Reduced insulin-receptor mediated modulation of striatal dopamine release by basal insulin as a possible contributing factor to hyperdopaminergia in schizophrenia (2015)

Reduced insulin-receptor mediated modulation of striatal dopamine release by basal insulin as a possible contributing factor to hyperdopaminergia in schizophrenia  (2015)

Schizophrenia is a severe and chronic neuropsychiatric disorder which affects 1% of the world population. Using the brain imaging technique positron emission tomography (PET) it has been demonstrated that persons with schizophrenia have greater dopamine transmission in the striatum compared to healthy controls. However, little progress has been made as to elucidating other biological mechanisms which may account for this hyperdopaminergic state in this disease. Studies in animals have demonstrated that insulin receptors are expressed on midbrain dopamine neurons, and that insulin from the periphery acts on these receptors to modify dopamine transmission in the striatum. This is pertinent given that several lines of evidence suggest that insulin receptor functioning may be abnormal in the brains of persons with schizophrenia. Post-mortem studies have shown that persons with schizophrenia have less than half the number of cortical insulin receptors compared to healthy persons. Moreover, these post-mortem findings are unlikely due to the effects of antipsychotic treatment; studies in cell lines and animals suggest antipsychotics enhance insulin receptor functioning. Further, hyperinsulinemia – even prior to antipsychotic use – seems to be related to less psychotic symptoms in patients with schizophrenia. Collectively, these data suggest that midbrain insulin receptor functioning may be abnormal in persons with schizophrenia, resulting in reduced insulin-mediated regulation of dopamine transmission in the striatum. Such a deficit may account for the hyperdopaminergic state observed in these patients and would help guide the development of novel treatment strategies. We hypothesize that, (i) insulin receptor expression and/or function is reduced in midbrain dopamine neurons in persons with schizophrenia, (ii) basal insulin should reduce dopaminergic transmission in the striatum via these receptors, and (iii) this modulation of dopaminergic transmission by basal insulin is reduced in the brains of persons with schizophrenia.

Peripheral insulin acting on insulin receptors in the brain modulates striatal dopamine levels

“…IRs are expressed on midbrain DA neurons (substantia nigra/ventral tegmental area; SN/VTA), and insulin from the periphery can act on these receptors to modify DA levels in the striatum. Specifically, several animal studies suggest that IR activation on midbrain DA neurons acts to inhibit DA synthesis and release into the striatum. In turn, insulin can modify DA-dependent behaviors which are relevant to the pathophysiology of schizophrenia, such as sensitivity to DA release in response to psychostimulants. Collectively, this evidence suggests that enhancing IR signaling in the SN/VTA may reduce DA levels in the striatum. Thus, for persons with schizophrenia enhanced IR activation should reduce striatal DA levels (improving symptoms), while reduced IR signaling should enhance striatal DA levels (worsening symptoms).”

Insulin acting on insulin receptors in the ventral tegmental area can inhibit dopamine neurons and dopamine release into the striatum. [source]

Greater insulin resistance and fasting levels of insulin are related to less endogenous dopamine in the striatum of healthy persons measured with PET

“Several lines of evidence in animals and humans suggest that insulin resistance and/or diabetes is related to less striatal DA synthesis  and metabolism.

…Using the D2/3R radiotracer [11C]-(+)-PHNO, and the DA depletion paradigm, we have demonstrated in healthy non-obese persons that greater insulin resistance is correlated with less endogenous DA levels in the ventral striatum/nucleus accumbens (VS) (r2 = .71). Specifically, greater fasting levels of insulin were correlated with less endogenous DA levels in this region (r2 = .72). These findings are consistent with previous PET studies which have employed other D2/3R radiotracers to examine the relationship between baseline D2/3R availability and insulin sensitivity. Moreover, these results are consistent with previous [11C]-(+)-PHNO studies examining the relationship between baseline D2/3R availability and body mass index.

Collectively, this data in conjunction with the animal literature suggests that states of hyperinsulinemia, with or without the presence of diabetes, may be related to less DA signaling in the striatum. It is hypothesized that this is due to the enhanced activation of midbrain IRs by greater circulating fasting levels of insulin”

Brain insulin receptors and insulin receptor signaling may be reduced in schizophrenia

“Several lines of evidence suggest that there is abnormal IR functioning in the brains of persons with schizophrenia. Post-mortem studies have demonstrated that persons with schizophrenia have dramatically reduced IR concentrations (−50%) and IR cellular signaling compared to healthy controls in the dorsolateral prefrontal cortex. Importantly, these reductions in IR expression and function are not easily attributable to the potential effects of chronic antipsychotic exposure. This is because studies in animals and cell lines suggest antipsychotics used in the treatment of schizophrenia enhance IR-mediated cell signaling. For example, brain IR knockout mice demonstrate increased intracellular glycogen synthase kinase-3β (GSK-3β) activity. It has been hypothesized that GSK-3β activity is increased in schizophrenia and antipsychotics have been shown to consistently decrease GSK-3β signaling. Importantly, several DA mediated behaviors relevant to schizophrenia can be inhibited by blocking GSK-3β signaling. Notably, one study observed that IR knockout in the brains of mice results in behavioral disturbances such as increased anxiety and depression-like behaviors.

Collectively, these data suggest that IR signaling is reduced in the brains of persons with schizophrenia. However, no post-mortem or in vivo brain imaging study has examined whether IR expression and/or signaling is reduced in midbrain DA neurons of persons with schizophrenia. This can most certainly be tested. If IR expression levels were found to be reduced in midbrain DA neurons in schizophrenia patients, this in turn could result in a reduction in insulin-mediated modulation of DA levels in the striatum, and could potentially account for the hyperdopaminergia observed therein. Importantly, what current data suggests is that current antipsychotics may work to enhance IR signaling in the brain”

To conclude:

“Our “midbrain IR-deficiency hypothesis” developed from the following points of observation. Namely, (i) IRs on midbrain DA neurons can modulate striatal DA release, (ii) IR-expression and function may be reduced throughout the brain of persons with schizophrenia, (iii) metabolic abnormalities co-occur in persons with schizophrenia even before antipsychotic treatment, and (iv) hyperinsulinemic states – which are exacerbated by antipsychotic administration – may be related to both reduced striatal DA levels and improved psychotic symptoms in persons with schizophrenia. However, how ubiquitous brain IR deficiency affects global brain functioning in schizophrenia, and the mechanisms by which reduced brain IR expression may occur in the first place, is beyond the scope of our theory. We leave such speculations to further evidence and research.

The extent of striatal D2/3R blockade by antipsychotics in vitro and in vivo still represents the best correlates of clinical response in persons with schizophrenia. However, recent evidence suggests that there is a proportion of patients with schizophrenia who do not appear to have increased striatal DA, and do not respond to conventional antipsychotic treatment. This suggests that there may be a subgroup of patients with schizophrenia for whom increased striatal DA transmission is not relevant to the manifestation of the clinical symptomatology. In fact, the earliest study examining striatal DA levels in schizophrenia found that those patients with the greatest striatal DA demonstrated the greatest improvement given antipsychotic treatment. Thus, our “midbrain IR-deficiency hypothesis” may only apply to a subgroup of patients: those who have increased striatal DA and classically respond to antipsychotics. More research is needed to better understand the potential “subtypes” of schizophrenia. Such research will likely be guided by elucidating brain-specific biomarkers associated with clinical non-response to antipsychotics”

See also:

Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression.

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