Effects of histamine H3 receptor agonists and antagonists on cognitive performance and scopolamine-induced amnesia

doi:10.1016/S0166-4328(99)00063-7

Behavioural Brain Research

Volume 104, Issues 1–2, October 1999, Pages 147-155

https://doi.org/10.1016/S0166-4328(99)00063-7 Get rights and content

Abstract

In previous research we found that pre-training administration of histamine H₃ receptor agonists such as (R)-α-methylhistamine and imetit impaired rat performance in object recognition and a passive avoidance response at the same doses at which they inhibited the release of cortical acetylcholine in vivo. Conversely, in the present study we report that the post-training administration of (R)-α-methylhistamine and imetit failed to affect rat performance in object recognition and a passive avoidance response, suggesting that H₃ receptor influences the acquisition and not the recall processes. We also investigated the effects of two H₃ receptor antagonists, thioperamide and clobenpropit, in the same behavioral tasks. Pre-training administration of thioperamide and clobenpropit failed to exhibit any procognitive effects in normal animals but prevented scopolamine-induced amnesia. However, also post-training administration of thioperamide prevented scopolamine-induced amnesia. Hence, the ameliorating effects of scopolamine-induced amnesia by H₃ receptor antagonism are not only mediated by relieving the inhibitory action of cortical H₃ receptors, but other mechanisms are also involved. Nevertheless, H₃ receptor antagonists may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.

Introduction

Over the past decade evidence accumulated that the ‘cholinergic hypothesis of learning’ [6] is too reductionistic [20], [42]. Other neurotransmitters, such as dopamine, GABA, glutamate, noradrenaline and serotonin may affect cognitive processes [11], and early evidence clearly implicates also histamine. For example, intracerebroventricular administration of histamine facilitated recall in a step-down inhibitory avoidance task [10], while H₁ receptor antagonists impaired retention of the step-through active avoidance response in rats [22]. These impairing effects of H₁ receptor antagonists were prevented by both histamine and acetylcholine [24]. Furthermore, administration of histidine, the precursor of histamine, ameliorated scopolamine-induced learning deficits in mice exposed to an elevated plus-maze test [28], and facilitated social memory in rats [40]. However, chronic blockade of the histamine-synthesizing enzyme, resulting in both facilitation as well as attenuation of active avoidance acquisition [8], [23], contradicts in part the previous results. Moreover, there is evidence of facilitation of learning after lesions of the tuberomammillary nucleus, thus suggesting that removal of histaminergic tone is facilitatory for cognitive processes [16], [21]. These effects can be only understood through knowledge of the distinct and opposing modulatory actions histaminergic tuberomammillary neurons may have, by activating different receptor subtypes, on other systems involved in processes of learning. Recently, a role of H₃ receptors in cognition has been reported, and the mechanism might rest on histaminergic–cholinergic interactions [29], [37]. Indeed, rat cognitive performance in object recognition, and a passive avoidance response is impaired by administration of imetit and (R)-α-methylhistamine (RAMH), both highly selective H₃ receptor agonists [1], [17], at doses that also reduce potassium-evoked release of cortical acetylcholine [7]. There is evidence that reduced availability of acetylcholine in the synaptic cleft results in cognitive deficits [41]. Another histamine H₃ receptor agonist, immepip [47], impairs animal performance in the olfactory, social memory test [40]. In these studies H₃ receptor agonists were administered before training, so H₃ receptor activation may act by suppressing acquisition, although a role for the H₃ receptor in recall cannot be excluded. Moreover, since H₃ receptor agonists impair cognitive performances, one might envisage that H₃ receptor antagonists might exert procognitive effects. Indeed, thioperamide, an H₃ receptor antagonist, improved rat performance in the olfactory, social memory test [40]. Other studies, however, report that the procognitive effects of H₃ receptor antagonists become fully evident only when behavioral deficits are pronounced. For example, while thioperamide improves significantly the response latency in a passive avoidance response in senescence-accelerated mice (these animals showed a marked age-accelerated deterioration in learning tasks of passive avoidance), it is ineffective in normal-rate ageing mice [26]. The present study was designed to evaluate the capacity of H₃ receptor antagonists to influence scopolamine-induced amnesia in rats, measured by object recognition and a passive avoidance response, two short-term memory paradigms. Since the frontal cortex [19] and the amygdala [36] are possibly involved in this form of memory, the presence in these regions of H₃ receptors in a rather high density [39] would support their role in short-term memory tasks. Also the possibility of an H₃ receptor involvement in recall processes was investigated by assessing the effects of post-training administration of H₃ receptor agonists on object recognition and a passive avoidance response.

Section snippets

Animals

Male Wistar rats (200–250 g body weight, Harlan Nossan, Italy) were allowed free access to food pellets and water, and were housed three per cage, in a room maintained at approximately 22°C, 50% humidity, and with a 12-h light–dark cycle. Experiments were performed in a similar environment. All experiments were done in strict compliance with the recommendations of the EEC (86/609/CEE) for the care and use of laboratory animals and were approved by the Animal Care Committee of the Department of

Passive avoidance response

Fig. 1 shows the effects of pre-training, systemic administration of thioperamide, clobenpropit, another H₃ receptor antagonist [46], and scopolamine on passive avoidance test performance. Saline was injected i.p. to control animals. According to their brain penetration characteristics after peripheral administration [4], [32], [35], thioperamide (5 mg/kg, i.p.) and clobenpropit (10 and 15 mg/kg, s.c.) were injected 120 min prior to the training trial. Saline (250 μl, i.p.) and scopolamine (0.2

