Cholinergic-dopaminergic interactions in radial-arm maze performance

Although acetylcholine and dopamine are believed to play complementary roles in motor function, a comparable neurochemical interaction has not been established for cognitive function. The muscarinic receptor blocker scopolamine and the dopaminergic antagonist haloperidol have been found to impair choice accuracy of rats in the radial-arm maze. In the present study, low doses of these two drugs were administered intraperitoneally either alone or in combination to rats trained on a working memory task (food reward) in an eight-arm radial maze. Scopolamine, 0.125 mg/kg, produced a significant decrease in choice accuracy (i.e., arm entries until an error). Haloperidol, 0.0625 mg/kg, did not cause a significant decrease in accuracy, but there was a trend in that direction. The combination of haloperidol with scopolamine attenuated significantly the amnestic effect of scopolamine. These results suggest that, like motor behavior, cognitive function may be influenced by the balance between acetylcholine and dopamine.     

Scopolamine amnesia of passive avoidance: a deficit of information acquisition

Despite its increasing use as an animal model of memory deficit in human dementia, relatively few studies have attempted to assess the memory processes involved in the anticholinergic-induced impairment of passive avoidance retention. In the present experiments, the influence of scopolamine administered prior to or immediately following training on 24-h retention of step-through passive avoidance was studied in NMRI mice. In low doses (0.3-3.0 mg/kg ip) pretraining administration (-5 min) of scopolamine induced a very strong amnesia. Post-training scopolamine induced a significant effect only at the highest dose tested (30 mg/kg). In a retention test of longer than normal duration (600 vs 180 s), which resulted in a more favorable comparison value in the control group, an intermediate post-training dose (10 mg/kg) induced a small effect which approached significance; a finding which may account for conflicting reports in the literature concerning the ability of scopolamine to induce a post-training deficit. The pretraining effect does not appear to have been solely the result of state-dependent learning; scopolamine (3 mg/kg) administered before both the training and test sessions induced a deficit of approximately the same magnitude as that found when administered before training or before testing only. The results indicate that scopolamine can induce a small post-trial effect, presumably through an influence on consolidation processes. The much larger effect of pretrial scopolamine, however, indicates a primary influence on processes related to information acquisition. Together with findings from the literature, the present experiments suggest that scopolamine-induced amnesia partially, but not completely, models the memory deficits of human dementia.     

The effects of concurrent manipulations of cholinergic and noradrenergic systems on neocortical EEG and spatial learning

In the spatial learning test, young animals were divided into three groups receiving saline, scopolamine (0.15 mg/kg), or scopolamine (0.8 mg/kg). Half of the animals in each group were lesioned with DSP-4 to destroy noradrenergic fibers. DSP-4 lesions did not produce any significant impairment alone or in combination with a lower dose of scopolamine (0.15 mg/kg), but they did further augment the scopolamine (0.8 mg/kg)-induced defect. In the electroencephalography (EEG) experiment, both control rats and DSP-4-lesioned rats were recorded after receiving saline, scopolamine (0.15 mg/kg), and scopolamine (0.8 mg/kg) injections. Scopolamine induced a dose- and behavioral state-dependent EEG slowing, whereas DSP-4 lesions did not change either baseline EEG activity or EEG reactivity to scopolamine.     

Long lasting increase in nociceptive threshold induced in mice by forced swimming: involvement of an endorphinergic mechanism

Mice submitted to forced swimming session(s) displayed a long lasting modification in their nociceptive threshold, assessed through their jump latency from a hot plate (55 degrees C). Thus two forced swimming sessions (6 min each, 8h apart), in water at 33 degrees C, increased by about 50% the jump latency when the hot plate test was performed 14 hours, 3 days or 6 days thereafter. The water temperature (16 degrees C vs 33 degrees C) had no critical influence in this respect. To be clearly effective (at 33 degrees C) the swimming session had to be performed twice (when performed only once it was irregularly effective); it apparently culminated for a 6 min duration, since its effectiveness was not significantly increased by extending the swimming time to 12 min or 18 min. Performing 2 forced swimming sessions (6 min each, 8h apart), 5 consecutive days, resulted in a suppression of the increase in jump latency in the hot plate test. The two forced swimming episodes-induced analgesia was prevented by the s.c. administration of diazepam (from 0.125 mg/kg) or morphine (from 5 mg/kg) or scopolamine (1 mg/kg) before each forced swimming episode. Morphine (7.5 mg/kg) was uneffective to prevent the induction of two forced swimming episodes-induced analgesia when it was administered immediately after each forced swimming session. Finally this analgesia was dose dependently reversed by naloxone (ID(50) = 0.14 mg/kg, s.c., 30 min before the hot plate test). It is hypothesized that the handling of mice immediately before the hot plate test induces the remembrance of the stress induced by previous forced swimming episodes, triggering a fear reaction which increases the nociceptive threshold.     

