Facilitation of short-term memory by histaminergic neurons in the nucleus accumbens is independent of cholinergic and glutamatergic transmission

Background and Purpose

Here, we have investigated whether learning and/or short-term memory was associated with release of ACh and glutamate in the rat nucleus accumbens (NAc). Additionally, neurotransmitter release in the NAc was assessed during facilitation of cognitive processes by antagonists of inhibitory histamine autoreceptors.

Experimental Approach

The olfactory, social memory test was used in combination with push–pull superfusion of the NAc. A male, juvenile rat was exposed twice to an adult male rat at intervals of 60 or 90 min, and release of ACh and glutamate was determined in the NAc of the conscious adult rat. Histamine receptor antagonists were applied i.c.v.

Key Results

First exposure of a juvenile rat to an adult rat increased ACh and glutamate release in the NAc of the adult rat. Repetition of exposure after 60 min did not change release of ACh and glutamate, while contact time to recognition (CTR) was shortened. Repetition of exposure after an interval of 90 min prolonged CTR and enhanced accumbal ACh and glutamate release rates. Injection (i.c.v.) of thioperamide (histamine H₃ receptor antagonist) together with famotidine (H₂ receptor antagonist), 80 min prior to second exposure, diminished CTR and abolished ACh and glutamate release when second exposure was carried out 90 min after the first one.

Conclusions and Implications

Histaminergic neurons per se facilitated short-term memory, without activation of cholinergic and/or glutamatergic neurons in the NAc of rats. Cholinergic and glutamatergic neurons within the NAc contributed to learning but not to recall of memory.

Linked Articles

This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1     

Gastric acid secretory responses to cholinergic and histaminergic stimulation in chronic morphine-treated rats

The effects of chronic morphine administration on cholinergic and histaminergic activities were evaluated in rats by observing their gastric acid secretory responses to secretagogues. The responses of in-vivo perfused stomachs to 2-deoxy-D-glucose or pentagastrin, and of the isolated gastric mucosa to histamine or bethanechol, were not significantly different between naive and chronic morphine-treated animals. It is suggested that the chronic morphine-treated rats exhibit normal cholinergic and histaminergic activities as well as receptor sensitivities to acetylcholine and histamine.     

Genetic and pharmacological approaches to evaluate the interaction between the cannabinoid and cholinergic systems in cognitive processes

BACKGROUND AND PURPOSE: The objective of this study was to investigate the possible interactions between the cannabinoid and cholinergic systems in memory and learning processes by using genetic and pharmacological approaches in two different behavioural models, the active avoidance and the object recognition test. EXPERIMENTAL APPROACH: The effects induced by nicotine, physostigmine and scopolamine were studied in CB(1) receptor knockout and wild-type mice in the active avoidance paradigm. In addition, the effects of pretreatment with the CB(1) receptor antagonist rimonabant were evaluated on the responses induced by nicotine in the active avoidance and the object recognition tasks in wild-type mice. KEY RESULTS: Nicotine (0.5 mg kg(-1) s.c.) did not modify the performance of CB(1) knockout and wild-type mice in this model, whereas scopolamine (0.5 mgkg(-1) i.p.) impaired the performance in both genotypes. Physostigmine (0.1 mg kg(-1) i.p.) increased the active avoidance performance in wild-type but not in CB(1) knockout mice. Rimonabant (0.3, 1, 3, and 10 mg kg(-1)) did not modify the performance in the active avoidance test, given alone or co-administered with nicotine. In contrast, nicotine enhanced the performance in the object recognition task but this response was attenuated by rimonabant co-administration. CONCLUSIONS AND IMPLICATIONS: The present findings revealed that the cognitive effects of nicotine and physostigmine were attenuated in the absence of CB(1) receptor activity. Scopolamine effects were independent from CB(1) receptors.     

