Effects of concurrent nicotinic antagonist and PCPA treatments on spatial and passive avoidance learning

doi:10.1016/0006-8993(92)90086-O

Brain Research

Volume 575, Issue 2, 20 March 1992, Pages 247-250

https://doi.org/10.1016/0006-8993(92)90086-O Get rights and content

The present study investigates the effects of concurrent manipulations of nicotinic cholinergic receptors (mecamylamine 10 mg/kg, i.p.) and serotonin neurons (PCPA, 400 mg on each of 4 days) on spatial navigation (water maze, WM) and passive avoidance (PA) performance. PCPA treatment had no effect on WM navigation or PA performance of intact rats, but greatly aggravated mecamylamine induced performance deficit. Either single or combined treatments with hexamethonium (5.0 mg/kg, s.c.) and PCPA had no effect on WM or PA performance. These findings may suggest that nicotinic cholinergic receptors are also importantly involved in the cholinergic-serotonergic regulation of cognitive functioning.

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The role of serotonin in learning and memory: a rich pallet of experimental studies
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Citation Excerpt :
A subamnestic dose of atropine has also been described as producing cognitive perturbations in rats given 5,7-DHT into the ventricles or directly into the fimbria-fornix, while sham-operated rats showed normal performance (Richter-Levin, Greenberger, & Segal, 1994). Riekkinen, Riekkinen, Sirviö, and Riekkinen (1992) also demonstrated that nicotinic receptors may be involved in the cholinergic–serotonergic regulation of cognitive function. Indeed, this group has investigated the cognitive effects of mecamylamine (10 mg/kg, i.p.), a nicotinic antagonist, in rats subjected to massive pCPA-induced 5-HT depletion.
In invertebrates, the formation of memories is made more difficult after serotonin (5-HT) depletion, but is facilitated when 5-HT functions are stimulated. The role of 5-HT on learning and memory in higher vertebrates appears more complex: when 5-HT systems are selectively damaged, the lesions produce behavioral consequences, but learning is still possible and memory most often appears normal. Serotonergic functions may also be enhanced. Such enhancement may have two types of effects: when given before training, memory functions appear unchanged in some reports or altered in others; exceptionally, they can be improved. Given after training, selective serotonin reuptake inhibitors have no effect on memory or may improve it. Modifications of 5-HT functions may interact with treatments affecting other neurotransmitter functions. Therefore, roles of the ascending serotonergic system could encompass modulating more direct functional implications of other neurotransmitter systems. These modulations could operate in a region-specific and perhaps even receptor-specific manner.
Experimental Studies on the Role(s) of Serotonin in Learning and Memory Functions
2010, Handbook of Behavioral Neuroscience
Citation Excerpt :
A subamnestic dose of atropine has also been described to produce cognitive perturbations in rats given 5,7-DHT into the ventricles or directly into the fimbria-fornix, while sham-operated rats showed normal performance (Richter-Levin et al., 1994). Riekkinen et al. (1992) also demonstrated that nicotinic receptors may be involved in the cholinergic-serotonergic regulation of cognitive function. Indeed, this group has investigated the cognitive effects of mecamylamine (10 mg/kg, i.p.), a nicotinic antagonist, in rats subjected to massive 5-HT depletion (pCPA).
In invertebrates, serotonin (5-HT) is involved in both non-associative and associative learning, and thus memory formation. Indeed, as shown in Aplysia californica, snails, leeches, etc., whereas the formation of memories is more difficult after 5-HT depletion, it is facilitated when serotonin functions are stimulated. Although it is generally considered that the evolution can be relatively conservative, the overall picture is much more complicated in higher vertebrates: when 5-HT systems are selectively damaged, the lesions have behavioral consequences, as can be evidenced, for instance, in rats or mice (e.g., on impulsivity), but learning is still possible, and most often memory capabilities appear normal. Serotonergic functions may also be enhanced by pharmacological tools, such as drugs inhibiting the reuptake of 5-HT (SSRIs). Although there is no consensus in the literature, SSRIs may have two types of effects according to whether they are given before or after training. When SSRIs are given before training, memory functions appear unchanged in some reports or altered in others; exceptionally, they can be improved. Given immediately after training, such drugs have no effect on memory or may improve it. In higher vertebrates, modifications of 5-HT functions have nevertheless consequences on the mnesic impact of treatments affecting other neurotransmitter functions, such as blockade of cholinergic receptors or cholinergic lesions. Therefore, with regard to learning and memory, one of the roles of the ascending serotonergic system taken as a whole could be to modulate more direct functional implications of other neurotransmitter systems. These modulations could operate in a region-specific and perhaps receptor-specific manner.
Water maze impairments after combined depletion of somatostatin and serotonin in the rat
2007, Behavioural Brain Research
