title: Endogenous GDNF in ventral tegmental area and nucleus accumbens does not play a role in the incubation of heroin craving.
abstract: Glial cell line-derived neurotrophic factor (GDNF) activity in ventral tegmental area (VTA) mediates the time-dependent increases in cue-induced cocaine-seeking after withdrawal (incubation of cocaine craving). Here, we studied the generality of these findings to incubation of heroin craving. Rats were trained to self-administer heroin for 10 days (6 hours/day; 0.075 mg/kg/infusion; infusions were paired with a tone-light cue) and tested for cue-induced heroin-seeking in extinction tests after 1, 11 or 30 withdrawal days. Cue-induced heroin seeking was higher after 11 or 30 days than after 1 day (incubation of heroin craving), and the time-dependent increases in extinction responding were associated with time-dependent changes in GDNF mRNA expression in VTA and nucleus accumbens. Additionally, acute accumbens (but not VTA) GDNF injections (12.5 µg/side) administered 1-3 hours after the last heroin self-administration training session enhanced the time-dependent increases in extinction responding after withdrawal. However, the time-dependent increases in extinction responding after withdrawal were not associated with changes in GDNF protein expression in VTA and accumbens. Additionally, interfering with endogenous GDNF function by chronic delivery of anti-GDNF monoclonal neutralizing antibodies (600 ng/side/day) into VTA or accumbens had no effect on the time-dependent increases in extinction responding. In summary, heroin self-administration and withdrawal regulate VTA and accumbens GDNF mRNA expression in a time-dependent manner, and exogenous GDNF administration into accumbens but not VTA potentiates cue-induced heroin seeking. However, based on the GDNF protein expression and the anti-GDNF monoclonal neutralizing antibodies manipulation data, we conclude that neither accumbens nor VTA endogenous GDNF mediates the incubation of heroin craving.
authors.affiliation: Intramural Research Program and National Institute on Drug Abuse, NIH, Baltimore, MD 21224, USA.
authors.forename: Mikko
authors.initials: M
authors.lastname: Airavaara
authors.forename: Charles L
authors.initials: CL
authors.lastname: Pickens
authors.forename: Anna L
authors.initials: AL
authors.lastname: Stern
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Wihbey
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Harvey
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bossert
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Liu
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Hoffer
authors.forename: Yavin
authors.initials: Y
authors.lastname: Shaham
mesh_terms: D000818:Animals; D001245:Association Learning / Q000187:drug effects / Q000502:physiology; D003463:Cues; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D003932:Heroin / Q000633:toxicity*; D006556:Heroin Dependence / Q000503:physiopathology* / Q000523:psychology; D008297:Male; D009294:Narcotics / Q000633:toxicity*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020318:Rats, Long-Evans; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology* / Q000523:psychology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D009294:Narcotics; D012333:RNA, Messenger; D003932:Heroin