Scopolamine Selectively Disrupts the Acquisition of Contextual Fear Conditioning in Rats

doi:10.1006/nlme.1995.0001

Neurobiology of Learning and Memory

Volume 64, Issue 3, November 1995, Pages 191-194

https://doi.org/10.1006/nlme.1995.0001 Get rights and content

Abstract

Muscarinic cholinergic antagonism produces learning and memory deficits in a variety of hippocampal-dependent tasks. Hippocampal lesions produce both acquisition deficits and retrograde amnesia for contextual fear conditioning, but do not impact fear conditioning to discrete cues. In order to examine the effects of muscarinic antagonism in this paradigm, rats were given scopolamine (1 mg/kg) either before or for 3 days after a Pavlovian fear-conditioning session in which tones were paired with aversive footshocks. Fear to the context and the tone was assessed by measuring freezing in separate tests. It was found that pretraining, but not posttraining, scopolamine severely impaired contextual fear conditioning; tone conditioning was not affected under either condition (cf., Young, Bohenek, & Fanselow,Neurobiology of Learning and Memory,63,174–180, 1995).

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Muscarinic antagonists impair multiple aspects of operant discrimination learning and performance
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Acetylcholine signaling can strengthen associations between environmental cues and reward availability. Diverse subtypes (M1-M5) of the muscarinic acetylcholine receptor (mAChR) family may have distinct roles in different learning and memory processes, such as encoding cue-reward associations and consolidating these associations in long-term memory. Using an operant discrimination learning task in which mice are trained to nose poke during a tone to receive a food reward, we found that acquisition of the task requires mAChR signaling in the central nervous system. In addition, post-session injections of a broad mAChR antagonist, scopolamine impaired consolidation of the cue-reward memory. Further, after successful learning of a cue-reward contingency across multiple training sessions, mice that received a single pre-session injection of scopolamine were unable to use the learned cue association to receive rewards. Taken together, these data demonstrate distinct roles for muscarinic signaling in acquisition, consolidation and recall of the operant discrimination learning task. Understanding mechanisms underlying natural reward-related responding may provide insight into other maladaptive forms of reward learning such as addiction.
Hippocampus-dependent fear conditioning is not sensitized by muscarinic receptor activation following systemic injection of pilocarpine
2019, Neurology Psychiatry and Brain Research
Citation Excerpt :
Systemic administration of scopolamine – a mAChR antagonist – prior to training decreases the acquisition of CFC in rats at doses that do not change auditory conditioning, in a protocol with multiple conditioning parameters. Furthermore, the immediate or 24-h after intervention in training did not alter freezing duration, showing a modulatory role of the cholinergic system in acquisition, but not in consolidation of aversive memories (Anagnostaras, Maren, & Fanselow, 1995). In contrast, injections of scopolamine before or up to 3 h after Pavlovian conditioning alter auditory-cue and contextual conditioning when a single footshock is delivered.
The regulation of muscarinic acetylcholine receptors (mAChR) critically influences emotional outcomes. Previous researches indicate that a single systemic injection of pilocarpine – a mAChR agonist – displays long-term defensive behaviors in rats evaluated in distinct unconditioned tests up to 3 months following treatment. However, it is not clear whether these effects share underlying behavioral phenotypes involved in conditioned responses. With this in mind, we examined whether mAChR activation modulates contextual fear conditioning (CFC) and/or hippocampal synaptic plasticity. Adult male Wistar rats were injected with pilocarpine (150 mg/kg) and behaviorally evaluated in the CFC test or followed by synaptic plasticity (LTP/LTD) investigation in CA1 stratum radiatum of hippocampal slices. There was no difference between groups in the quantification of freezing behavior during the test period (24 h after treatment) besides a decrease of freezing 1 month later. Similarly, no changes were observed in rats conditioned 24 h later and tested 1 month after. Synaptic plasticity investigation following short- or long-term treatment revealed no differences between control and treated subjects. In summary, our results show that hippocampus-dependent fear behavior and memory consolidation mediated by hippocampal cholinergic inputs are not sensitive to activation of mAChR by a systemic nonconvulsant dose of pilocarpine. Therefore, we suggest that the long-term defensive behaviors and anxiogenic-like features displayed by pilocarpine observed in rats are mediated by different underlying mechanisms and or set of synapses.
