GABAergic Drugs and Memory Formation Administrations into Brain Structures

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The possibility that GABAergic agonists and antagonists exert their effects on memory as a consequence of specific actions on central GABAergic receptors has been examined by a number of studies.

The first brain structure considered has been the amygdala. It is known that retention can be modulated by posttraining intra-amygdala injections of drugs affecting several neurotrans-

Figure 3. Effect of immediately posttraining intra-amygdala administrations of baclofen on retention of a one-trial step-through inhibitory avoidance task in rats. Data are expressed as the median testing minus training step-through latency (+ interquartile range), in seconds (from ref. 19).

mitters and neuromodulatory systems.76 Further, GABAergic neurons are widely distributed in this structure and GABAergic cells project mainly within the amygdala.6,17,67,71,90

In a study carried out with rats tested in a one-trial step-through inhibitory avoidance task, immediate bilateral intra-amygdala administrations of baclofen impaired retention performance on a 48 h retention test (Fig. 3).23 Further, bicuculline methiodide (BMI) improved, while muscimol impaired retention (48 h later) in rats tested in a one-trial step-through inhibitory avoidance task and injected into the amygdala with the drugs immediately after training. In particular, the memory enhancing effect of BMI was produced by a dose lower than that necessary to induce convulsions. In a further series of experiments of this study posttraining injections of BMI into the caudate-putamen, a structure which is dorsal to the amygdala, did not affect retention (Figs. 4 and 5). 5 In another study84 the effects of intra-amygdala infusions of muscimol prior to retention testing was examined. Two sets of experiments were carried out. In the first set, rats were trained in a one-trial step-through inhibitory avoidance task and given bilateral intra-amygdala infusions of vehicle or muscimol, or simultaneous unilateral infusions of each, 5 min before the retention test, 24 h after training. The same procedure was adopted in experiment 2, but two retention measures were taken: initial step-through latency and the number of trials to reach criterion during continuous multiple-trial inhibitory avoidance (CMIA) training. The results showed that infusions of muscimol into the amygdalae prior to the retention test impaired performance in the inhibitory avoidance task. Further, unilateral infusions of muscimol into the right, but not into the left amygdala, prior to the retention test was sufficient to impair retention performance. Although bilateral infusions of muscimol impaired CMIA acquisition, unilateral infusions of the drug into either the right or the left amygdala did not significantly affect the number of trials required to reach criterion during the CMIA acquisition. These results show that the right and the left amygdala are differentially involved in the expression of memory for inhibitory avoidance training and suggest that the different effects observed after unilateral amygdalae infusions of muscimol may depend on the type of task examined.84 Other experiments, in which muscimol or bicuculline were infused into the amygdala immediately after a reward shift, have shown that GABAergic system is involved in the memory modulation for changes in reward magnitude.98 Further, facilitation of trace conditioning of odor aversion has been observed following intra-amygdala (basolateral amygdala) bilateral injections of BMI after the presentation of the conditioned stimulus in rats.43 Long-term memory enhancement in rats tested in a one-trial step-down inhibitory avoidance task and injected immediately after training with picrotoxin in the junction between the central and the

Saline Sic 0.1 rmol Saline Bic 0.1 nmol

Amygdala Caudate

Saline Sic 0.1 rmol Saline Bic 0.1 nmol

Amygdala Caudate

Figure 4. Effect ofbicuculline methiodide injections in the amygdala and the caudate-putamen on retention of a one-trial step-through inhibitory avoidance task. The rats with chronic implanted cannulae were trained in the inhibitory avoidance, and were injected immediately after training. Each column represents the mean ± SEM testing minus training latency in seconds (from ref. 15).

basolateral nuclei of amygdala, has also been demonstrated.7 A series of experiments has been recently carried out in which rats were injected with muscimol into the amygdala immediately after Pavlovian fear conditioning and one-trial inhibitory avoidance tasks.112 Immediate posttraining infusions of muscimol had no effect on Pavlovian conditioning, but produced a dose-dependent impairing effect in the inhibitory avoidance. However, Pavlovian conditioning was dose-dependently disrupted by pretraining infusions of muscimol. The results of this study indicate that the amygdala plays a critical role in the acquisition of Pavlovian fear conditioning, and is involved in the modulation of memory consolidation of inhibitory avoidance but not of Pavlovian fear conditioning. Further evidence that amygdala is involved in modulating the effects of GABAergic agonists and antagonists on memory comes from lesion studies. Some experiments,1 carried out with CD1 mice tested in a one-trial step-through inhibitory avoidance task, have shown that bilateral lesions of the amygdala (or the dorsal hippocampus) blocked the memory enhancing effect of posttraining i.p. injections of bicuculline as well as the memory impairing effect of muscimol. In contrast, lesions of the caudate did not influence the retention-modulating effects of posttraining administrations of the two drugs.