This study examined the effect of both separate and combined depletion of brain somatostatin and serotonin on acquisition of the water maze (WM) task. Naïve male Long-Evans rats received injections of p-chlorophenylalanine (PCPA; 500 mg/kg × 2) to deplete serotonin or cysteamine (90 or 200 mg/kg) to deplete somatostatin, or both treatments prior to spatial and reversal training in the water maze. Some rats first received Morris’ nonspatial pretraining to train them in the behavioral strategies that are required for successful spatial place learning in this task, prior to drug treatment and spatial training. A detailed behavioral analysis indicated that somatostatin or serotonin depletion alone caused little or no impairment in naïve animals. Depletion of both somatostatin and serotonin in naïve rats impaired performance, with differences in the impairments that depended on the dose of cysteamine. Nonspatially pretrained rats were not impaired. Thus, neither somatostatin nor serotonin alone is crucial for the water maze task, but impairments occur if both somatostatin and serotonin are depleted in naïve rats. The results indicate that some of the performance impairment was due to strategies impairment rather than a spatial place learning impairment. Depletion of both somatostatin and serotonin in naïve rats produces results comparable to the spatial navigation deficits seen in some Alzheimer patients and suggests that combinations of antagonist treatments may better model this disorder than single antagonist treatments do.
p-Chloroamphetamine blocks physostigmine-induced memory enhancement in rats with unilateral nucleus basalis lesions
2004, Pharmacology Biochemistry and Behavior
The present experiment examined whether p-chloroamphetamine (PCA), a serotonergic releasing/depleting agent, would block the memory-enhancing effect of physostigmine in rats with N-methyl-d-aspartic acid (NMDA)-induced unilateral lesions of the nucleus basalis of Meynert (uni-nbM). Six groups of subjects with uni-nbM lesions in addition to an isolated sham-operated control group were included. Subjects were trained and tested 72 h later on a one-trial passive avoidance task. Thirty minutes before training, rats with uni-nbM lesions were injected with either 1.0 or 5.0 mg/kg PCA or saline. Immediately after training, approximately half the subjects in each group were injected with either saline or 0.06 mg/kg physostigmine. Animals in the sham group received saline injections. Saline-injected animals with uni-nbM lesions performed poorly at test, a deficit that was reversed with physostigmine. Pretraining injections of PCA blocked physostigmine's memory-enhancing effect, although motor impairment during training may have contributed to decrements in test performance in animals injected with 5.0 mg/kg. Subjects were killed about 10 days later and their frontal cortices examined for choline acetyltransferase (ChAT). Results from the neurochemical analysis revealed that the lesion decreased ChAT levels and that the injection of 1.0 mg/kg PCA exaggerated this lesion-induced depletion. Implications for the interaction between acetylcholine and serotonin are discussed.
Neurotransmitter systems involved in learning and memory in the rat: A meta-analysis based on studies of four behavioral tasks
2003, Brain Research Reviews
From previous literature, it appears that most classical neurotransmitter systems can in some way influence learning and memory in the rat. A matter of crucial interest is, however, whether the chemical systems contribute in a similar manner or whether they have different abilities to support cognitive processes. The purpose of the present study was to investigate this issue. The investigation was carried out by reviewing relevant studies of neurochemistry and cognition. Inclusion criteria were set for selection of behavioral tasks to be elucidated and for studies employing acceptable tasks. Morris water maze, radial maze, passive avoidance, and spontaneous alternation met the criteria for inclusion, and a table for each of these tests summarizes the neurochemical results of the studies accepted for inclusion. In this way, a reliable comparability of results from relevant studies was obtained. The comparisons revealed that for both systemic and targeted infusions of agents the neurochemical systems possess different abilities to influence learning and memory. Calculation of impact factors (percentage of significant effects of chemical agents like agonists, antagonists, neurotoxins) showed that glutamate was ranking highest (93), followed by GABA (81), dopamine (81), acetylcholine (81), serotonin (55), and norepinephrine (48). No task specific roles were observed for the transmitter systems. The highest sensitivity (percentage of significant effects) to interference with neurochemical systems was found for the spontaneous alternation task (86), followed by water maze (76), passive avoidance (72), and radial maze (58). The multiple memory systems in the rat brain can hardly be related to specific transmitter systems, because of the great extent of interactions between the systems.
Nicotinic-serotonergic interactions in brain and behaviour
2002, Pharmacology Biochemistry and Behavior
This review focuses on nicotinic–serotonergic interactions in the central nervous system (CNS). Nicotine increases 5-hydroxytryptamine (5-HT) release in the cortex, striatum, hippocampus, dorsal raphé nucleus (DRN), hypothalamus, and spinal cord. As yet, there is little firm evidence for nicotinic receptors on serotonergic terminals and thus nicotine's effects on 5-HT may not necessarily be directly mediated, but there is strong evidence that the 5-HT tone plays a permissive role in nicotine's effects. The effects in the cortex, hippocampus, and DRN involve stimulation of 5-HT_1A receptors, and in the striatum, 5-HT₃ receptors. The 5-HT_1A receptors in the DRN play a role in mediating the anxiolytic effects of nicotine and the 5-HT_1A receptors in the dorsal hippocampus and lateral septum mediate its anxiogenic effects. The increased startle and anxiety during nicotine withdrawal is mediated by 5-HT_1A and 5-HT₃ receptors. The locomotor stimulant effect of acute nicotine is mediated by 5-HT_1A receptors and 5-HT₂ receptors may play a role in the expression of a sensitised response after chronic nicotine treatment. Unfortunately, the role of 5-HT_1A receptors in mediating nicotine seeking has not yet been investigated and would seem an important area for future research. There is also evidence for nicotinic–serotonergic interactions in the acquisition of the water maze, passive avoidance, and impulsivity in the five-choice serial reaction task.