Scopolamine effects on memory retention in mice: a model of dementia?

Scopolamine-treated normal young human subjects exhibit memory dysfunctions analogous to those observed in demented patients. The dysfunctions are reversible by physostigmine but not by d-amphetamine which suggests that the memory impairment is specifically related to reduced cholinergic transmission caused by scopolamine. Scopolamine-induced amnesia has been proposed as a model for dementia where reduced cholinergic function is the suspected cause. We report seven experiments in young adult mice which examine scopolamine's effects on memory retention and whether its amnestic effects are specifically blocked by cholinergic agonists or cholinomimetics. Young adult mice were trained to avoid footshock in a T maze and their retention tested 1 week after training. Pretraining subcutaneous injection of scopolamine improved retention scores of "undertrained" mice at a dose of 0.01 mg/kg but impaired at a dose of 0.1 mg/kg. Post-training injection showed no effect at 0.01 mg/kg, enhanced retention scores at 0.1 mg/kg, and impaired at 1.0 mg/kg. The impairment by 1.0 mg/kg was blocked by injection 45 min post-training of each of two cholinergic drugs but was also counteracted by six drugs which act upon five other neural systems (catecholamine, serotonin, glycine, GABA, and hormonal). When scopolamine was injected 40 min pretraining, and each of eight drugs was injected immediately after training, the amnestic effect of scopolamine was only partially counteracted. This suggests that scopolamine impaired acquisition, in addition to some impairment of memory processing. This was confirmed by a direct study of acquisition rates of the avoidance response; 0.1 mg/kg of scopolamine impaired acquisition. The overall results indicate that pretraining administration of scopolamine impairs learning and to some degree memory processing. Counteracting scopolamine-induced amnesia, by either pretraining or post-training drug administration, is not specific to the cholinergic system.     

Blood glucose and brain function: interactions with CNS cholinergic systems

We recently found that glucose injections attenuate amnesia and hyperactivity produced by scopolamine, a muscarinic antagonist. The present study examined whether glucose would augment behavioral effects produced by a muscarinic agonist, physostigmine. In experiment I, doses were first determined for which neither glucose (10 mg/kg) nor physostigmine (0.05 mg/kg) altered scopolamine-induced hyperactivity. However, combined glucose-physostigmine injections significantly reduced scopolamine hyperactivity. Experiment II evaluated the effects of glucose on physostigmine-induced tremors. Glucose (10, 100, and 250 mg/kg) or saline injections were given 20 min before physostigmine injections (0.4 or 0.05 mg/kg). Observations of glucose effects on the severity of physostigmine-induced tremors were then obtained at 5-min intervals for 25 min after physostigmine injections. Glucose (100 mg/kg) significantly facilitated the onset of tremors when injected before either dose of physostigmine, and augmented (at 100 and 250 mg/kg) tremor severity when injected before the lower dose of physostigmine. These findings indicate that glucose can facilitate the actions of a cholinergic agonist on two behaviors, locomotor activity and tremors, adding support to the view that circulating glucose levels can modulate central cholinergic function. More generally, the results provide additional evidence that circulating glucose levels can influence brain function.     

The effect of scopolamine and physostigmine on working and reference memory in pigeons

A comparison of the effects of scopolamine and physostigmine on working memory and reference memory in White Carneaux pigeons was undertaken. In Experiment 1, the pigeons received injections of scopolamine hydrobromide (0.03 mg/kg), or saline. Scopolamine hydrobromide had greater disruptive effects on working memory trials than on reference memory trials, and the centrally active form of scopolamine disrupted working memory trial accuracy more than the peripherally active form. The differential sensitivity of accuracy on working memory trials to disruption by central cholinergic blockade was obtained even though the discrimination required on reference memory trials was more difficult. In Experiment 2, the pigeons received injections of scopolamine hydrobromide (0.015 mg/kg), physostigmine (0.075 mg/kg) both scopolamine and physostigmine, or saline. Physostigmine given with scopolamine was able to reverse the scopolamine-induced reduction of accuracy on working memory trials. In neither study did scopolamine promote accelerated forgetting as the delay interval was increased. These results indicate that manipulation of central cholinergic neurotransmitter systems influences working memory processes in the pigeon, but these effects occur without alterations in the ability of the birds to actively maintain information during the retention interval.     

