Cocaine use disorder (CUD) is associated with dopaminergic abnormalities, but post-mortem evidence has not clarified whether molecular changes preferentially involve presynaptic dopamine regulation rather than broader monoaminergic alterations. We conducted a PRISMA 2020 systematic review of post-mortem case-control studies comparing individuals with CUD versus controls and quantifying dopaminergic, serotonergic, or noradrenergic markers using molecular, transcriptional, or ligand-binding measures. PubMed, Scopus, and Web of Science were searched through 31 August 2026. Seventeen studies met inclusion criteria, comprising 887 brains (533 CUD; 354 controls). Across studies, the most consistent pattern involved presynaptic dopaminergic dysregulation. Dopamine transporter measures (DAT/SLC6A3) were frequently altered, with reports of discordance between striatal binding/immunoreactivity and reduced ventral midbrain DAT mRNA expression. Several studies reported reduced vesicular monoamine transporter 2 (VMAT2/SLC18A2) measures, particularly in the striatum. Midbrain expression of dopaminergic maintenance and identity regulators was reduced in subsets of studies, including NR4A2 (NURR1), tyrosine hydroxylase (TH), and FOXA2. Two studies reported increased α-synuclein (SNCA) in dopaminergic regions. Serotonergic and noradrenergic studies were fewer than dopaminergic studies and did not show consistent signals. Findings were reported across striatum, nucleus accumbens, prefrontal cortex, and midbrain regions, including ventral tegmental area and substantia nigra. Interpretation is limited by assay/region heterogeneity, post-mortem interval, toxicology/cause of death and underrepresentation of females. Overall, post-mortem evidence shows an associative pattern of presynaptic dopaminergic marker alterations in CUD, including heterogeneous DAT measures, reduced VMAT2 measures, reduced NR4A2/NURR1, TH, and FOXA2 expression, and increased α-synuclein expression; causal relationships cannot be established from cross-sectional post-mortem evidence.
Post-mortem human brain evidence for presynaptic dopaminergic dysregulation in cocaine use disorder: A systematic review
Serretti, Alessandro;
2026-01-01
Abstract
Cocaine use disorder (CUD) is associated with dopaminergic abnormalities, but post-mortem evidence has not clarified whether molecular changes preferentially involve presynaptic dopamine regulation rather than broader monoaminergic alterations. We conducted a PRISMA 2020 systematic review of post-mortem case-control studies comparing individuals with CUD versus controls and quantifying dopaminergic, serotonergic, or noradrenergic markers using molecular, transcriptional, or ligand-binding measures. PubMed, Scopus, and Web of Science were searched through 31 August 2026. Seventeen studies met inclusion criteria, comprising 887 brains (533 CUD; 354 controls). Across studies, the most consistent pattern involved presynaptic dopaminergic dysregulation. Dopamine transporter measures (DAT/SLC6A3) were frequently altered, with reports of discordance between striatal binding/immunoreactivity and reduced ventral midbrain DAT mRNA expression. Several studies reported reduced vesicular monoamine transporter 2 (VMAT2/SLC18A2) measures, particularly in the striatum. Midbrain expression of dopaminergic maintenance and identity regulators was reduced in subsets of studies, including NR4A2 (NURR1), tyrosine hydroxylase (TH), and FOXA2. Two studies reported increased α-synuclein (SNCA) in dopaminergic regions. Serotonergic and noradrenergic studies were fewer than dopaminergic studies and did not show consistent signals. Findings were reported across striatum, nucleus accumbens, prefrontal cortex, and midbrain regions, including ventral tegmental area and substantia nigra. Interpretation is limited by assay/region heterogeneity, post-mortem interval, toxicology/cause of death and underrepresentation of females. Overall, post-mortem evidence shows an associative pattern of presynaptic dopaminergic marker alterations in CUD, including heterogeneous DAT measures, reduced VMAT2 measures, reduced NR4A2/NURR1, TH, and FOXA2 expression, and increased α-synuclein expression; causal relationships cannot be established from cross-sectional post-mortem evidence.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
