Year: 2004
Type: article
Abstract: Nicotine addiction emerges as a result of long-term plastic changes in the brain including altered intracellular signaling, gene transcription and receptor function.The endogenous opioids may contribute to aspects of nicotine's addictive psychopharmacological properties.Presently, the response to both acute nicotine and chronic nicotine withdrawal was evaluated with respect to effects on the regulation of opioid peptides, opioid receptor function and the signaling events that link these processes.Acute nicotine biphasically increased striatal dynorphin content with peaks at 1 hr and 18hr after injection.The mRNA for prodynorphin (PD), as well as the immediate early genes c-fos, c-jun and egr-1 was increased from 30 min to 12 hr following acute injection.Increased p-CREB immunoreactivity and CREB-PD promoter binding was observed in the early stages after acute nicotine.Antagonist pre-treatments revealed that dopamine and muscarinic receptors contribute to the 1 hr and 18 hr dynorphin increases after acute nicotine treatment.For withdrawal studies, mice were treated with nicotine four times daily for 14 days and killed at 0-96 hr after the last injection.During nicotine withdrawal, PD mRNA was increased in the striatum, whereas dynorphin was decreased for 72 hr.Analysis of CREB, adenylyl cyclase and the PD promoter suggest these are coordinated in an atypical manner, resulting in decreased adenylyl cyclase activity concomitant to an increased CREB activity.Preliminary data suggesting a role for the transcriptional repressor protein, DREAM in this interaction is presented.Analysis of the delta (DOR) and kappa (KOR) opioid receptors was assessed for altered function during nicotine withdrawal.While changes in DOR and KOR binding were subtle, evidence for DOR and KOR uncoupling from intracellular signaling iii pathways was observed.Data suggest that regulation of G-proteins and adenylyl cyclase during nicotine withdrawal may contribute to these functional alterations in the DOR and KOR.Taken together, nicotine engages signaling mechanisms that regulate PD transcription.Perturbations of this interaction may disrupt dynorphin release in the striatum during nicotine withdrawal.Alterations in DOR and KOR function were observed during withdrawal.These findings together provide a substrate by which the endogenous opioid system could mediate aspects of the nicotine withdrawal syndrome.
Author: Michael J. McCarthy
Institution: The Ohio State University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2530135510