Physostigmine''s Impact on Brief Shock-Induced Hypoalgesia Parallels Its Effect on Memory

Past research indicates that the anticholinergic drug scopolamine disrupts memory and environmentally induced hypoalgesia in rats. The present study examined the impact of the centrally active cholinesterase inhibitor physostigmine, which enhances memory and central cholinergic activity, on brief shock-induced hypoalgesia on the tail-flick test using Sprague–Dawley rats. It is reported that physostigmine (0.1 mg/kg) potentiates the magnitude of this hypoalgesia. Contrary to past research, our results showed that omission of baseline testing did not eliminate hypoalgesia or its potentiation by physostigmine. Similar to its effects on memory, physostigmine (0.04, 0.1, and 0.25 mg/kg) has a nonmonotonic impact on brief shock-induced hypoalgesia; low doses potentiated hypoalgesia (0.1 mg/kg), whereas a high dose (0.25 mg/kg) disrupted it. These results provide further evidence that the cholinergic system indirectly affects pain reactivity by modulating the memory of the aversive event.     

Effects of some physiological and pharmacological manipulations on shock- facilitated mouse killing by onychomys leucogaster (Northern grasshopper mouse)

Onychomys leucogaster (northern grasshopper mice) were induced to kill mice with response-contingent shock, and the effects of several physiological, pharmacological, and endocrinological variables were assessed. Lesions of the septum facilitated mouse killing, while lesions of the amygdala abolished spontaneous mouse killing and delayed shock-facilitated killing. Chlorpromazine (2.5–5 mg/kg) and chlordiazepoxide (5–10 mg/kg) facilitated mouse killing on postdrug trials but did not affect killing when the animals were drugged. Adrenalectomy, castration, and castration adrenalectomy did not alter the frequency of kill nor were sex-related differences in killing noted. These results were compared to those found by others studying the effects of lesions and drugs on mouse killing by rats.     

The ameliorating effect of oroxylin A on scopolamine-induced memory impairment in mice

Oroxylin A is a flavonoid and was originally isolated from the root of Scutellaria baicalensis Georgi., one of the most important medicinal herbs in traditional Chinese medicine. The aim of this study was to investigate the ameliorating effects of oroxylin A on memory impairment using the passive avoidance test, the Y-maze test, and the Morris water maze test in mice. Drug-induced amnesia was induced by administering scopolamine (1 mg/kg, i.p.) or diazepam (1 mg/kg, i.p.). Oroxylin A (5 mg/kg) significantly reversed cognitive impairments in mice by passive avoidance and the Y-maze testing (P<.05). Oroxylin A also improved escape latencies in training trials and increased swimming times and distances within the target zone of the Morris water maze (P<.05). Moreover, the ameliorating effects of oroxylin A were antagonized by both muscimol and diazepam (0.25 mg/kg, i.p., respectively), which are GABA(A) receptor agonists. Furthermore, oroxylin A (100 microM) was found to inhibit GABA-induced inward Cl(-) current in a single cortical neuron. These results suggest that oroxylin A may be useful for the treatment of cognitive impairments induced by cholinergic dysfunction via the GABAergic nervous system.     

The effects of cholinergic drugs upon recognition memory in rats

This study measured the effects of the muscarinic blocker, scopolamine, upon object recognition. In order to test object recognition, rats were trained to choose between two distinctive goal boxes, one of which was familiar, and the other was novel. Selection of the unfamiliar goal box was always rewarded (nonmatching-to-sample), and new pairs of start/goal boxes were used on every trial.

