The role of tropomyosin-related kinase receptors in neurotrophin-induced rapid eye movement sleep in the cat.
The microinjection of nerve growth factor and neurotrophin-3 into the rostro-dorsal pontine tegmentum of the cat evokes a state that is comparable to naturally-occurring rapid eye movement sleep. Using two experimental paradigms, we tested the hypothesis that neurotrophin high-affinity receptors (trkA and trkC, tropomyosin-related kinase A and C, respectively) mediate this effect. First, trk and fos immunohistochemistry were combined to determine whether tyrosine kinase receptor-containing neurons in the dorsal pontine tegmentum are active in cats that exhibit long-lasting periods of rapid eye movement sleep following the local microinjection of nerve growth factor. During approximately two hours of recording, nerve growth factor-treated cats spent 59.8% of the time in a rapid eye movement sleep-like state; vehicle-injected (control) animals remained in quiet wakefulness and non-rapid eye movement sleep. Whereas control and nerve growth factor-treated cats exhibited a similar mean number of trkA- and trkC-immunoreactive neurons in the dorsal pontine tegmentum, the number of trkA- and trkC-immunoreactive neurons that expressed Fos, i.e. double-labeled cells that are presumably activated, was significantly larger in cats that were injected with nerve growth factor. Axon terminals contained tyrosine kinase receptor immunoreactivity in this region; many were apposed to Fos-immunoreactive neurons. In addition, patterns of tyrosine kinase receptor and Fos immunoreactivity similar to those observed in nerve growth factor-injected cats were present, in conjunction with long-lasting rapid eye movement sleep, following the microinjection of carbachol into the dorsal pons. In a second series of studies, nerve growth factor or neurotrophin-3 was injected alone or after K-252a, a blocker of tyrosine kinase receptors, into the rostro-dorsal pontine tegmentum. Nerve growth factor or neurotrophin-3 alone produced, with a mean latency of 4 min, a rapid eye movement sleep-like state. However, neurotrophin injections preceded by K-252a were not effective in inducing rapid eye movement sleep. These results indicate that the activation of trkA and trkC receptors in neurons in the pontine tegmentum is responsible, at least in part, for the rapid eye movement sleep-inducing effect of nerve growth factor and neurotrophin-3. Furthermore, the data suggest that these neurotrophins are capable of acting both pre- and postsynaptically to activate pontine neurons that are involved in the generation of rapid eye movement sleep.
Yamuy
J
J
Department of Physiology, UCLA School of Medicine, Los Angeles, CA 90095, USA. jyamuy@ucla.edu
Ramos
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Torterolo
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Sampogna
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S
Chase
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MH
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002415:Cats; D004347:Drug Interactions; D004569:Electroencephalography / Q000379:methods; D004576:Electromyography / Q000379:methods; D004585:Electrooculography / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry / Q000379:methods; D026121:Indole Alkaloids; D008297:Male; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020933:Neurotrophin 3 / Q000494:pharmacology*; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D011149:Pons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000145:classification / Q000502:physiology*; D012895:Sleep, REM / Q000187:drug effects*; D013997:Time Factors
D018712:Analgesics, Non-Narcotic; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D020933:Neurotrophin 3; D016761:Oncogene Proteins v-fos; D002217:Carbachol; D020932:Nerve Growth Factor; C049985:staurosporine aglycone; D020794:Receptor Protein-Tyrosine Kinases