One functional single nucleotide polymorphism in dopamine receptor D2 (DRD2), rs1076560, is involved in regulating splicing of the gene and alters the ratio of DRD2 isoforms located pre- and postsynaptically. rs1076560 has been previously associated with cocaine abuse and we set out to confirm this association in a sample of European American (EA) (n = 336) and African American (AA) (n = 1034) cocaine addicts and EA (n = 656) and AA (n = 668) controls.
To assess the role of DRD2 variants in cocaine abuse, we measured levels of D2S and D2L mRNA in human brain autopsy tissues (prefrontal cortex and putamen) obtained from cocaine abusers and controls, and genotyped a panel of DRD2 SNPs (119 abusers and 95 controls).
In developing an vivo drug-interception therapy to treat cocaine abuse and hinder relapse into drug seeking provoked by re-encounter with cocaine, two promising agents are: (1) a cocaine hydrolase enzyme (CocH) derived from human butyrylcholinesterase and delivered by gene transfer; (2) an anti-cocaine antibody elicited by vaccination.
We are investigating treatments for cocaine abuse based on viral gene transfer of a cocaine hydrolase (CocH) derived from human butyrylcholinesterase, which can reduce cocaine-stimulated locomotion and cocaine-primed reinstatement of drug-seeking behavior in rats for many months.
The available PET data imply that an effective therapeutic enzyme for treatment of cocaine abuse could be an exogenous cocaine-metabolizing enzyme with a catalytic activity against (-)-cocaine comparable to that of wild-type BChE against (+)-cocaine.
In the present study, we show that each of these transcription factors is robustly expressed in adult dopamine neurons in human midbrain, and that cocaine abuse is associated with a significant decrease in the abundance of Nurr1 and Pitx3 in these cells.
The observed microarray phenotype in the human hippocampus identified RECK and other region-specific genes that may promote long-lasting structural changes with repeated cocaine abuse.
Our findings add to the evidence that drugs targeting CB1 receptors are good candidates for the treatment of cocaine abuse and provide further insights into the mechanisms underlying endocannabinoid signaling within the brain reward system in the context of cocaine abuse.
In the present study, we show that each of these transcription factors is robustly expressed in adult dopamine neurons in human midbrain, and that cocaine abuse is associated with a significant decrease in the abundance of Nurr1 and Pitx3 in these cells.
Cocaine abuse was the most significant moderator of DeltaPRL (peak PRL-baseline PRL), and the interaction of genetic, behavioral and psychopathological measures helped predict most of the observed DeltaPRL (62.5%).
Based on these findings, altered expression of PLP1 in most areas of the striatum suggests that widespread changes to the myelin structure could be associated with the adaptive changes following chronic cocaine abuse.
Emerging preclinical evidence has implicated both serotonin (5-HT) 2C and 2A receptors as potential mechanisms for mediating serotonergic attenuation of cocaine abuse-related neurochemical and behavioral effects.
Thus, we provide the first evidence of FosB gene expression in human HPC and PFC in these psychiatric disorders, and in light of recent findings demonstrating the critical role of HPC ΔFosB in rodent models of learning and memory, these data suggest that reduced ΔFosB in HPC could potentially underlie cognitive deficits accompanying chronic cocaine abuse or depression.
However, the accumulation of alpha-synuclein protein with long-term cocaine abuse may put addicts at increased risk for developing the motor abnormalities of Parkinson's disease.
While we found no association of the 5-HTTLPR variants with severity of cocaine abuse or any cocaine-related outcome measures, the data suggested that the 5-HTTLPR polymorphism may distinguish responders from non-responders to behavioral treatment in terms of alcohol use.