Neurosteroids and cholinergic systems: implications for sleep and cognitive processes and potential role of age-related changes

Rationale The neurosteroids pregnenolone sulfate (PREGS), dehydroepiandrosterone sulfate (DHEAS) and allopregnanolone (3α,5α THPROG) have been implicated as powerful modulators of memory processes and sleep states in young and aged subjects with memory impairment. As these processes depend on the integrity of cholinergic systems, a specific effect of neurosteroids on these systems may account for their effects on sleep and memory.Objective To review the evidence for a specific and differential effect of neurosteroids on cholinergic systems.Methods We carried out keyword searches in “Medline” to identify articles concerning (1) the effects of neurosteroids on cholinergic systems, sleep and memory processes, and (2) changes in neurosteroid concentrations during aging. Few results are available for humans. Most data concerned rodents.Results Peripheral and central administrations of PREGS, DHEAS, and 3α,5α THPROG modulate the basal forebrain and brainstem projection cholinergic neurons but not striatal cholinergic interneurons. Local administration of neurosteroids to the basal forebrain and brainstem cholinergic neurons alters sleep and memory in rodents. There are a few conflicting reports concerning the effects of aging on neurosteroid concentrations in normal and pathological conditions.Conclusions The specific modulation of basal forebrain and brainstem cholinergic systems by neurosteroids may account for the effects of these compounds on sleep and memory processes. To improve our understanding of the role of neurosteroids in cholinergic systems during normal and pathological aging, we need to determine whether there is specific regionalization of neurosteroids, and we need to investigate the relationship between neurosteroid concentrations in cholinergic nuclei and age-related sleep and memory impairments.     

Comparison of the urinary bladder base and detrusor to cholinergic and histaminergic receptor activation in the rabbit.

The effects of cholinergic and histaminergic agonists and antagonists on the receptor responsiveness of the bladder as well as the fundus were compared. Carbachol and histamine were more potent and generated a greater force of contraction in the detrusor muscle than in the neck region. Histamine characteristically produced a rapid twitch-like contraction followed by an increase in motility in the neck smooth muscle while it produced an increased sustained contraction similarly induced by carbachol in the detrusor preparation. Pyrilamine was equally effective in competitively blocking histamine response in both the detrusor and neck preparations. We conclude that the bladder neck, like the detrusor regions, has cholinergic and H1 histaminergic receptors.     

Role of central histaminergic system in lorazepam withdrawal syndrome in rats.

Effects of histaminergic agonists and antagonists were investigated on withdrawal signs in lorazepam-dependent rats. Physical dependence was developed by giving lorazepam admixed with the food in the following dose schedule (in mg/kg given daily x days): 10 x 4, 20 x 4, 40 x 4, 80 x 4, and 120 x 7. The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), reaction time to pain, foot shock aggression (FSA), and audiogenic seizures. During the withdrawal period, the rats were divided into groups of 10 each. Control-withdrawal group did not receive any drug. The drugs (in mg/kg administered intramuscularly)--L-histidine (50), histamine-N-methyl (2), promethazine (10), pheniramine (10), astemizole (10), and thioperamide (1)--were given separately in other groups daily during the withdrawal period. The withdrawal signs in control group were hyperkinesia, hyperaggression, and audiogenic seizures. L-Histidine, precursor of histamine, and thioperamide, antagonist of H3 receptor, potentiated hyperkinesia, hyperaggression, and audiogenic seizures. Histamine-N-methyl, agonist of H3 receptor, and H1 receptor antagonists, promethazine and pheniramine, blocked all the withdrawal signs. Astemizole, a peripheral antagonist of H1 receptor, could not affect any withdrawal sign. It may be concluded that histamine H1 receptors are facilitatory and H3 receptors are inhibitory for benzodiazepine (BZD) withdrawal syndrome.     

Role of orexin and prostaglandin E(2) in activating histaminergic neurotransmission

Although the molecular mechanisms underlying the control of sleep have been extensively studied in the past, relatively little attention has been paid to the regulatory mechanisms involved in the maintenance and control of wakefulness until today. In this article, recent developments leading to our better understanding of the arousal system will be reviewed with the main emphasis on three messengers: histamine, prostaglandin E(2) and orexin. The results reported herein may provide new insights into the molecular mechanisms of sleep-wake regulation and may lead to the development of new anti-sleep drugs as well as new hypnotic agents.     

