C

Figure 5. Electrophysiological properties of dopaminergic neurons and their response to hypocretins/orexins. (A) Voltage responses to current pulses (-0.4' 0' +0.1 pA). (B) Spontaneous action potentials before and after application of Orexin A (100 nM). chart recording of membrane potential (current clamp). (C) Burst firing induced by Orexin B. (D) Tetrodotoxin-insensitive depolarization by Orexin B (100 nM). Modified from Korotkova et al.22

Haldol also blocked some of the memory enhancing effects of Hcrt1 on passive avoidance learning in rodents.120 Dopamine receptors have been implicated in protein synthesis-dependent synaptic plasticity and memory consolidation107. Hypocretinergic modulation of dopamine signaling may thus be important for normal memory as well as compulsion' addiction and psychosis.58'107-109

Finally' hypocretins also interfere with dopaminergic control of neuroendocrine functions' like prolactin release. Central administration of Hcrt1 suppressed basal and D2R-antagonist (domperidone) stimulated plasma prolactin release'121 while fasting' a prominent activator of the hypocretin system2'3'5'89'90'94'118 increased tuberoinfundibular dopamine outflow and inhibited prolactin secretion in estrogen-primed ovariectomized rats through up-regulation of the central hypocretin system.122

3.4. Locus Coeruleus (Noradrenaline)

The strongest projections of hypocretin-fibers and the highest density of Hcrtl receptors among all aminergic cell groups is found in noradrenergic neurons of the locus coeruleus.32,123,124 Action potential firing and temporal synchrony of noradrenergic LC neurons is increased by Hcrtl receptor-dependent direct postsynaptic and indirect glutamatergic mechanisms.66423425 In addition, hypocretins facilitate noradrenaline and glutamate release in cortical and subcortical targets.56,57 Catecholamines in turn, convergent with serotonin and GABA, provide negative inhibitory feedback to the hypothalamic hypocretin neurons in vitro26 Interestingly, preliminary evidence suggests a dynamic control of noradrenergic feedback on hypocretin neurons according to aminergic tone and behavioral state.l26

The interplay between hypocretins and catecholamines has implications not only for control of behavioral state,l24,l27 nurture, plasticity30,l28 and memory retrievall29 but probably also for a number of side-effects of sympathomimetics and sympatholytics.29 Van den Pol and Aston-Jones give a detailed description of interactions between the noradrenergic system and hypocretin neurons in this book.

3.5. Laterodorsal Tegmentum / Basal forebrain (Acetylcholine)

The cholinergic systems in the laterodorsal tegmentum (LdT)l3° and basal forebrain are major targets of hypocretinergic innervation and modulation39,85,l30,l3l(reviewed by Leonard in this book). Hypocretins uniformly excite cholinergic and GABAergic neurons. Acetylcholine in turn, opposite to catecholamines and serotonin but convergent with glutamate, excites hypothalamic hypocretin neurons in vitro26,27 providing feed forward mechanisms implicated in muscle tone control, gating of REM sleep, cortical activation, arousal, attentional set shifting, binding, and reversal learning.l32,l33

Notably, acetylcholine becomes the major excitatory transmitter in the absence of glutamate in the hypothalamus (but not in the cortex) in vitro, providing a plasticity mechanism invoking glutamate/GABA and excitation/inhibition balance.l34 Likewise, cholinergic tone in vivo in the thalamus and cortex, concurrent with large scale oscillatory brain activities, varies according to behavioral state and opposite or complementary to the activity of other aminergic systems.62,63

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