Although many studies have demonstrated that systemically administered GABAergic drugs influence memory storage through effects involving the amygdala, it has been shown that learning and memory can be influenced also by injections of GABAergic drugs in brain regions other than this structure. Early studies have for example demonstrated that injections of picrotoxin into the hippocampus50 and the substantia nigra,64 and of muscimol into the basal forebrain90 are followed by retention impairment. It is well known that the processing of spatial information requires an intact hippocampal function, and is sensitive to the disruption of the septal-hippocampal cholinergic pathway. Acquisition improvements of spatial information have been observed in rats after septal lesions, that reduce hippocampal cholinergic activity.113 Muscimol injections in the medial septum reduce the high affinity choline uptake in the hippocampus. It is interesting to underline that muscimol injections in this structure have been shown to impair, in rats, place navigation in the Morris water maze at the same dose that reduces the high affinity choline uptake in the hippocampus, and without affecting the nonspatial strategies of the animals.13 In another study,89 experiments were carried out in which the effects of muscimol administration into the medial septal area prior to training were studied, and

Figure 5. Testing-training latencies to step-through after muscimol injections in the amygdala. Rats with chronic implanted cannulae were trained in a one-trial step-through inhibitory avoidance task and were injected immediately after training. Each column represents the mean ± SEM testing minus training latency in seconds (from ref. 15).

Figure 5. Testing-training latencies to step-through after muscimol injections in the amygdala. Rats with chronic implanted cannulae were trained in a one-trial step-through inhibitory avoidance task and were injected immediately after training. Each column represents the mean ± SEM testing minus training latency in seconds (from ref. 15).

memory was tested at different retention delays in 3 tasks: inhibitory avoidance task, one-trial place learning task and reward alternation task. In all 3 tasks muscimol administration did not impair memory performance at short retention delays, but impaired retention at the longer retention delays. The same authors showed in previous experiments that injections of muscimol into the medial septal area impaired retention performance in an inhibitory avoidance task and in a multiple-trial place learning task, when the injections were carried out pretraining but not posttraining.13,88In summary, the findings of Nagahara and McGaugh 9 suggest that the intra-septal muscimol treatment impairs long-term memory by acting on a memory-related process that occurs at the time of training rather than by acting on posttraining consolidation processes. The existence of interactions between the medial septal area and the basolateral amygdala (BLA, which modulates memory encoding in other brain areas including hippocampus) in the processing of memory storage was demonstrated by a recent study.106The effects of intra-medial septal infusions of muscimol in rats with BLA lesions were studied. The animals received sham surgery or excitotoxic BLA lesions and were infused with either vehicle or muscimol into the medial septal area 5 min prior to training in a step-through inhibitory avoidance and water maze tasks. The results showed that BLA lesions potentiated the muscimol-induced memory impairment in the inhibitory avoidance task. Further, BLA-lesioned animals given muscimol infusions into the median septal area showed memory impairment also in the water maze task. Taken together, these results give the evidence that BLA interacts with medial septal area in the processing of memory storage.

In a series of experiments the effect of the infusion of muscimol on the role of the entorhinal cortex, amygdala and hippocampus in memory processes was studied62 in rats bilaterally implanted with cannulae into these structures and trained, after recovery, in a one-trial step-down inhibitory avoidance task. Testing occurred 24 h after training. In particular it has been examined whether the pretraining or pretest intra-entorhinal infusion of muscimol had any influence on the amnesic effect of a posttraining infusion of the same drug into the amygdala and the hippocampus, and on the amnesic effect of cianonitroquinoxaline-dione (CNQX), an antagonist of AMPA glutamatergic receptors, given prior to testing into the amygdala, hippocampus or entorhinal cortex. The results showed that muscimol, infused in the entorhinal cor-

tex 20 min prior to testing, inhibited the amnesic effect of muscimol infused into this area 100 min after training. This result demonstrated that memory-relevant information must be processed by the entorhinal cortex at the time of training in order that this cortex may play a late posttraining role in memory processing. Further: a) pretraining intra-entorhinal muscimol administration did not affect the amnesic effect of the posttraining infusion of muscimol into the amygdala and the hippocampus, or the inhibition of memory expression induced by pretest infusion of CNQX into the amygdala and hippocampus or into the entorhinal cortex; b) pretest intra-entorhinal muscimol administration did not influence the effect of pretest intra-amygdala and intra-hippocampal CNQX administration. According to the authors, these findings indicate that "the cells of the entorhinal cortex that are sensitive to pretraining muscimol are not part of the inputs that lead to posttraining processing by the amygdala and hippocampus or to the intervention of the amygdala, hippocampus and entorhinal cortex in memory expression. Instead, the entorhinal cortex may be an output of the amygdala and hippocampus at the time of memory expression."62 In a series of experiments,116 Wistar rats were implanted with cannulae into the CA1 region of the dorsal hippocampus and into the amygdaloid nucleus, the entorhinal cortex and the posterior parietal cortex. The animals were trained in a step-down inhibitory avoidance and received vehicle or muscimol injections 0, 30, 60 or 90 min after training. Retention was measured 24 h after training. The results showed that retention performance was hindered by muscimol administration into both hippocampus and amygdala at 0, but not 30 min posttraining. Furthermore, the drug was amnesic when given into the entorhinal cortex 30, 60 or 90 min after training, or into the parietal cortex only 60 or 90 min after training. The data show a sequential entry in operation, during the posttraining period, of the hippocampus and amygdala, the entorhinal cortex and the posterior parietal cortex in memory processing.