The cholinergic hypothesis of cognitive aging revisited again: cholinergic functional compensation

It is now possible to reevaluate the cholinergic hypothesis of age-related cognitive dysfunction based on a synthesis of new evidence from cholinergic stimulation studies and cognitive models. We propose that a change of functional circuitry that can be observed through a combination of pharmacologic challenge and functional neuroimaging is associated with age-related changes in cholinergic system functioning. Psychopharmacological manipulations using cholinergic agonists and antagonists have been consistent in replicating patterns of aging seen in functional imaging studies. In addition, studies of anticholinesterase drugs in patients with Alzheimer's disease and mild cognitive impairment show support for the proposal that cholinergic compensation causes alterations in task-related brain activity. Thus, the cholinergic hypothesis of age-related cognitive dysfunction deserves further consideration as new methodologies for evaluating its validity are increasingly being used. Future directions for testing hypotheses generated from this model are presented.     

Involvement of central histaminergic and cholinergic systems in the morphine-induced increase in blood-brain barrier permeability to sodium fluorescein in mice

Summary Morphine (5 mg/kg, s.c.) caused a submaximal increase in the brain level of sodium fluorescein administered i.v. Histamine H₁-antagonists, diphenhydramine and mepyramine, given either i.p. or i.c.v., had no significant influence on the effect of morphine. H₂-Antagonists, cimetidine and ranitidine, administered i.c.v., but not i.p., significantly inhibited the morphine effect. -Fluoromethylhistidine, a specific histidine decarboxylase inhibitor (given i.p. and i.e.v.) and antimuscarinic drugs, atropine and biperiden, but not methylatropine (given i.p.) also significantly reduced the morphine effect. Physostigmine (i.p.) significantly enhanced the effects of 0.5 and 1 mg/kg of morphine. Similar effects of histaminergic and cholinergic drugs were also observed on the buprenorphine- and DAGO-induced increase in blood-brain barrier (BBB) permeability to sodium fluorescein. None of the treatments with 6-hydroxydopamine, -methylayrosine, 5,7-dihydroxytryptamine or p-chlorophenylamine had any significant effect on the morphine-induced increase in BBB permeability. These findings suggest that the activation of brain H₂-receptors by neuronal histamine and muscarinic receptors by acetylcholine is involved in the increase in BBB permeability to sodium fluorescein caused by opioid receptor agonists. Send offprint requests to K. Saeki at the above address     

Effects of dietary poly-unsaturated fatty acids on tracheal histaminergic and cholinergic responsiveness in experimental models of bronchial hypersensitivity and hyperreactivity

Respiratory histaminergic and cholinergic receptor function was investigated in isolated tracheal spirals of guinea pigs receiving different diets. Comparison was made between saline treated (controls) and Haemophilus influenzae treated animals in non sensitized conditions, the latter being a model for bronchial hyperreactivity, and in sensitized conditions, being a model for allergen induced bronchial hypersensitivity. The different semi-synthetic diets (35 energy% fat), varying in linoleic acid content (5.85, 11.25 and 22.05 en% fat) and one diet with low linoleic acid (3.55 en%) in which linolenic acid was added additionally (5.30 en%), exerted profound effects on tracheal reactivity to histamine. In sensitized animals the maximal induced histamine contraction was significantly diminished in the dietary group receiving 5.85 en% linoleic acid as compared with the other dietary groups (35% decrease in the H. influenzae-treated, 20-30% decrease in saline treated animals). Results in non-sensitized animals were similar, though less pronounced. No effect on food intake or growth of the animals could be demonstrated during the six week experimental periods. The carbachol induced contraction of the tracheal spirals of sensitized animals receiving low linoleic acid was also significantly decreased as compared to the other dietary groups (30% for saline treated and 20-30% for H. influenzae-treated animals). No difference in carbachol responsiveness could be detected between the different dietary groups under non-sensitized conditions. The results are discussed in view of the current concepts for bronchial hyperreactivity, especially in relation to eicosanoid involvement.     

Role of histaminergic mechanisms in the regulation of some stress responses in rats.

The involvement of histaminergic mechanisms in the regulation of some stress responses was studied in rats. The brain neuronal histamine (HA) depletor, alpha-fluoromethyl histidine (alpha-FMH), at doses (50 or 100 mg/kg) which markedly lower brain HA, significantly attenuated the gastric ulcer formation and the elevation in plasma corticosterone in response to cold restraint stress (CRS). alpha-FMH also appreciably reduced gastric mucosal HA content. The H1-antagonist, pheniramine (25 mg/kg), attenuated both the gastric mucosal and endocrine response to CRS, while the effects of the H2-antagonist, cimetidine (200 mg/kg), were on the plasma corticosterone levels. These results are discussed in light of complex HA-ergic mechanisms in the maintenance of physiological homeostasis during stress.     

