Effects of midazolam on acquisition and extinction of conditioned taste aversion memory in rats

Abstract

Some intravenous anesthetic agents such as midazolam are known to induce anterograde and retrograde amnesia. We analysed the effect of midazolam by the conditioned taste aversion (CTA) acquisition and retention. After the rats were offered 0.1% sodium saccharin (Sac) as conditioned stimulus (CS), an intraperitoneal (i.p.) injection of several concentrations (5 ~ 30 mg/kg) of midazolam was followed by an i.p. injection of 0.15 M LiCl (2% of body weight) as unconditioned stimulus (US). The rats, which acquired CTA by every CS-US paradigm, strongly avoided Sac on the 1st test day after conditioning and maintained the avoidance for 3 days. We have already reported that Sac intake abruptly increased on the 2nd test day and the almost complete extinction occurred on the 3rd test day after conditioning by injection of subhypnotic dose of propofol before LiCl-injection. In contrast, we found that subhypnotic dose of midazolam suppressed not only CTA acquisition, but also CTA retention. On the other hand, an α2-adrenergic blocker, yohimbin (1 mg/kg) suppressed only the CTA retention. These results suggest that the subhypnotic doses of midazolam firstly affect the acquisition mechanism of the CTA memory (CTAM ), resulting the suppression of the retention of CTAM.Key words: midazolam ; CTA; memory; acquisition; extinction; amnesia, Yohimbin, noradrenergic system -3 -Intravenous anesthetics such as midazolam, one of benzodiazepine anesthetic agents, which possess both γ-aminobutylic acid (GABA)-like [13,29], are known to induce anterograde and retrograde amnesia in human [16,17] and rodents [24,26]. In rodents, it has been reported that anterograde amnesia of an avoidance task was elicited by subhypnotic doses of the intravenous anesthetics, but retrograde amnesia was induced merely by hypnotic doses of these anesthetics [24,25,27].Previous works using a CTA paradigm, where conditioned taste aversion memory (CTAM) related to malaise is formed when an animal consumes a novel taste such as saccharin (conditioned stimulus, CS) and then experiences the symptoms of poisoning such as LiCl (unconditioned stimulus, US) [9], show that the strong CTA is established rapidly by novel taste stimuli in a single learning procedure [5,32]. The association between the CS and the US can proceed under deep anesthesia induced by pentobarbital or ketamine when hypnotic doses of these anesthetics are administrated after CS-presentation, or subhypnotic doses of them, which do not impair drinking, was applied before CS-presentation [6,33].However, subhypnotic doses of the intravenous anesthetics are often used for disabled patients even in light operation such as extraction of teeth to sedate their hyperactivity [22,31]. We often encounter patients, who have lost the memory during operation after administration of sedative dose of these intravenous anesthetics while they preserved their consciousness during operation [22]. In the previous paper [15], we reported that subhypnotic but not hypnotic doses of propofol, one of non-benzodiazepine...

The effect of androgen on the retention of extinction memory after conditioned taste aversion in mice

“…Pre-conditioning control values of standard DW intake (SDW) are the mean of DW intake for the final 3 days of the water-restriction training period. Total Sac intake (%) on conditioning (C1-C3) and extinction (E1-E7) days were calculated as percentages against SDW, because saccharin intake on C1 is highly influenced by degree of neophobia to CS as a novel taste [16,20]. Because E1 was the day after the final conditioning day (C3), we used Sac intake on E1 as the parameter for acquisition of CTA memory.…”

“…The difference between the acquisition and retention processes of memory has been demonstrated by a number of reports using the local blockade of N-methyl-D-aspartate receptor [6,7], protein synthesis of b-adrenergic receptor [13,14] in brain regions related to CTA memory or the extinction memory, the intraperitoneal injection of anesthetics, such as propofol or the a2-adrenergic blocker, yohimbine, [15,16] or a point mutation strategy in mice [17].…”

The anaesthetic combination of ketamine/midazolam does not alter the acquisition of spatial and motor tasks in adult mice

“…17 As was observed in humans, 18 midazolam caused temporary deficits in the acquisition of new memories (anterograde amnesia) in rodents. 19…”

“…17 As was observed in humans, 18 midazolam caused temporary deficits in the acquisition of new memories (anterograde amnesia) in rodents. 19 The possible effects of the ketamine/midazolam combination on cognition may have not only clinical, but also research implications related to the welfare and normal behaviour of the animals. A deviation in behaviour caused by the anaesthesia could alter the outcome of research projects, especially in the neuroscience area.…”

Gene Network Analysis in Amygdala following Taste Aversion Learning in Rats

“…Adrenergic receptor antagonists are found to induce activity of noradrenergic neurons by blocking autoreceptors [ 38 ]. Recent studies also showed that an α 2-adrenergic blocker, yohimbine (1 mg/kg) suppressed the CTA acquisition and retention in rats [ 39 ]. In another study, an alpha-2 adrenoreceptor antagonist, methoxy-idazoxan (RX821002), was found to enhance the extinction of CTA in rats by enhancing arousal, alertness, awareness, or attention [ 36 ].…”