Figure 4.

Proposed model of dopamine dysregulation in the nigrostriatal pathway in schizophrenia. Gene expression of multiple DA-regulating molecules (red box) involved in autoreception (DRD2), transport (DAT and VMAT) and catabolism (MAO) are changed in the substantia nigra in schizophrenia, and together may contribute to DA dysregulation at the level of the DA cell bodies and/or at the DA terminals in the striatum. DA is synthesised from tyrosine (tyr) by TH and AADC, but these do not appear to be changed in level. MAO and COMT breakdown DA to metabolites, DOPAC and HVA and MAO mRNA is increased. DAT removes DA from the synaptic cleft and is reduced at the mRNA level but not at the protein level in the midbrain. VMAT packages DA into vesicles and is reduced at the mRNA level. DRD2 (blue triangle) autoreception inhibits DA firing, DA synthesis and DA release, and we found a significant decrease in DRD2S mRNA. DRD3 mRNA was unchanged. DA activation of DRD2 (blue triangle) on the postsynaptic neuron inhibits AC leading to disinhibition of the inhibitory medium spiny neurons. Increased DRD2 expression in the striatum in schizophrenia⁶⁹ would further contribute to DA dysregulation. AADC, aromatic acid decarboxylase; AC, adenylate cyclase; COMT, catechol-O-methyl transferase; DA, dopamine; DRD, dopamine receptor D; MAO, monoamine oxidase; TH, tyrosine hydroxylase; VMAT2, vesicular monoamine transporter 2.