Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility

Abstract

The increase in presynaptic striatal dopamine is the main dopaminergic abnormality in schizophrenia (SCZ). SCZ is primarily treated by modulating the activity of monoamine systems, with a focus on dopamine and serotonin receptors. Glial cell line-derived neurotrophic factor (GDNF) is a strong dopaminergic factor, that recently was shown to correlate with SCZ in human CSF and in striatal tissue. A 2-3-fold increase in GDNF in the brain was sufficient to induce SCZ-like dopaminergic and behavioural changes in mice. Here, we analysed the effect of acute, chronic, and embryonic methamphetamine, a drug known to enhance the risk of psychosis, on Gdnf and its receptors, Gfra1 and Ret, as well as on monoamine metabolism-related gene expression in the mouse brain. We found that acute methamphetamine application increases Gdnf expression in the striatum and chronic methamphetamine decreases the striatal expression of GDNF receptors Gfra1 and Ret. Both chronic and acute methamphetamine treatment upregulated the expression of genes related to dopamine and serotonin metabolism in the striatum, prefrontal cortex, and substantia nigra. Our results suggest a potential mechanism as to how methamphetamine elicits individual psychosis risk in young adults—variation in initial striatal GDNF induction and subsequent GFRα1 and RET downregulation may determine individual susceptibility to psychosis. Our results may guide future experiments and precision medicine development for methamphetamine-induced psychosis using GDNF/GFRa1/RET antagonists.

Striatal GDNF Neurons Chemoattract RET-Positive Dopamine Axons at Seven Times Farther Distance Than Medium Spiny Neurons

“…Thus, excess GDNF may drive or contribute to schizophrenia. Further supporting this idea, dopamine-enhancing GDNF expression in various animal models [22][23][24]. Thus, excess GDNF may drive or contribute to schizophrenia.…”

“…GDNF is a strong dopamine function-enhancing factor expressed specifically in only about 0.6% of striatal cells, namely in the striatal interneurons [ 36 , 49 ]. Recent evidence suggests that abnormally high—about two-fold increase in endogenous GDNF expression—may drive schizophrenia in a subgroup of patients [ 21 , 22 ]. On the other hand, when striatal DA is lost in PD, a two- to three-fold increase in endogenous GDNF expression may carry potential to treat this disorder [ 2 , 3 , 50 ].…”

“…In mice, similar upregulation of endogenous GDNF expression results in a range of SCZ-like features [ 21 ], suggesting that excess GDNF may drive the disease in a subset of SCZ patients. Supporting this idea, methamphetamine, a known enhancer of psychosis risk, also transiently upregulates striatal GDNF expression in various animal models [ 22 , 23 , 24 ]. Thus, excess GDNF may drive or contribute to schizophrenia.…”

Increased NLRP1 mRNA and Protein Expression Suggests Inflammasome Activation in the Dorsolateral Prefrontal and Medial Orbitofrontal Cortex in Schizophrenia

“…Methamphetamine exposure in rats recapitulates this impaired, uncertainty-driven belief updating and rigid anticipation of a volatile environment [ 91 ]. In a mouse model, both chronic and acute methamphetamine treatment upregulated the expression of genes related to dopamine and serotonin metabolism in the striatum and PFC, suggesting a potential mechanism for how methamphetamine elicits an individual’s psychosis risk [ 92 ].…”

Striatal GDNF System Elicits Chemoattraction to RET Positive Dopamine Axons Seven Times Longer in Distance than the Abundant Medium Spiny Neurons and Covers Approximately One Twelfth of the Striatal Neuronal Volume

“…2 patients. Supporting this idea, methamphetamine, a known enhancer of psychosis risk, also transiently upregulates striatal GDNF expression in various animal models [22][23][24]. Thus, excess GDNF may drive, or contribute to Schizophrenia.…”