thioperamide and Amnesia

In the literature, there is some evidence indicating that H3 histamine receptor antagonists, in particular thioperamide, can facilitate learning and memory retrieval in laboratory rodents. The present study aimed at verifying whether this also holds for memory consolidation, a phase of memory for which there is scarcity of convincing data on the effects of H3 receptor antagonists given systemically. To that end, memory consolidation was assessed in C57BL/6J mice using the one-trial step-through inhibitory avoidance task, the compounds being injected immediately after training (foot-shock) and performance measured 24 h later. More specifically, the following effects of thioperamide (1.25-20 mg/kg) were dose-dependently analysed: (1) its potential direct effects on memory consolidation; (2) its potential reversing effects on retrograde amnesia induced by the NMDA antagonist dizocilpine (MK-801, 0.5 mg/kg) and (3) its potential reversing effects on the well-known amnesia induced by the muscarinic antagonist scopolamine (0.25 mg/kg). We found that thioperamide exerted a dose-dependent facilitative effect on memory consolidation. Furthermore, the H3 receptor antagonist reversed scopolamine- and especially dizocilpine-induced amnesia. The results strongly support the view that the brain mechanisms of memory consolidation involve a functional interaction between the NMDA and the H3 sites.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Histamine Antagonists; Male; Memory; Mice; Mice, Inbred C57BL; Piperidines; Reaction Time; Scopolamine

Brain histamine H(3) receptors are predominantly presynaptic and serve an important autoregulatory function for the release of histamine and other neurotransmitters. They have been implicated in a variety of brain functions, including arousal, locomotor activity, thermoregulation, food intake, and memory. The recent cloning of the H(3) receptor in our laboratory has made it possible to create a transgenic line of mice devoid of H(3) receptors. This paper provides the first description of the H(3) receptor-deficient mouse (H(3)(-/-)), including molecular and pharmacologic verification of the receptor deletion as well as phenotypic screens. The H(3)(-/-) mice showed a decrease in overall locomotion, wheel-running behavior, and body temperature during the dark phase but maintained normal circadian rhythmicity. H(3)(-/-) mice were insensitive to the wake-promoting effects of the H(3) receptor antagonist thioperamide. We also observed a slightly decreased stereotypic response to the dopamine releaser, methamphetamine, and an insensitivity to the amnesic effects of the cholinergic receptor antagonist, scopolamine. These data indicate that the H(3) receptor-deficient mouse represents a valuable model for studying histaminergic regulation of a variety of behaviors and neurotransmitter systems, including dopamine and acetylcholine.

Topics: Adjuvants, Anesthesia; Amnesia; Animals; Avoidance Learning; Brain; Dopamine; Dopamine Agents; Histamine Antagonists; Methamphetamine; Mice; Mice, Knockout; Motor Activity; Norepinephrine; Piperidines; Radioligand Assay; Receptors, Histamine H3; Running; Scopolamine; Serotonin

In previous research we found that pre-training administration of histamine H3 receptor agonists such as (R)-alpha-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)-alpha-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.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Cognition; Histamine Agonists; Histamine Antagonists; Imidazoles; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Methylhistamines; Pattern Recognition, Visual; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Scopolamine; Thiourea