups of rats responding under baselines that assessed learning and memory separately. The first baseline was a multiple schedule of repeated acquisition and performance of tandem response sequences, whereas the second baseline was a retention or memory procedure where a tandem response sequence was acquired and then retested after a 30-min delay. Under both procedures, responding was maintained under a second-order fixed-ratio (FR) 2 schedule of food reinforcement, and incorrect responding (errors) produced a 5-sec timeout. With regard to the effects of the three drugs on sequence acquisition (learning), all three drugs dose-dependently decreased the overall response rate and increased the percentage of errors. Both flunitrazepam and β-CCE affected accuracy more potently than response rate, whereas ethanol was equipotent in affecting these two dependent measures. With regard to the effects of these drugs on sequence retention (memory), both flunitrazepam and ethanol dose-dependently decreased retention at doses that had little or no effect on sequence acquisition under the multiple schedule, whereas β-CCE decreased retention and sequence acquisition similarly at the doses tested. Together, these data demonstrate that drugs with differing capacities for altering the function of GABA A receptors differ in their capacity for disrupting the acquisition and retention of response sequences and that positive modulation of this receptor complex may be more predictive of disruptions in memory than disruptions in learning.

Effects of pregnanolone and flunitrazepam on the retention of response sequences in rats

“…When administered alone, the dose-dependent decreases in retention obtained with pregnanolone were similar to the decreases seen with flunitrazepam, a benzodiazepine that gained notoriety in the 1990's for its use in drug-facilitated rape (Ohshima, 2006; Saum and Inciardi, 1997). More specifically, pregnanolone produced decreases in retention at doses that did not affect response rate or the percentage of errors, similar to flunitrazepam (Leonard et al , 2009; Pompeia et al , 1996) and other benzodiazepines (Auta et al , 1995; Block and Berchou, 1984; Woodworth and Schlosberg, 1961) that have been shown to disrupt retention/retrieval. In the study by Leonard et al (2009), the disruptions in retention also occurred at doses lower than those that disrupted the acquisition and performance of response sequences under a multiple schedule.…”

“…More specifically, pregnanolone produced decreases in retention at doses that did not affect response rate or the percentage of errors, similar to flunitrazepam (Leonard et al , 2009; Pompeia et al , 1996) and other benzodiazepines (Auta et al , 1995; Block and Berchou, 1984; Woodworth and Schlosberg, 1961) that have been shown to disrupt retention/retrieval. In the study by Leonard et al (2009), the disruptions in retention also occurred at doses lower than those that disrupted the acquisition and performance of response sequences under a multiple schedule. The potent effects of the benzodiazepines on the retention of an acquired were not surprising, however, as Thompson et al (1986) previously showed that “within-session” performance was more sensitive to the amnestic effects of phencyclidine than “between-session” performance in patas monkeys.…”

“…Similar to previous studies conducted in this laboratory (Leonard et al , 2009; Thompson et al , 1986), the present study used a repeated acquisition and delayed-performance baseline to assess the effects of two drugs (pregnanolone and flunitrazepam) on the retention of recently acquired information over both a short (30-minute) and long (180-minute) delay. In general, the observed decrease in retention over time indicated that the baseline was sensitive for measuring time-dependent disruptions in retention, while the observed decreases in retention after drug administration indicated that both drugs have retrograde amnestic effects.…”

“…In order to assess the capacity of pregnanolone to disrupt retention, a repeated-acquisition technique (Thompson, 1986) was used, which assayed retention by requiring subjects to acquire a sequence of responses and then, within that same session, repeat that sequence of responses after some delay. This procedure has been shown to produce both high and low levels of retention depending on the delay and produce drug-induced disruptions of retention in monkeys (Thompson et al , 1986) and rats (Leonard et al , 2009). The procedure is considered to be a repeated-acquistion procedure because a different sequence was acquired each session.…”

“…He points to the results with “memory enhancers” in particular, which enhance memory under many of these existing tasks, but rarely enhance memory in humans (Sarter et al , 1992a; Sarter et al , 1992b). One advantage of the repeated-acquisition technique, in particular, is that it has been used to characterize the effects of a variety of drugs on learning and memory in animals and humans, and these effects have been consistent across species (Auta et al , 1995; Desjardins et al , 1982; Leonard et al , 2009; Savage et al , 1996; Thompson et al , 1986). …”