Drug addiction is a serious problem globally, recently exacerbated by the
COVID-19 pandemic.
Glial cell-derived neurotrophic factor (
GDNF) is considered a potentially effective strategy for the treatment of addiction. Previous animal experiments have proven that
GDNF has a good
therapeutic effect on
drug addiction, but its clinical application is limited due to its poor blood-brain barrier (BBB) permeability. Low-frequency focused ultrasound, combined with
microbubbles, is a non-invasive and reversible technique for locally-targeted BBB opening. In the present study, magnetic resonance imaging-guided low-frequency focused ultrasound, combined with
GDNF microbubbles, was used to target BBB opening in the ventral tegmental area (VTA) region. The effects of
GDNF on
morphine-induced conditioned place preference (
CPP) and acute
withdrawal symptoms in rats after a partially opened BBB were evaluated by behavioral observation. Western blot was used to detect changes in
tyrosine hydroxylase (TH) expression levels in the VTA region after different treatments, and high performance liquid chromatography was used to detect the changes in monoamine
neurotransmitter content. The results showed that ultrasound combined with
GDNF microbubbles targeted and opened the BBB in the VTA region, and significantly increased
GDNF content, destroyed
morphine-induced
CPP, and reduced the
withdrawal symptoms of
morphine addiction in rats. Furthermore, the up-regulation of TH expression and the increase of
norepinephrine and
dopamine content induced by
morphine were significantly reversed, and the increase of
5-hydroxytryptamine content was partially reversed. Therefore, ultrasound combined with
GDNF microbubbles to target and open the BBB can effectively increase the content of central
GDNF, thus playing a therapeutic role in
morphine addiction. Our study provides a new approach to locally open the BBB and target delivery of
neurotrophic factors, such as
GDNF, to treat
brain diseases like addiction.