Microsoft Word - Thesis Laukkanen V Final 210516.docx

Alcoholism is a disease that often goes undiagnosed and untreated. The current treatment results of alcoholism are far from satisfactory. One reason for this situation is that there is extensive heterogeneity among alcoholics. Cloninger’s typology divides alcoholics into two subgroups: late-onset, anxiety-prone type 1 alcoholics and early-onset, impulsive type 2 alcoholics. The composition of the neurotransmitter systems of a subject plays a central role in the development and maintenance of alcoholism. The -aminobutyric acid (GABA), glutamate and opioids are important neurotransmitters involved in alcoholism. The main aim of this thesis was to investigate possible differences between Cloninger type 1 (n= 10) and 2 alcoholics (n= 8) and control subjects (n= 10) in the binding density of GABAA receptor, metabotropic glutamate receptor 2 and 3 (mGluR2/3) and μ-opioid receptor (MOR), in the brain areas relevant for decision making, memory, habituation and reward. The research method involved post-mortem human whole hemisphere autoradiography with [3H]flunitrazepam as a binding ligand to study GABAA receptor binding density (study 1), [3H]LY341495 to reveal the binding density of mGluR2 and mGluR3 (study 2) and [3H]naloxone and [3H]DAMGO to study MOR binding density (study 3). In study 1, GABAA receptor binding density was statistically significantly decreased in the internal globus pallidus and hippocampus of both alcoholic subtypes, and in the dentate gyrus of Cloninger type 2 alcoholics, in comparison to the controls. These findings point to altered GABAA receptor function in both alcoholic subgroups. In study 2, the mGluR2/3 binding density of Cloninger type 2 alcoholics was significantly increased in the perigenual anterior cingulate cortex, when compared with the controls. This alteration may be linked to the impulsive tendencies of this alcoholic subgroup. Study 3 detected a statistically significantly decreased [3H]naloxone binding density in the dentate gyrus of Cloninger type 1 alcoholics. There was a trend towards decreased [3H]naloxone and [3H]DAMGO binding in type 1 alcoholics in all brain areas examined in this work, perhaps indicative of impaired MOR function in Cloninger type 1 anxiety-prone alcoholics. These findings reveal alterations in the GABAA receptor, mGluR2/3 and MOR –mediated neurotransmitter function in alcoholism. Altered mGluR2/3 and MOR binding characteristics were specific to a certain subgroup of alcoholics, whereas reduced GABAA receptor binding was observed in all alcoholics. These findings deepen our understanding of the neurotransmitter systems involved in different types of alcoholism. Hopefully, they will provide new prospects for the treatment of patients as well as a launching pad for future research. National Library of Medicine Classification: QV 84, WL 102.8, WL 300, WM 274 Medical Subject Headings: Alcoholic Beverages; Alcoholics; Alcohol Drinking; Alcohol-Induced Disorders; Anxiety; Impulsive Behavior; Receptors, Neurotransmitter; Receptors, GABA-A; Receptors, Metabotropic Glutamate; Receptors, Opioid, mu; Brain; Gyrus Cinguli; Dentate Gyrus; Globus Pallidus; Hippocampus; Alcoholism/drug therapy