Drug-related deaths in Budapest and the neurobiology of heroin abuse

Heroin abuse is a widespread phenomenon which in Hungary, just as in other parts of the world, has been slowly but gradually increasing in the past 15 years. Our work was aimed at characterizing the population of drug-related death cases, with a special emphasis on the demographic and toxicological evaluation of the subjects. We analyzed 309 drug related death cases registered between 1994 and 2006 at the Department of Forensic Medicine at Semmelweis University, Budapest. We found that the number of drug-related deaths is slowly but constantly increasing; the majority of drug-related deaths were caused by accidental heroin overdoses whose victims were usually male, aged between 20-30 years of age, with an approximately 3.5 years of drug-use history, almost all Hungarian citizens. We also analyzed the prevalence of some infectious diseases within the population; HIV was very rare (1 case during 6 years) while hepatitis C and B and syphilis had a prevalence of 23%, 7% and 7% respectively.;In a subpopulation of the heroin overdose and control cases we collected human brain samples for further scientific assessment. In our attempt to understand the neurobiology of human heroin abuse, we examined the major brain regions linked to the "reward pathway": the ventral tegmental area (VTA) in the midbrain and the nucleus accumbens (Nacc) within the striatum. The systems most implicated in the neurobiology of heroin abuse are the dopaminergic and opioid systems; for this reasons we examined the major markers of these within the midbrain and the striatum.;As a result of our experiments, a consistent alteration of the VTA paranigral nucleus (PN) subdivision was revealed for most of the DAergic markers which strongly suggests that there is a more profound disturbance of the mesolimbic reward circuit in heroin-dependent individuals. The paralleled disturbance of dopamine transporter (DAT) mRNA and protein levels in the PN and Nacc, respectively, emphasizes the continuum of disturbances throughout the mesolimbic circuit.;In our population of subjects, 90% of individuals with an A118G polymorphism of the mu opioid receptor gene (OPMR1) were heroin abusers. Down-regulation of opioid neuropeptide genes detected in the heroin users were exaggerated in 118G subjects and were most prominent for preproenkephalin in the Nacc shell. Reduced opioid neuropeptide transcription was accompanied by increased dynorphin and enkephalin peptide concentrations exclusively in 118G heroin subjects, suggesting that the peptide processing is associated with the OPRM1 genotype. Overall, the findings from these studies emphasize a prominent mesolimbic disturbance in the brain of heroin abusers.