title: Nicotinic α4 Receptor-Mediated Cholinergic Influences on Food Intake and Activity Patterns in Hypothalamic Circuits.
abstract: Nicotinic acetylcholine receptors (nAChRs) play an important role in regulating appetite and have been shown to do so by influencing neural activity in the hypothalamus. To shed light on the hypothalamic circuits governing acetylcholine's (ACh) regulation of appetite this study investigated the influence of hypothalamic nAChRs expressing the α4 subunit. We found that antagonizing the α4β2 nAChR locally in the lateral hypothalamus with di-hydro-ß-erythroidine (DHβE), an α4 nAChR antagonist with moderate affinity, caused an increase in food intake following free access to food after a 12 hour fast, compared to saline-infused animals. Immunocytochemical analysis revealed that orexin/hypocretin (HO), oxytocin, and tyrosine hydroxylase (TH)-containing neurons in the A13 and A12 of the hypothalamus expressed the nAChR α4 subunit in varying amounts (34%, 42%, 50%, and 51%, respectively) whereas melanin concentrating hormone (MCH) neurons did not, suggesting that DHβE-mediated increases in food intake may be due to a direct activation of specific hypothalamic circuits. Systemic DHβE (2 mg/kg) administration similarly increased food intake following a 12 hour fast. In these animals a subpopulation of orexin/hypocretin neurons showed elevated activity compared to control animals and MCH neuronal activity was overall lower as measured by expression of the immediate early gene marker for neuronal activity cFos. However, oxytocin neurons in the paraventricular hypothalamus and TH-containing neurons in the A13 and A12 did not show differential activity patterns. These results indicate that various neurochemically distinct hypothalamic populations are under the influence of α4β2 nAChRs and that cholinergic inputs to the lateral hypothalamus can affect satiety signals through activation of local α4β2 nAChR-mediated transmission.
authors.affiliation: Department of Pharmacology, University of Cambridge; Cambridge, United Kingdom; Laboratory of Molecular Neurobiology, Biomedical Research Institute (BIOMED) UCA-CONICET, Faculty of Medical Sciences, Catholic University of Argentina, Buenos Aires, Argentina.
authors.forename: Ana P
authors.initials: AP
authors.lastname: García
authors.affiliation: Department of Pharmacology, University of Cambridge; Cambridge, United Kingdom.
authors.forename: Teemu
authors.initials: T
authors.lastname: Aitta-aho
authors.affiliation: Department of Pharmacology, University of Cambridge; Cambridge, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Schaaf
authors.affiliation: Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Heeley
authors.affiliation: Department of Pharmacology, University of Cambridge; Cambridge, United Kingdom.
authors.forename: Lena
authors.initials: L
authors.lastname: Heuschmid
authors.affiliation: Department of Pharmacology, University of Cambridge; Cambridge, United Kingdom; Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yunjing
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Laboratory of Molecular Neurobiology, Biomedical Research Institute (BIOMED) UCA-CONICET, Faculty of Medical Sciences, Catholic University of Argentina, Buenos Aires, Argentina.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Barrantes
authors.affiliation: Department of Pharmacology, University of Cambridge; Cambridge, United Kingdom; Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Apergis-Schoute
mesh_terms: D000818:Animals; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D000068797:Orexins / Q000378:metabolism; D010121:Oxytocin / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018733:Nicotinic Antagonists; D000068797:Orexins; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D004079:Dihydro-beta-Erythroidine; D010121:Oxytocin; D014446:Tyrosine 3-Monooxygenase