In the first experiment it was found that injections of 0.05 mg/kg scopolamine hydrochloride and above produced significant impairments on this nonspatial test of working memory. A second experiment examined whether scopolamine caused a loss of retention by comparing the effects of the drug when the interval between stimulus presentation and choice test was increased from just over 0 sec to 60 sec. While the highest dose of scopolamine hydrobromide (0.06 mg/kg) was sufficient to produce a significant impairment on the longer retention interval, there was no evidence that this dose produced faster forgetting of the stimuli. This result suggests that the drug caused a general depression in performance, which may or may not reflect amnesic properties. In contrast, simultaneous tests with the anticholinesterase, physostigmine, indicated that increasing available acetyl choline might attenuate the effects of the retention intervals. A final series of control tests revealed that the rats relied on cues from a variety of sensory modalities in order to perform the nonmatching task.     

Effects of glucose on scopolamine-induced learning deficits in rats performing the Morris water maze task

In order to assess the effects of glucose on drug-induced spatial learning deficits, three experiments were conducted using the Morris water maze. Scopolamine and glucose were injected ip at various stages of training. Rats of Wistar strain served as subjects. In Experiment 1, scopolamine (0.4 mg/kg) and 10, 100, or 500 mg/kg of glucose were administered every day from the start of training, and the effect on acquisition was evaluated. In Experiment 2, scopolamine and 100 or 500 mg/kg of glucose were administered after 6 days of training, and the effect on performance was assessed. In Experiment 3, scopolamine and 500 mg/kg of glucose were injected after 2 days of training, and the effect on the following trial was tested. In all experiments, scopolamine impaired acquisition/performance of the task. Glucose at 500 mg/kg showed a significant enhancing effect on acquisition regardless of scopolamine injection only when injected daily from the start of training (Experiment 1). Glucose injected after the performance has reached asymptote (Experiment 2) did not affect performance, and glucose in the middle of training showed a slight but insignificant enhancing effect (Experiment 3). These results may suggest that the effect of glucose changes as a function of the degree of learning of the spatial learning task. The possibility of task specificity of the glucose effect was also discussed in relation to the cholinergic systems and local cerebral glucose utilization.     

Memory-Enhancing Treatments Do Not Reverse the Impairment of Inhibitory Avoidance Retention Induced by NMDA Receptor Blockade

The aim of the present research was to verify whether the impairment of retention induced by the N-methyl-d-aspartate (NMDA) receptor blocker (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cycloheptene-5,10 imine (MK-801) can be reversed by memory-enhancing treatments. Adult female Wistar rats were trained and tested in a step-down inhibitory avoidance task (0.3-mA foot shock, 24-h training-test interval). Animals were given an ip injection of saline (SAL) or MK-801 (0.0625 mg/kg) 30 minutes before training, and an ip injection of SAL, epinephrine (EPI) (25 microg/kg), the opioid receptor antagonist naloxone (NAL) (0.4 mg/kg), the glucocorticoid receptor agonist dexamethasone (DEX) (0.3 mg/kg), or glucose (GLU) (320 mg/kg) immediately after training. There was an impairment of inhibitory avoidance retention in the MK-801-SAL, MK-801-EPI, MK-801-NAL, MK-801-DEX, and MK-801-GLU groups. There was an enhancement of retention in the SAL-EPI, SAL-NAL, SAL-DEX, and SAL-GLU groups. A control experiment showed that the amnestic effects of MK-801 could not be attributed to decreased reactivity to the foot shock. The results suggest that memory-enhancing treatments directed at modulatory mechanisms do not reverse the memory impairment induced by NMDA receptor blockade.     

Estrogen Improves Performance of Reinforced T-Maze Alternation and Prevents the Amnestic Effects of Scopolamine Administered Systemically or Intrahippocampally

In a previous study, administration of high doses of estradiol benzoate (100 μg/kg for 3 days im) to ovariectomized Long-Evans rats counteracted impairments of reinforced T-maze alternation induced by systemic administration of scopolamine, a muscarinic receptor blocker. In the current study, daily administration of lower doses of estradiol benzoate (5 μg/kg for 3 weeks sc) increased the number of correct reinforced alternations during T-maze acquisition in ovariectomized rats compared to oil-treated controls and prevented impairments of reinforced alternation induced by injection of scopolamine hydrobromide (0.2 mg/kg ip). Furthermore, scopolamine (20 μg) delivered bilaterally to the dorsal hippocampus reduced reinforced T-maze alternation in ovariectomized rats previously trained to complete this task while daily treatment with estradiol benzoate (5 μg/kg sc) for 1 week prior to scopolamine infusion counteracted this impairment. In summary, physiological levels of estrogen improved performance during acquisition of reinforced T-maze alternation and prevented impairments induced by scopolamine administered systemically or intrahippocampally.     

