Enhanced L-β-Aminoisobutyric Acid Is Involved in the Pathophysiology of Effectiveness for Treatment-Resistant Schizophrenia and Adverse Reactions of Clozapine

Abstract

Clozapine is an effective antipsychotic for the treatment of antipsychotic-resistant schizophrenia; however, specific types of A/B adverse effects and clozapine-discontinuation syndromes are also well known. To date, both the critical mechanisms of clinical actions (effective for antipsychotic-resistant schizophrenia) and the adverse effects of clozapine remain to be elucidated. Recently, we demonstrated that clozapine increased the synthesis of L-β-aminoisobutyric acid (L-BAIBA) in the hypothalamus. L-BAIBA is an activator of the adenosine monophosphate-activated protein kinase (AMPK), glycine receptor, GABAA receptor, and GABAB receptor (GABAB-R). These targets of L-BAIBA overlap as potential targets other than the monoamine receptors of clozapine. However, the direct binding of clozapine to these aminoacidic transmitter/modulator receptors remains to be clarified. Therefore, to explore the contribution of increased L-BAIBA on the clinical action of clozapine, this study determined the effects of clozapine and L-BAIBA on tripartite synaptic transmission, including GABAB-R and the group-III metabotropic glutamate receptor (III-mGluR) using cultured astrocytes, as well as on the thalamocortical hyper-glutamatergic transmission induced by impaired glutamate/NMDA receptors using microdialysis. Clozapine increased astroglial L-BAIBA synthesis in time/concentration-dependent manners. Increased L-BAIBA synthesis was observed until 3 days after clozapine discontinuation. Clozapine did not directly bind III-mGluR or GABAB-R, whereas L-BAIBA activated these receptors in the astrocytes. Local administration of MK801 into the reticular thalamic nucleus (RTN) increased L-glutamate release in the medial frontal cortex (mPFC) (MK801-evoked L-glutamate release). Local administration of L-BAIBA into the mPFC suppressed MK801-evoked L-glutamate release. These actions of L-BAIBA were inhibited by antagonists of III-mGluR and GABAB-R, similar to clozapine. These in vitro and in vivo analyses suggest that increased frontal L-BAIBA signaling likely plays an important role in the pharmacological actions of clozapine, such as improving the effectiveness of treating treatment-resistant schizophrenia and several clozapine discontinuation syndromes via the activation of III-mGluR and GABAB-R in the mPFC.

A Novel Gliotransmitter, L-β-Aminoisobutyric Acid, Contributes to Pathophysiology of Clinical Efficacies and Adverse Reactions of Clozapine

“…Chronic administration of therapeutically relevant doses of clozapine, quetiapine, brexpiprazole, and lurasidone decreased IP3 synthesis, and increased AMP levels in the rat hypothalamus [ 46 , 47 , 67 ]. However, contrary to expectations, AMPK signallings were activated and unaffected by high-risk (clozapine and quetiapine) and low-risk (brexpiprazole and lurasidone) antipsychotics for weight gain, respectively [ 44 , 45 , 46 , 47 , 68 ].…”

“…Chronic administration of therapeutically relevant doses of clozapine, quetiapine, brexpiprazole, and lurasidone decreased IP3 synthesis, and increased AMP levels in the rat hypothalamus [ 46 , 47 , 67 ]. However, contrary to expectations, AMPK signallings were activated and unaffected by high-risk (clozapine and quetiapine) and low-risk (brexpiprazole and lurasidone) antipsychotics for weight gain, respectively [ 44 , 45 , 46 , 47 , 68 ]. Both clozapine and quetiapine are high-affinity antagonists of the histamine H1 receptor and the 5-HT2A receptor, whereas brexpiprazole and lurasidone are high-affinity 5-HT2A receptors but have low binding affinity to the H1 receptor [ 60 , 69 ].…”

“…Based on previous clinical and preclinical findings, it is hypothesised that clozapine activates hypothalamic signalling associated with AMPK via enhanced BAIBA signalling. The BAIBA enantiomer activates AMPK signalling in the hypothalamus and astrocytes [ 46 , 47 , 67 ] ( Figure 2 ). According to our hypothesis, chronic administration of therapeutically relevant doses of clozapine increases the synthesis and release of the BAIBA enantiomer, but neither brexpiprazole nor lurasidone affects BAIBA in the hypothalamus [ 46 , 47 , 67 ].…”

“…The BAIBA enantiomer activates AMPK signalling in the hypothalamus and astrocytes [ 46 , 47 , 67 ] ( Figure 2 ). According to our hypothesis, chronic administration of therapeutically relevant doses of clozapine increases the synthesis and release of the BAIBA enantiomer, but neither brexpiprazole nor lurasidone affects BAIBA in the hypothalamus [ 46 , 47 , 67 ]. This effect of clozapine on the BAIBA enantiomer is primarily on L-BAIBA, whereas the D-BAIBA level in the hypothalamus is lower than the limit of detection [ 46 , 47 , 67 ].…”

“…Tripartite synaptic transmission involving molecules other than monoamine receptors has recently been speculated to play important roles in the pharmacological mechanisms of clozapine’s therapeutic effects and adverse reactions, which is distinct from other atypical antipsychotics [ 38 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. In these pharmacodynamic researches, it has been identified that L-β-aminoisobutyric acid (L-BAIBA) plays an important role in the pathophysiology underlying the mechanisms of clozapine’s clinical efficacy for the treatment of schizophrenia and TRS as well as in adverse reactions, such as weight gain and metabolic complications [ 46 , 47 ]. In other words, L-BAIBA is a candidate target molecule that can rationally explain the mechanisms of clozapine’s therapeutic effects and adverse reactions, which have not been elucidated so far, via modulating various signalling pathways.…”