TY - JOUR
T1 - FGF2 activity regulates operant alcohol self-administration and mesolimbic dopamine transmission
AU - Grinchii, Daniil
AU - Levin-Greenwald, Matar
AU - Lezmy, Noa
AU - Gordon, Tamar
AU - Paliokha, Ruslan
AU - Khoury, Talah
AU - Racicky, Matej
AU - Herburg, Leonie
AU - Grothe, Claudia
AU - Dremencov, Eliyahu
AU - Barak, Segev
N1 - Publisher Copyright:
© 2023 Elsevier B.V.
PY - 2023/7/1
Y1 - 2023/7/1
N2 - Fibroblast growth factor 2 (FGF2) is involved in the development and maintenance of the brain dopamine system. We previously showed that alcohol exposure alters the expression of FGF2 and its receptor, FGF receptor 1 (FGFR1) in mesolimbic and nigrostriatal brain regions, and that FGF2 is a positive regulator of alcohol drinking. Here, we determined the effects of FGF2 and of FGFR1 inhibition on alcohol consumption, seeking and relapse, using a rat operant self-administration paradigm. In addition, we characterized the effects of FGF2-FGFR1 activation and inhibition on mesolimbic and nigrostriatal dopamine neuron activation using in vivo electrophysiology. We found that recombinant FGF2 (rFGF2) increased the firing rate and burst firing activity of dopaminergic neurons in the mesolimbic and nigrostriatal systems and led to increased operant alcohol self-administration. In contrast, the FGFR1 inhibitor PD173074 suppressed the firing rate of these dopaminergic neurons, and reduced operant alcohol self-administration. Alcohol seeking behavior was not affected by PD173074, but this FGFR1 inhibitor reduced post-abstinence relapse to alcohol consumption, albeit only in male rats. The latter was paralleled by the increased potency and efficacy of PD173074 in inhibiting dopamine neuron firing. Together, our findings suggest that targeting the FGF2-FGFR1 pathway can reduce alcohol consumption, possibly via altering mesolimbic and nigrostriatal neuronal activity.
AB - Fibroblast growth factor 2 (FGF2) is involved in the development and maintenance of the brain dopamine system. We previously showed that alcohol exposure alters the expression of FGF2 and its receptor, FGF receptor 1 (FGFR1) in mesolimbic and nigrostriatal brain regions, and that FGF2 is a positive regulator of alcohol drinking. Here, we determined the effects of FGF2 and of FGFR1 inhibition on alcohol consumption, seeking and relapse, using a rat operant self-administration paradigm. In addition, we characterized the effects of FGF2-FGFR1 activation and inhibition on mesolimbic and nigrostriatal dopamine neuron activation using in vivo electrophysiology. We found that recombinant FGF2 (rFGF2) increased the firing rate and burst firing activity of dopaminergic neurons in the mesolimbic and nigrostriatal systems and led to increased operant alcohol self-administration. In contrast, the FGFR1 inhibitor PD173074 suppressed the firing rate of these dopaminergic neurons, and reduced operant alcohol self-administration. Alcohol seeking behavior was not affected by PD173074, but this FGFR1 inhibitor reduced post-abstinence relapse to alcohol consumption, albeit only in male rats. The latter was paralleled by the increased potency and efficacy of PD173074 in inhibiting dopamine neuron firing. Together, our findings suggest that targeting the FGF2-FGFR1 pathway can reduce alcohol consumption, possibly via altering mesolimbic and nigrostriatal neuronal activity.
KW - Addiction
KW - Alcohol
KW - Animal models
KW - Dopamine
KW - Fibroblast growth factor 2
KW - Substantia nigra
KW - Ventral tegmental area
UR - http://www.scopus.com/inward/record.url?scp=85160074493&partnerID=8YFLogxK
U2 - 10.1016/j.drugalcdep.2023.109920
DO - 10.1016/j.drugalcdep.2023.109920
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 37224676
AN - SCOPUS:85160074493
SN - 0376-8716
VL - 248
JO - Drug and Alcohol Dependence
JF - Drug and Alcohol Dependence
M1 - 109920
ER -