Inhibition of cortical acetylcholine release and cognitive performance by histamine H₃ receptor activation in rats

Abstract

1 The effects of histamine and agents acting at histamine receptors on spontaneous and 100 mM K+-evoked release of acetylcholine, measured by microdialysis from the cortex of freely moving rats, and on cognitive tests are described. 2 Local administration of histamine (0.1-100 pM) failed to affect spontaneous but inhibited 100 mM K+-stimulated release of acetylcholine up to about 50%. The H3 receptor agonists (R)-ca-methylhistamine (RAMH) (0.1-10 yM), imetit (0.01-10 yM) and immepip (0.01-10 yM) mimicked the effect of histamine.3 Neither 2-thiazolylethylamine (TEA), an agonist showing some selectivity for H, receptors, nor the H2 receptor agonist, dimaprit, modified 100 mM K+-evoked release of acetylcholine. 4 The inhibitory effect of 100 pM histamine was completely prevented by the highly selective histamine H3 receptor antagonist, clobenpropit but was resistant to antagonism by triprolidine and cimetidine, antagonists at histamine H, and H2 but not H3 receptors.5 The H3 receptor-induced inhibition of K+-evoked release of acetylcholine was fully sensitive to tetrodotoxin (TTX).6 The effects of intraperitoneal (i.p.) injection of imetit (5 mg kg-') and RAMH (5 mg kg-') were tested on acetylcholine release and short term memory paradigms. Both drugs reduced 100 mM K+-evoked release of cortical acetylcholine, and impaired object recognition and a passive avoidance response.7 These observations provide the first evidence of a regulatory role of histamine H3 receptors on cortical acetylcholine release in vivo. Moreover, they suggest a role for histamine in learning and memory and may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.

Role of H3-Receptor-Mediated Signaling in Anxiety and Cognition in Wild-Type and Apoe–/– Mice

“…Administration of thioperamide, histamine, or histidine, decreased investigation time of a juvenile rat by an adult rat while immepip or inhibition of histamine synthesis by afluoromethylhistidine prolonged recognition time (Prast et al, 1996). However, H 3 receptor blockade might be beneficial under condition of cognitive impairments caused by cholinergic dysfunction (Miyazaki et al, 1995a(Miyazaki et al, , b, 1997Blandina et al, 1996Blandina et al, , 1998Gulat-Marnay et al, 1989a, b;Giovannini et al, 1999;Molinengo et al, 1999). In a two-arm maze using a metal box and a glass bottle as objects in the retention trial and two identical objects in the first trial, H 3 receptor blockade antagonized scopolamine-induced object recognition impairments and object recognition impairments at 90-and 120-min intertrial intervals at which male and female rats, respectively, did not exhibit object recognition anymore in this version of the test .…”

Interactions between histaminergic and cholinergic systems in learning and memory

“…Conversely, it inhibited concentration-dependently potassium-elicited release of ACh. The H 3 receptor agonists R-a-methylhistamine, imetit [46,62,126], and immepip [128] mimicked the effect of histamine, showing a slightly greater potency than histamine [14]. Oppositely, neither 2-thiazolylethylamine [45], an agonist showing some selectivity for H 1 receptors, nor the H 2 receptor agonist dimaprit [98] modified potassium-evoked release of ACh [14].…”

“…The H 3 receptor agonists R-a-methylhistamine, imetit [46,62,126], and immepip [128] mimicked the effect of histamine, showing a slightly greater potency than histamine [14]. Oppositely, neither 2-thiazolylethylamine [45], an agonist showing some selectivity for H 1 receptors, nor the H 2 receptor agonist dimaprit [98] modified potassium-evoked release of ACh [14]. The inhibitory effect of 100 mM histamine, a concentration producing the maximal effect [14], was completely prevented by histamine H 3 receptor antagonists, such as clobenpropit [126] and thioperamide, but was resistant to antagonism by triprolidine [65] and cimetidine, antagonists at histamine H 1 and H 2 but not H 3 receptors [14,15].…”

“…Oppositely, neither 2-thiazolylethylamine [45], an agonist showing some selectivity for H 1 receptors, nor the H 2 receptor agonist dimaprit [98] modified potassium-evoked release of ACh [14]. The inhibitory effect of 100 mM histamine, a concentration producing the maximal effect [14], was completely prevented by histamine H 3 receptor antagonists, such as clobenpropit [126] and thioperamide, but was resistant to antagonism by triprolidine [65] and cimetidine, antagonists at histamine H 1 and H 2 but not H 3 receptors [14,15]. All agonists and antagonists were administered locally, dissolved into the perfusion medium.…”

“…Two different laboratories reported that histamine inhibited potassium-evoked release of [ 3 H]-ACh from rat cortical slices preloaded with [ 3 H]-choline through activation of H 3 receptors [3,23]. The effects of histamine and agents acting at histamine receptors on spontaneous and potassium-evoked release of ACh were also investigated in vivo, using microdialysis to simultaneously administer histamine and monitor changes in endogenous ACh release from cortex of freely moving rats [14,15]. Histamine, administered locally into the cortex, failed to affect ACh spontaneous release.…”