Discussion

The present study confirms an earlier suggestion [7], [31], [43] of an H₃ receptor involvement in cognitive functions by assessing the effects of two H₃ receptor antagonists, thioperamide and clobenpropit, alone and in combination with the muscarinic antagonist scopolamine, and two H₃ receptor agonists, imetit and RAMH, on object recognition and a passive avoidance response. Rats receiving prior to the training trial of the passive avoidance response, or to the first trial of the object

Conclusion

In conclusion, H₃ receptor agonists appear to impair the acquisition but not the recall processes, and both pre- and post-training administration of H₃ receptor antagonists result in amelioration of scopolamine-induced amnesia, thus suggesting a role for the interaction between the cholinergic and histaminergic systems in learning and memory. However, a beneficial effect on a scopolamine-induced deficit is a concomitant observation, but does not prove in any way that cholinergic neurons are

Acknowledgements

This work was supported by grants 40% (M.U.R.S.T) and 60% (M.U.R.S.T.–Universitá di Firenze, Italy).

References (47)

J.C. Barnes et al.
Pharmacological activity of VUF 9153, an isothiourea histamine H₃ receptor antagonist
Eur. J. Pharmacol.
(1993)
L. Bartolini et al.
Aniracetam restores object recognition impaired by age, scopolamine, and nucleus basalis lesions
Pharmacol. Biochem. Behav.
(1996)
F.P. Eckenstein et al.
An anatomical study of cholinergic innervation in rat cerebral cortex
Neuroscience
(1988)
A. Ennaceur et al.
A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data
Behav. Brain Res.
(1988)
V. Haroutunian et al.
Implications of multiple transmitter system lesions for cholinomimetic therapy in Alzheimer’s disease
J.P. Huston et al.
The tuberomammilary nucleus projections in the control of learning, memory and reinforcement processes: evidence for an inhibitory role
Behav. Brain Res.
(1997)
C. Kamei et al.
Participation of histamine in the step-through active avoidance response and its inhibition by H₁-blockers
Jpn. J. Pharmacol.
(1991)
K.-I. Meguro et al.
Effects of thioperamide, a histamine H₃ antagonist, on the step-through passive avoidance response and histidine decarboxylase activity in senescence-accelerated mice
Pharmacol. Biochem. Behav.
(1995)
M.M. Mesulam et al.
Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1–Ch6)
Neuroscience
(1983)
S. Miyazaki et al.
Ameliorating effects of histidine on scopolamine-induced learning deficits using an elevated plus-maze test in mice
Life Sci.
(1995)

S. Miyazaki et al.

Effects of thioperamide, a histamine H₃-receptor antagonist, on a scopolamine-induced learning deficit using an elevated plus-maze test in mice

Life Sci.

(1995)

S. Miyazaki et al.

Effects of clobenpropit (VUF-9153), a histamine H₃-receptor antagonist, on learning and memory, and on cholinergic and monoaminergic systems in mice

Life Sci.

(1997)

T. Mochizuki et al.

Brain penetration of the histamine H₃ receptor antagonists thioperamide and clobenpropit in rat and mouse, determined with ex vivo [¹²⁵H]iodophenpropit binding

Brain Res.

(1996)

K.J. Page et al.

Dissociable effects on spatial maze and passive avoidance acquisition and retention following AMPA- and ibotenic acid-induced excitotoxic lesions of the basal forebrain in rats: differential dependence on cholinergic neuronal loss

Neuroscience

(1991)

M. Petrides

Frontal lobes and behaviour

Curr. Opin. Neurobiol.

(1994)

H. Pollard et al.

A detailed autoradiographic mapping of histamine H₃ receptors in rat brain areas

Neuroscience

(1993)

H. Prast et al.

Histaminergic neurons facilitate social memory in rats

Brain Res.

(1996)

G. Spignoli et al.

Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine

Pharmacol. Biochem. Behav.

(1987)

C.E. Tedford

Clinical application of HA H₃ receptor antagonists in learning and memory disorders

H. VanderGoot et al.

Isothiourea analogues of histamine as potent agonists or antagonists of the histamine H₃-receptor

Eur. J. Med. Chem.

(1992)

J.M. Arrang et al.

Highly-potent and selective ligands for histamine-H₃ receptors

Nature

(1987)

J.M. Arrang et al.

Auto-inhibition of brain histamine release mediated by a novel class (H₃) of histamine receptor

Nature

(1983)

L. Bacciottini et al.

Acetylcholine release from hippocampus of freely moving rats is modulated by endogenous histamine

Inflamm. Res.

(1999)

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Research reportEffects of histamine H3 receptor agonists and antagonists on cognitive performance and scopolamine-induced amnesia

Abstract

Introduction

Section snippets

Animals

Passive avoidance response

Discussion

Conclusion

Acknowledgements

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Neuroscience

Behav. Brain Res.

Behav. Brain Res.

Jpn. J. Pharmacol.

Pharmacol. Biochem. Behav.

Neuroscience

Life Sci.

Life Sci.

Life Sci.

Brain Res.

Neuroscience

Curr. Opin. Neurobiol.

Neuroscience

Brain Res.

Pharmacol. Biochem. Behav.

Eur. J. Med. Chem.

Highly-potent and selective ligands for histamine-H3 receptors

Nature

Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor

Nature

Acetylcholine release from hippocampus of freely moving rats is modulated by endogenous histamine

Inflamm. Res.

Research report
Effects of histamine H₃ receptor agonists and antagonists on cognitive performance and scopolamine-induced amnesia

Highly-potent and selective ligands for histamine-H₃ receptors

Auto-inhibition of brain histamine release mediated by a novel class (H₃) of histamine receptor