FGF2 activity regulates operant alcohol self-administration and mesolimbic dopamine transmission

IF 3.9 2区 医学 Q1 PSYCHIATRY Drug and alcohol dependence Pub Date : 2023-07-01 DOI:10.1016/j.drugalcdep.2023.109920
Daniil Grinchii , Matar Levin-Greenwald , Noa Lezmy , Tamar Gordon , Ruslan Paliokha , Talah Khoury , Matej Racicky , Leonie Herburg , Claudia Grothe , Eliyahu Dremencov , Segev Barak
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Abstract

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.

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FGF2活性调节操作性酒精自我给药和中脑边缘多巴胺传递
成纤维细胞生长因子2(FGF2)参与大脑多巴胺系统的发育和维持。我们之前发现,酒精暴露会改变大脑中边缘和黑质纹状体区域FGF2及其受体FGF受体1(FGFR1)的表达,FGF2是饮酒的积极调节因子。在这里,我们使用大鼠操作性自我给药范式确定了FGF2和FGFR1抑制对饮酒、寻求和复发的影响。此外,我们使用体内电生理学表征了FGF2-FGFR1激活和抑制对中边缘和黑质纹状体多巴胺神经元激活的影响。我们发现重组FGF2(rFGF2)增加了中边缘和黑质纹状体系统中多巴胺能神经元的放电速率和爆发放电活性,并导致操作性酒精自我给药增加。相反,FGFR1抑制剂PD173074抑制了这些多巴胺能神经元的放电速率,并减少了操作性酒精自我给药。酒精寻求行为不受PD173074的影响,但这种FGFR1抑制剂减少了禁欲后饮酒的复发,尽管仅在雄性大鼠中。后者与PD173074在抑制多巴胺神经元放电方面的效力和功效增加相平行。总之,我们的研究结果表明,靶向FGF2-FGFR1通路可以减少饮酒,可能是通过改变中边缘和黑质纹状体神经元的活动。
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来源期刊
Drug and alcohol dependence
Drug and alcohol dependence 医学-精神病学
CiteScore
7.40
自引率
7.10%
发文量
409
审稿时长
41 days
期刊介绍: Drug and Alcohol Dependence is an international journal devoted to publishing original research, scholarly reviews, commentaries, and policy analyses in the area of drug, alcohol and tobacco use and dependence. Articles range from studies of the chemistry of substances of abuse, their actions at molecular and cellular sites, in vitro and in vivo investigations of their biochemical, pharmacological and behavioural actions, laboratory-based and clinical research in humans, substance abuse treatment and prevention research, and studies employing methods from epidemiology, sociology, and economics.
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