15. Schizophrenia as a dopaminergic Disorder

Schizophrenia is associated with increased dopamine levels in the dorsal and ventral¹ striatum (positive psychotic symptoms) and decreased dopamine levels in the PFC² (negative symptoms).
Another explanation cites hyperactivity of dopaminergic neurons (positive symptoms) and hypoactivity of glutamatergic neurons (negative symptoms)³

According to the endocannabinpid hypothesis, endocannabinoids such as anandamide⁴ (up to 8-fold)⁵ and palmitylethanolamide⁴ are increased in cerebrospinal fluid and blood plasma (AEA 3-fold, which decreased after remission⁶ ) in schizophrenia, while 2-AG was greatly reduced⁴.
Since increased anandamide levels correlated with reduced psychotic symptoms, the increased AEA level in schizophrenia could also represent a compensatory reaction.⁵
Four studies found increased CB1R density in schizophrenia, one study found unchanged CB1R binding and one study found decreased CB1R binding.³

Anandamide and 2-AG appear to be elevated in ADHD.

The selective activation of dopamine neurons projecting to the dorsal striatum:⁷

• increased dopamine release in the dorsal striatum
• slightly reduced release of dopamine in the cortex
• increased movement activity
  • which was normalized by haloperidol
• impaired social interaction
  • which remained unchanged by haloperidol
• impaired working memory
  • which was only partially normalized by haloperidol

According to our understanding of the interaction of the dopamine system between the striatum and PFC (dopamine seesaw, see The dopamine seesaw between PFC and subcortical regions (e.g. striatum)), we would have expected a unilaterally increased striatal dopamine to result in a reduction of dopamine in the PFC, which in turn would be a conclusive explanation for the negative symptoms that occur. Whether the slightly reduced dopamine levels in the PFC found by Moya et al. are sufficient to cause the negative symptoms is unclear to us.

A number of dopaminergic abnormalities are found in schizophrenia, including:²

• Impaired control of the PFC
• Changes in the dorsal striatum
• Increased dopamine synthesis
• Increased release of dopamine
• Dopamine synthesis/release decreased again during remission
• Hypodopaminergic PFC
• DAT mirror changed
• Dopamine sensitization
• SCZ risk genes control the expression of the D2 signaling pathway
• Anti-NMDA antibodies reduce D1 trafficking/neuromelanin imaging
• Clinical effect of TAAR1 agonists