GABAergic Antagonists Picrotoxin

The first study showing a possible involvement of the GABAergic system in memory was carried out by Breen and McGaugh11 with rats tested in an appetitively-motivated multiple T-maze. Posttraining intraperitoneal (i.p.) administrations of picrotoxin reduced significantly the number of errors made by the animals. This initial finding was confirmed by the observation of other investigators, using aversively-motivated as well as appetitively-motivated tasks. Studies carried out by Bovet et al9 showed that posttraining i.p. administrations of picrotoxin enhanced the rate of acquisition of a two-way avoidance learning in mice. Furthermore, enhanced learning of rats posttraining injected i.p. with this drug and trained in a Hebb-Williams maze was demonstrated by Garg and Holland.46

It must be stressed that, at the time of these studies, the mechanism of action of picrotoxin at the biochemical level was as yet unknown, and only later it was shown that its effects involved activation of the GABAergic neurotransmitter system.

More recently retention improvements have been shown, following posttraining i.p. administration of picrotoxin, in CD1 and CFW mice tested in a one-trial step-through inhibitory avoidance task and in a Y-maze task (Fig. 1).14,24,28 In these experiments the effects of picrotoxin were dose- and time-dependent. In particular the effects were no more evident when the animals were injected 120 min after training suggesting that they were due to a specific action of the drug on the time-dependent memory consolidation process. Furthermore, picrotoxin treatment did not affect the retention performance of animals unless they received footshock on the training trial. This excludes the possibility that the effects of the drug on retention performance were due to nonspecific influences on response latencies.72,77 It must

Figure 2. Dose-dependent effects ofimmediately posttraining i.p. injections ofmuscimol (upper graph) and bicuculline (lower graph) on retention, by mice, of a one-trial step-through inhibitory avoidance task. Each column indicates mean step-through latency (± SEM), in seconds, on the retention test trial (from ref. 27).

Figure 2. Dose-dependent effects ofimmediately posttraining i.p. injections ofmuscimol (upper graph) and bicuculline (lower graph) on retention, by mice, of a one-trial step-through inhibitory avoidance task. Each column indicates mean step-through latency (± SEM), in seconds, on the retention test trial (from ref. 27).

be finally considered that enhancement of latent extinction of conditioned fear, following posttraining i.p. administrations of picrotoxin, has been described in mice tested in a visual discrimination task.78

Amnesia, instead of memory improvement, has been reported following posttraining i.p. administration of picrotoxin in rats trained in a one-trial step-down inhibitory avoidance test. 6 As observed by Brioni12, it is possible that this effect was the consequence of the high shock intensity used in these experiments, and that picrotoxin could induce amnesia at high doses if a high shock is used. In particular, the controls in the Nabeshima and Noda86 study showed high retention latencies, suggesting that the footshock intensity was high for the animals used in their study. Indeed, some posttraining treatments, such as acetylcholine and epinephrine, enhance retention performance when low footshock intensities are administered in the training, but impair retention when, in the training session, high footshock intensity is used.48,49,59,60

Bicuculline

Effects on memory comparable to those exerted by picrotoxin have been found in a number of studies following peripheral (i.p.) bicuculline administration.

Retention enhancement following posttraining bicuculline administrations in rats tested in an active avoidance task has been reported.115 In further studies CD1 mice were used (Fig. 2).27 They were injected with the drug immediately or 120 min after training in a one-trial step-through inhibitory avoidance task. As compared with saline injected animals, retention improvement was observed in animals injected immediately after training, while no effect was evident in mice following 120 min posttraining injection. This suggests that the effects exerted by bicuculline were due to a specific action on the time-dependent memory consolidation process. Further, posttraining administrations of bicuculline did not affect retention latencies of unshocked controls, indicating that the effects of the drug on retention performance were not due to nonspecific effects on response latencies.24 In a further study,1 carried out with CFW mice, the animals were injected i.p. after training with bicuculline in two aversively-motivated tasks, inhibitory avoidance and Y maze discrimination. Bicuculline methiodide (BMI, a GABAa receptor antagonist that does not readily cross the blood-brain barrier)-injected groups were also used. In both tasks bicuculline enhanced retention performance of the animals in a dose- and time-dependent way. Further, retention was not affected by the posttraining administration of bicuculline methiodide. These findings suggest the involvement of central GABAergic processes in the effects observed. It must be underlined that other studies have more recently confirmed that bicuculline improves memory consolidation in CD1 mice tested in a one-trial step-through inhibitory avoidance task.22,25,54 Nabeshima et al87 found, as in the case of picrotoxin, amnesia also following posttraining i.p. administration of bicuculline in mice tested in an inhibitory avoidance task. As for picrotoxin, this finding could be due to the high footshock intensity used in these experiments (see also above, picro-toxin section).

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