Possible Mechanisms for the Effects of Orexin on Hippocampal Functioning and Spatial Learning (analytical review)

Abstract

Orexin (hypocretin) is one of the key neuropeptidesresponsible for controlling the sleep-waking cycle [3, 64].This substance is required for transition to the state of wak-ing, while antagonists of orexin-sensitive receptors effec-tively prevent sleeplessness [64] and the death of orexin-releasing neurons leads to narcolepsy [8, 15]. Thisneuropeptide, released by a small group of neurons in thelateral and posterior hypothalamus, acts via type 1 G-pro-tein-coupled receptors (OX1) sensitive mainly to orexin A(hypocretin 1) and type 2 receptors (OX2) sensitive to bothorexin B (hypocretin 2) and orexin A [3]. Recent studieshave shown that orexin modulates the activity of neurons incircuits involved in reinforcement-mediated learning [22,64]. Thus, OX1 receptor antagonists have been found tocounter the reinforcing effects of narcotics and foodstuffs,while blockade of OX2 receptors decreases the reinforcingeffects of ethanol [51]. Orexin appears to be able to takepart in the processes forming various types of behavior, asneurons in the lateral hypothalamus releasing this neu-ropeptide innervate many CNS structures, including theforebrain, thalamus, hippocampus, septum, basal ganglia,dopaminergic nuclei, dorsal raphe nuclei, and the amyg-dala, i.e., structures involved in transmitting informationand regulating motor activity, spatial perception, and themechanisms of reinforcement [36, 39, 44, 46, 47]. Orexinhas been shown to influence the performance of spatialtasks requiring involvement of the hippocampus. Thus,administration of a selective OX1 receptor antagonist intofield CA1 led to impairment of the processes of consolida-tion and extraction of information from memory relating totraining in the Morris water maze [11]. Administration of anOX1 receptor antagonist into the dentate gyrus also degrad-ed memory for information associated with training in thewater maze [10]. It should be noted, however, that systemic