Scopolamine enhances generalization between odor representations in rat olfactory cortex

Acetylcholine (ACh) has a critical, modulatory role in plasticity in many sensory systems. In the rat olfactory system, both behavioral and physiological data indicate that ACh may be required for normal odor memory and synaptic plasticity. Based on these data, neural network models have hypothesized that ACh muscarinic receptors reduce interference between learned cortical representations of odors within the piriform cortex. In this study, odor receptive fields of rat anterior piriform cortex (aPCX) single-units for alkane odors were mapped before and after either a systemic injection of the muscarinic receptor antagonist scopolamine (0.5 mg/kg) or aPCX surface application of 500 μM scopolamine (or saline/ACSF controls). Cross-habituation between alkanes differing by two to four carbons was then examined following a 50-sec habituating stimulus. The results demonstrate that neither aPCX spontaneous activity nor odor-evoked activity (receptive field) was affected by scopolamine, but that cross-habituation in aPCX neurons was enhanced significantly by either systemic or cortical scopolamine. These results indicate that scopolamine selectively enhances generalization between odor representations in aPCX in a simple memory task. Given that ACh primarily affects intracortical association fibers in the aPCX, the results support a role for the association system in odor memory and discrimination and indicate an important ACh modulatory control over this basic sensory process.     

Strength of scopolamine-induced amnesia as a function of time between training and testing

Variations in the strength of scopolamine-induced amnesia as a function of age of the habit were studied in Swiss Webster mice. Animals were trained in an active avoidance task to a criterion of 9/10 avoidances and immediately following training injected with scopolamine hydrochloride (1.0 mg/kg) or saline. Retention of the avoidance learning was evaluated by testing different groups of animals 1, 3, 7, 10, 14, and 28 days following training. The retention test consisted of five trials in which the CS but not the UCS was presented. Results indicated that saline-treated mice exhibited near-perfect retention up to 14 days post-training with forgetting beginning to be apparent at 28 days. Scopolamine treatment produced strong amnesia in animals tested 1 and 3 days post-training but normal retention in animals tested 7 and 10 days after learning. The amnesia abruptly reappeared at 14 days after which time it remained stable. The marked similarity of the scopolamine retention curve to changes in the strength of memory of discrimination learning in undertrained rats reported by Deutsch suggested that scopolamine resulted in the storage of a weak memory of the avoidance response. To explore this idea further we trained mice to a criterion (4/5) which would result in a weak avoidance response and tested different groups 1, 3, 10, 14, and 28 days following learning. Results showed that strength of the memory of avoidance learning increased up to 10 days and then decreased abruptly at 14 days thus replicating the general shape of the retention curve produced by injecting scopolamine following strong training. These data suggest that scopolamine disrupts processes essential for the formation of durable memories.     

Conditioned fear-induced opiate analgesia on the Formalin test: Evidence for two aversive motivational systems

Fear, conditioned to apparatus cues associated with electric shock, was measured by recording freezing. Pain reactivity was simultaneously measured by recording the paw-licking and paw-lifting response to Formalin injected into a paw. Stimuli associated with shock produced freezing and inhibited the responses to Formalin; whereas various control stimuli did neither. These results indicate that one of the responses to fear is analgesia. The opiate antagonist naltrexone reversed this analgesia, suggesting that the analgesia has an opiate nature. The results were interpreted in terms of a two-aversive-motivational-systems model. One system, the pain system, is instigated by tissue-damaging stimuli and produces recuperative behavior that functions to promote healing. The other system, the fear system, is triggered by conditioned fear stimuli. It produces species-specific defensive reactions and also inhibits the pain system via analgesia.     

Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats

The 5-hydroxytryptamine₆ (5-HT₆) receptor has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the novel, selective 5-HT₆ antagonists compound (CMP) X and CMP Y and the reference 5-HT₆ antagonist GSK-742457 could ameliorate impairments in episodic memory in 3-months-old male Wistar rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer’s disease, AD) was used as a positive reference compound. First, effects of the 5-HT₆ antagonists CMP X, CMP Y and GSK-742457 were investigated on object recognition task (ORT) performance in rats treated with the muscarinic antagonist scopolamine (0.1 mg/kg, administered intraperitoneally, i.p., 30 min before trial 1). Second, effects of the combination of suboptimal doses of 5-HT₆ antagonists CMP X and CMP Y with the AChEI donepezil were studied, to determine whether the 5-HT₆ antagonists show additive synergism with donepezil in the ORT. Finally, effects of CMP Y, GSK-742457 and donepezil were investigated on object location task (OLT) performance in rats treated with scopolamine.Donepezil (1 mg/kg, oral administration, p.o.), GSK-742457 (3 mg/kg, i.p.), CMP X (3 mg/kg, i.p.) and CMP Y (30 mg/kg, p.o.), all ameliorated the scopolamine-induced deficits in object recognition. In the ORT, we have found that combined administration of subthreshold doses of CMP X (1 mg/kg, i.p.) and CMP Y (10 mg/kg, p.o.) with the AChEI donepezil (0.1 mg/kg, p.o.), enhanced memory performance in Wistar rats with deficits induced by scopolamine. Donepezil (0.1 mg/kg, p.o.) alone had no discernable effects on performance. This suggests additive synergistic effects of the 5-HT₆ antagonists (CMP X and CMP Y) with donepezil on cognitive impairment. Finally, donepezil (1 mg/kg, p.o.), GSK-742457 (10 mg/kg, p.o.) and CMP Y (30 mg/kg, p.o.) also reduced scopolamine-induced deficits in the OLT.In conclusion, the 5-HT₆ antagonists were found to clearly improve episodic memory deficits induced by scopolamine. In addition, co-administration of the 5-HT₆ receptor antagonists CMP X and CMP Y with the AChEI donepezil to cognitively impaired rats also resulted in potentially additive enhancing effects on cognition. This suggests that these compounds could have potential as monotherapy, but also as adjunctive therapy in patients with AD treated with common treatments such as donepezil.     

A threshold for the protective effect of over-reinforced passive avoidance against scopolamine-induced amnesia.

Acetylcholine-receptor blockers produce amnesia of aversively motivated behaviors. However, when animals are submitted to relatively high intensities of footshock (over-reinforcement), anticholinergic treatment does not induce memory impairments. The aim of this work was to determine whether the antiamnesic effect produced by increasing the magnitude of the negative reinforcer is gradually established or if a threshold should be reached to obtain such an effect. Wistar rats were trained in passive avoidance using 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0 mA; 5 min after training they were given one systemic injection of scopolamine (8 mg/kg). An amnesic state was produced in the groups that were trained with the lower intensities (2.5-2.7 mA); with the three higher intensities near-perfect retention was evident. These results suggest that acetylcholine is critically involved in memory consolidation, and that by increasing the magnitude of the negative reinforcer, a threshold is reached where cholinergic activity of the nervous system is not necessary for the development of the consolidation process.     

The effects of unilateral destruction of fimbria-fornix and supracallosal pathways in the rat

Rats with unilateral lesions of either the supracallosal regions (including the dorsal cingulate cortex) and the fimbria-fornix either on the same (S) or the opposite (O) sides of the brain were studied in a 16-hole open field without pharmacologic intervention and, subsequently, after 0.1 and after 1.0 mg/kg scopolamine HBr. Their performances were compared with those of unoperated control animals subjected to the same testing regime. Certain of their behaviors were compared with those of a larger number of animals with bilateral hippocampal destruction (and their control groups) from prior studies. Unilateral lesions of fimbria-fornix and supracallosal afferents to the hippocampal formation produced a decrease in hole poking activity relative to control animals. A further decrease in hole-poking behavior, coupled with increased locomotion, was observed in rats with fimbria-fornix and cingulate cortex lesions on opposite sides of the brain (group O). The smaller dose of scopolamine accentuated these effects. Indeed, the behavior of group O after scopolamine treatment was similar to animals with large bilateral hippocampal lesions. The large dose of scopolamine induced stereotyped rearing or hole poking in the brain-damaged animals but not in the control group. These findings suggest that both the fimbria-fornix and the supracallosal pathway is necessary for normal hippocampal function and that the behavioral deficit is greater when these structures are damaged on the opposite sides of the brain.