Behavioral and electrophysiological evidence of time-dependent cholinergic mechanisms mediating memory and response suppression



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Six experiments are reported which examined the behavioral and electrophysiological effects of pharmacological facilitation and antagonism of central cholinergic transmission. In Experiment 1, the rate of operant responding of rats, trained to lever press on a variable-interval schedule of food reinforcement, was not altered by systemic administration of the cholinergic antagonist scopolamine (0.4 mg/Kg). This same dose of scopolamine, injected prior to each training session, had no effect on the development of conditioned suppression of operant responding in Experiment 2. In Experiment 3, animals were trained in an operant discrimination task with reinforcement for a low response rate (DRL -15 seconds). Scopolamine did not change the rate of correct responding in these animals. Incorrect lever pressing did increase significantly, however, when scopolamine treatment preceded testing. The results of these experiments were interpreted as contradicting hypotheses that central cholinergic systems mediate response suppression. Since Grossman (1972) had reported that cholinergic drugs affected response suppression in aversively-motivated tasks but not in appetitive tasks, additional experiments were performed to examine the effects of cholinergic durgs on the acquisition and retention of active and passive avoidance tasks. The cholinergic blocker atropine sulfate facilitated acquisition of a shuttle-box avoidance task, but had no effect when injected prior to a 24 hour retention test. Atropine methylnitrate, a cholinergic blocker with primarily peripheral effects, did not alter acquisition or retention of this task. Neostigmine, a cholinesterase inhibitor with primarily peripheral action, caused a dose-related impairment in the acquisition and retention of shuttle-box avoidance when injected before training or retention testing. The acquisition of this task was also impaired by physostigmine, a drug producing both central and peripheral inhibition of cholinesterase activity. Physostigmine (0.04 mg/Kg), however, impaired acquisition at a dose equimolar to a dose of neostigmine which had no effect. V.hile at the highest dose tested (0.4 mg/Kg) the effects of physostigmine were similar to those of neostigmine, lower doses of physostigmine differed from neostigmine in their effects on avoidance retention. The effects of physostigmine on retention were dependent upon the dose and retention interval relative to the time of original learning. Animals trained in the shuttlebox task non-drugged and retested one day later following an intraperitoneal injection of physostigmine performed significantly better (with 0.04 mg/Kg physostigmine) or no different (with 0.1 mg/Kg physostigmine) than saline-injected animals. All of the doses of physostigmine tested impaired performance at longer retention intervals (7 or 14 days) with greatest impairment at the longest interval. None of these drugs (physostigmine, neostigmine, atropine sulfate, and atropine methylnitrate) altered the acquisition or retention of a passive avoidance task in Experiment 5. These finds that the effects of cholinergic drugs are dependent upon the stage of learning and the age of memory are not consistent with an hypothesis of the cholinergic mediation of response suppression. The results of Experiments 1 through 5 suggest that central cholinergic systems may be involved in stimulus selection or discrimination, or in memory storage and retrieval. Additional support for this interpretation is provided by the results of Experiment 6. In this study bipolar electrodes were implanted in the medial lateral thalamus, hippocampus, ventral tegmentum, occipital cortex, and motor cortex of 20 male, Sprague-Dawley rats. Recordings were obtained of the EEG activity of these areas following saline, physostigmine, and atropine, under conditions of spontaneous EEG or photic stimulation. Following these initial observations, animals were trained in a shuttle-box avoidance task with the photic stimulus as an avoidance cue. One day after training, EEG was again recorded following either saline, physostigmine, or atropine injections. The effects of physostigmine and atropine on the period analytic descriptors of the EEG and on visually evoked responses were examined both before and after avoidance training. Period analysis of the EEG indicated that, in general, physostigmine produced desynchronous activity similar to that resulting from the presentation of exteroceptive stimuli to an untreated subject. In fact, the period analytic descriptors of the EEG following physostigmine did not differ significantly from those after saline during the presentation of photic stimulation. Atropine had the reverse effect, decreasing period counts during photic stimulation such that EEG activity during photic stimulation following atropine was similar to the spontaneous recording period following saline. Physostigmine was found to increase the peak-to-peak amplitude of several evoked potential components, while atropine reduced evoked response amplitude. Physostigmine produced a significantly larger increase in the amplitude of thalamic responses after avoidance training. The effect of training in animals treated with atropine was a significant decrease in the amplitude of hippocampal evoked responses. These results suggest that cholinergic drugs may alter the responsiveness of subjects to exteroceptive stimuli. The results of these studies do not support hypotheses of cholinergic mechanisms mediating response suppression; rather, they suggest that central cholinergic neurons are involved in determining responsiveness to external stimuli and thus, perhaps, in mediating selective attention.