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References (25)

Afferents to the basal forebrain cholinergic cell area from the pontomesencephalic — catecholamine, serotonin, and acetylcholine — neurons

Neuroscience

Cortical projection patterns of magnocellular basal nucleus subdivisions as revealed by anterogradely transported Phaseolus vulgaris leucoagglutinin

Brain Research

Combined cholinergic and serotonergic denervation of the forebrain produces severe deficits in a spatial learning task in the rat

Brain Research

Changes in monoamines and their metabolite levels in some brain regions of aged rats

Neurobiol. Aging

A post-mortem study of noradrenergic, serotonergic and GABAergic neurons in Alzheimer's disease

J. Neurol. Sci.

Spatial performance is severely impaired in rats with combined reduction of serotonergic and cholinergic transmission

Brain Research

The correlation of passive avoidance deficit in aged rat with the loss of nucleus of basalis choline acetyltransferase-positive neurons

Brain Res. Bull.

Effects of concurrent manipulations of nicotinic and muscarinic receptors on spatial and passive avoidance learning

Pharmacol. Biochem. Behav.

Interaction between raphe dorsalis and nucleus basalis magnocellularis in the regulation of neocortical high-voltage spindle activity in rat neocortex

Brain Research

Interaction between raphe dorsalis and nucleus basalis magnocellularis in spatial learning

Brain Research

Similar memory impairments found in medial septal-vertical diagonal band of Broca and nucleus basalis lesioned rats: are memory defects induced by nucleus basalis lesions related to the degree of non-specific subcortical cell loss?

Behav. Brain Res.

Tetrahydroaminoacridine alleviates medial septal lesion-induced and age-related spatial reference but not working memory deficits

Physiol. Behavior.

Cited by (33)

The role of serotonin in learning and memory: a rich pallet of experimental studies

Experimental Studies on the Role(s) of Serotonin in Learning and Memory Functions

Water maze impairments after combined depletion of somatostatin and serotonin in the rat

p-Chloroamphetamine blocks physostigmine-induced memory enhancement in rats with unilateral nucleus basalis lesions

Neurotransmitter systems involved in learning and memory in the rat: A meta-analysis based on studies of four behavioral tasks

Nicotinic-serotonergic interactions in brain and behaviour