title: α3β4 nicotinic receptors in the medial habenula and substance P transmission in the interpeduncular nucleus modulate nicotine sensitization.
abstract: The medial habenula-interpeduncular nucleus (MHb-IPN) pathway has recently been shown to modulate multiple effects nicotine in vivo, however it remains unclear which receptor subtypes in this pathway are critical for mediating these responses. To identify MHb and IPN receptors that play a role in nicotine reward, we studied receptors prevalent in these nuclei, including nicotinic acetylcholine receptors (nAChRs) and the receptor for substance P (neuokinin-1; NK1 receptor) using a model of behavioral and neurochemical sensitization to nicotine. Our results show that blockade of the α3β4 nAChR in the MHb, but not the IPN prevented increases in locomotor responding as well as increases in accumbal dopamine overflow in sensitized animals. Additionally, when NK1 receptors were blocked in the IPN, but not the MHb, a similar effect on sensitized responding was seen. Together, these results suggest that the MHb and IPN differentially modulate nicotine sensitization. Because the neurotransmission within these brain regions is primarily cholinergic and substance P ergic and these receptors are expressed in high density in both nuclei, these results could suggest a different neurophysiological signaling role or different neuroanatomical location of these receptors in this pathway. Furthermore, while α3β4 nAChRs have been suggested as a possible pharmacological target for nicotine addiction, this is the first evidence that substance P also plays a role in mediating responding to nicotine.
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, United States. Electronic address: Egganb@mail.amc.edu.
authors.forename: Branden L
authors.initials: BL
authors.lastname: Eggan
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, United States. Electronic address: Mccalls@mail.amc.edu.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: McCallum
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D066268:Interpeduncular Nucleus / Q000187:drug effects*; D017551:Microdialysis; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013373:Substance P / Q000378:metabolism*
chemical_list: D001596:Benzylamines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018680:Cholinergic Antagonists; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; D004079:Dihydro-beta-Erythroidine; D013373:Substance P; C413864:ezlopitant; D009538:Nicotine; D004298:Dopamine
keywords: Ezlopitant; Interpeduncular nucleus; Locomotor activity; Medial habenula; Microdialysis; Nicotine; Sensitization; Substance P receptor; α-Conotoxin AuIB; α3β4 nicotinic acetylcholine receptor