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Brain injuries are often associated with the later development of epilepsy. Evidence suggests that morphological and functional changes occur in the remaining neural tissue during a silent (or latent) period in which no seizures are expressed. It is believed that this silent (reorganization) period may provide a therapeutic window for modifying the natural history of disease progression. Here we provide evidence that biperiden, a muscarinic anticholinergic agent, is able to alter disease progression in an animal model of epilepsy. We observed that biperiden was capable of slowing the manifestation of the first spontaneous epileptic seizure and effectively reduced the severity and number of recurrent, spontaneous epileptic seizures during the animals’ lifespan. Biomolecular (microdialysis) and electrophysiological (extracellular field recordings) studies determined that biperiden was capable of elevating the threshold of hippocampal excitability, thereby making the hippocampal glutamatergic pathways less responsive to stimuli when high concentrations of potassium were used in vivo or in vitro. Notably, there was no hindrance of long-term memory or learning (a potential problem given the amnestic nature of biperiden). We conclude that biperiden has antiepileptogenic potential and may represent an opportunity for the prevention of post-traumatic epilepsy.
Gene expression analysis of Arc mRNA as a neuronal cell activity marker in the hippocampus and amygdala in two-way active avoidance test in rats
2017, Journal of Pharmacological and Toxicological Methods
Immediate early genes are widely used as neuronal cell activity markers in neuroscience. The present study investigated the relationship between their expression and abnormality in context fear conditioning.
The learning test (two-way active avoidance test) was conducted in male rats administered with nonselective muscarinic antagonist scopolamine or selective dopamine D1-like receptor antagonist SCH 23390 at a dose level of 2.0 or 0.1 mg/kg, respectively, for 4 days. Expression levels of Arc and Fos mRNA in the hippocampus and amygdala were also evaluated on the second day of dosing by fluorescent in situ hybridization (FISH) and reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR).
Scopolamine had no effect on avoidance rate, but decreased freezing in the two-way active avoidance test. SCH 23390 decreased avoidance rate and increased freezing. In FISH and RT-qPCR assays, scopolamine decreased Arc mRNA in the hippocampus and amygdala, whereas SCH 23390 increased Arc mRNA in the hippocampus. By contrast, scopolamine and SCH 23390 did not change Fos mRNA expression compared to Arc mRNA expression.
The results of the learning test indicated that scopolamine or SCH 23390 respectively inhibited fear or context conditioning in rats. Furthermore, alteration of the expression of Arc mRNA but not of Fos mRNA in the hippocampus and amygdala of the brain was suggested to be a sensitive neuronal cell activity marker to detect behavioral abnormality in the two-way active avoidance test.
Antagonism of muscarinic acetylcholine receptors in medial prefrontal cortex disrupts the context preexposure facilitation effect
2017, Neurobiology of Learning and Memory
Cholinergic function plays a role in a variant of context fear conditioning known as the context preexposure facilitation effect (CPFE; Robinson-Drummer, Dokovna, Heroux, & Stanton, 2016). In the CPFE, acquisition of a context representation, the context-shock association, and expression of context fear occur across successive phases, usually 24 h apart. Systemic administration of scopolamine, a muscarinic acetylcholine receptor antagonist, prior to each phase (context preexposure, immediate-shock training, and testing) disrupts the CPFE in juvenile rats (Robinson-Drummer et al., 2016). Dorsal hippocampal (dHPC) cholinergic function contributes significantly to this effect, as local infusion of scopolamine into the dHPC prior to any individual phase of the CPFE produces a disruption identical to systemic administration (Robinson-Drummer et al., 2016). The current experiment extended these findings to another forebrain region implicated in the CPFE, the medial prefrontal cortex (mPFC). Adolescent rats received bilateral infusions of scopolamine (35 μg/side) or PBS 10 min before all three phases of the CPFE or only prior to a single phase. Intra-mPFC administration of scopolamine prior to all three phases significantly impaired fear conditioning suggesting that mPFC cholinergic function is necessary for successful CPFE performance. Analyses of the individual infusion days revealed a significant impairment of the CPFE when infusions occurred prior to preexposure or training (i.e. immediate footshock) but not prior to testing. In total, these findings suggests a role of mPFC cholinergic function in the acquisition and/or consolidation of a contextual representation and the context-shock association but not in retrieval or expression of fear memory. Implications for mPFC involvement in contextual fear conditioning and neurological dysfunction following neonatal alcohol exposure are discussed.

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RAPID COMMUNICATIONScopolamine Selectively Disrupts the Acquisition of Contextual Fear Conditioning in Rats

Abstract

RAPID COMMUNICATION
Scopolamine Selectively Disrupts the Acquisition of Contextual Fear Conditioning in Rats