Studies on cholinergic transmission in the medial geniculate nucleus

1. Studies were made on the effects of iontophoretically and intravenously administered cholinergic antagonists on the synaptic responses of medial geniculate (MG) neurones evoked by stimulation of the auditory cortex, inferior colliculus and mesencephalic reticular formation.2. Atropine specifically blocked a proportion of the excitatory responses evoked by stimulating the auditory cortex, inferior colliculus and reticular formation, although it was without effect on some of them.3. Neostigmine and eserine facilitated some excitatory synaptic responses evoked by inferior collicular stimulation.4. It is suggested that the feline MG nucleus receives excitatory cholinergic, as well as non-cholinergic, pathways from the auditory cortex, inferior colliculus and lower brain stem. The cholinergic pathways from the auditory cortex may be either corticofugal fibres or recurrent axon collaterals of afferent projections from the MG nucleus to the cortex. Those from the lower brain stem are possibly the cholinesterase-containing fibres described by Shute & Lewis (1967).     

Participation of cholinergic mechanisms in the regulation of immunological processes

Chronic administration of cholinomimetic (arecolin, pilocarpin, nicotin) and cholinolytic (bezohexonium, pedifen) drugs produces changes of different directions in the number of rosette-forming cells in the spleen of CBA mice immunized with sheep red blood cells. The analysis performed does not allow the effect of the drugs on immunologic processes to be accounted for by an immediate action on lymphoid cells or by an action of the function of the pituitary-adrenal system.     

Development of cholinergic nerve transmission in the chick oesophagus.

1. The onset and development of cholinergic mechanisms in the smooth muscle of the chick oesophagus were studied by estimating the changes in mechanical response and biochemical parameters between 9 days of incubation and 7 days after hatching. 2. Transmural and vagal nerve stimulation first evoked contraction in the oesophagus at 10 days and 11 days of incubation, respectively. These contractions were inhibited by atropine (1-2 microM) and potentiated by physostigmine (0.2 microM). On the other hand, hexamethonium (200 microM) had an inhibitory effect on vagal nerve stimulation but not on transmural nerve stimulation. 3. The relative amplitude of contraction induced by both vagal nerve and transmural stimulations compared to high K+ (80 mM)-induced contractions, progressively increased with age in embryos up to 19 days of incubation. 4. The activity of choline acetyltransferase (ChAT), an enzyme synthesizing acetylcholine (ACh), also gradually increased in the oesophagus during the period from 9 days to 19 days of incubation, which was similar to the change in the nerve-mediated contraction. On the other hand, the cholinesterase activity reached a maximum at 13 days of incubation and decreased until 7 days after hatching. 5. The contractile response to ACh and binding sites of [3H]-quinuclidinyl benzilate ([3H]-QNB) were observed in the oesophagus at 9 days of incubation. The maximum response produced by ACh (300 microM) tended to be greater in early stages (9-13 days of incubation) than in later stages. The sensitivity estimated from pD2 values increased up to 15 days of incubation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blockade and recovery of cholinergic transmission in rats treated with hemicholinium 3

Nerve-induced responses of parotid gland and gastrocnemius muscle were reduced by HC-3 (1 mg kg-1) in proportion to the number of stimuli. Contractions by somatic muscle at 100 Hz were abolished after 6.0 X 10(3) stimuli while 14 X 10(3) were applied at 20 Hz before secretion was blocked. As stimulus rate was decreased, blockade of secretion resulted from fewer stimuli but no difference in ACh content was found between stimulated and unstimulated glands. When stimuli were withheld for 1.5 h transmission recovered temporarily; initial secretory flow rate was only 50% of that in untreated controls when stimulation resumed. In both organs, the time during which responses were sustained, however, was much shorter than when the preparations were stimulated initially. After choline, recovery of transmission was dose-dependent: 150 mg kg-1 were required to restore responsiveness to the muscle and the gland comparable to that in HC-3-treated rats stimulated for the first time. Resting recovery, when stimuli are withheld, probably depends upon stored transmitter becoming mobilized rather than on de novo transmitter synthesis because the endogenous choline in plasma is only 1/1000 of that following exogenous choline.