Some experiments have been recently carried out in which the effects of muscimol on memory were studied in rats receiving posttraining intra-hippocampal administrations of muscimol.110 The results showed that the administration of muscimol into the CA1 region of the dorsal hippocampus impaired long-term memory of habituation to a 5 min exposure to an open field measured 24 h later.

After the study of Brioni et al15 showing lack of effect following posttraining bicuculline methiodide injections into caudate-putamen of rats tested in an inhibitory avoidance task, some other studies have been carried out in which the effect of posttraining GABAergic antagonists into the striatum have been examined. In a first study30 the effects of posttraining administrations of picrotoxin and bicuculline were investigated in rats tested in a one-trial step-through inhibitory avoidance task. The results showed that intra-striatal applications of the two GABA antagonists induced dose-dependent and long-lasting impairments of memory consolidation. The discrepancy between these findings and those of Brioni et al15 might be explained, according to the authors, on the basis of a regional functional heterogeneity of GABA within the structure.47 It is known that disruption of synaptic activity of some brain structures, including neostriatum and thalamus, is followed by marked deficits in retention of instrumentally conditioned behaviors. Further, when animals in these conditions are given a high number of training trials or high intensities of footshock during training, such disruption is less effective.38 Thus it has been studied32 whether, on the basis of the close anatomical and functional relationships between the neostriatum and the substantia nigra, enhanced training with a high level of footshock would prevent the amnesic state induced by picrotoxin and bicuculline infusion into the latter structure. Rats were trained in a step-through inhibitory avoidance task under two footshock levels, 0.2 or 0.4 mA, and were injected posttraining with the GABA antagonists into the substantia nigra and the posterior region of the zona incerta. Retention was measured 24 h later. The results showed amnesia only in the groups injected into the nigra following training under the lower shock intensity. According to the authors, the differences between their findings and previous findings12,58 showing that the main effect of injections of GABA blockers into amygdala, hippocampus and septum is an impairment of retention in rats tested in the inhibitory avoidance, might be explained on the basis of a dissimilar involvement of limbic and nigrostriatal GABA systems in memory processes, probably due to regional differences in the physiology of GABA. As concerns the lack of effect of GABAergic blockade of the nigra after the high (0.4 mA) intensity of footshock administered during training, it might be related, according to the authors, to central and peripheral events triggered by the increased aversive stimulation. The effects of regional blockade of the striatum on memory consolidation has been examined in some further experiments.99 In this study rats were trained in a step-through inhibitory avoidance task and received posttraining injections of picrotoxin. Retention test was carried out 24 h later. The data showed that a strong amnesia was produced by picrotoxin injections into the posteroventral and the lateral regions of the striatum, an intermediate degree of impairment was produced by injections into the dorsomedial region, while no retention deficit was evident when the GABA antagonist was injected into the ventromedial part of the anterior striatum. It was thus evident that the retention impairments were higher in the posterior and the lateral striatal regions than in the anterior and medial regions. These results provide strong evidence that the striatal GABAergic activity plays a crucial role in the consolidation of negatively reinforced behaviors. They also demonstrate the existence of a neurochemical heterogeneity within the striatum as concerns memory consolidation and further reflect a differential involvement of limbic and striatonigral GABA in memory processes.

Differential effects of muscimol infusions in different regions of the cingulate cortex on retention have been found.81 In a series of experiments Wistar rats were bilaterally implanted with cannulae at four different coordinates of the cingulate cortex: 1) the anterior cingulate (AC); 2) the rostral region of the posterior cingulate (RC); 3) the upper portion of the posterior cingulate (UC) and 4) the lower portion of the caudal region of the posterior cingulate (LC). The animals were trained in a step-down inhibitory avoidance task and received infusions of vehicle or muscimol either immediately or 90 or 180 min after training. Muscimol was amnesic when given into any of the three coordinates of the posterior cingulate cortex 90 min after training, and when given into LC immediately posttraining. None of the treatments was effective when given into AC. The results show that the posterior, but not the anterior cingulate cortex regulates memory processing of the inhibitory avoidance task through muscimol-sensitive synapses, relatively late after training.

The involvement of the GABAergic system in the medial precentral prefrontal cortex in memory consolidation has been recently examined.82 In this study Wistar rats were trained in a step-down inhibitory avoidance learning task and received infusions of muscimol or vehicle into the anterior medial precentral area (Fr2)(CI) or into the junction of Fr1-Fr2 (CII) at different times after training. Muscimol into CI was amnesic when given immediately, 90 or 180 min, but not 270 min after training. When injected into CII muscimol was amnesic when given 90 min, but not 0 or 180 min, after training. The results suggest that the GABAergic system in Fr2 is involved in the consolidation of memory for inhibitory avoidance learning and that timing of involvement of anterior Fr2(CI) is different from that of posterior Fr2(CII).

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