ABSTRACT
Immunoreactivities of adenylyl cyclase (AC) type I (AC-I), and basal, forskolin- and Mn2+-stimulated AC activities with or without calcium and calmodulin (Ca2+/CaM) were estimated in temporal cortex (TC)-and nucleus accumbens (NAc) membranes from brains of heroin addicts and controls. Immunoreactivity of AC-I was significantly decreased in TC from brains of heroin addicts, but that did not change in NAc. Ca2+/CaM-sensitive AC activity was significantly lower in TC from brains of heroin addicts, but that activity in NAc did not show significant difference compared with the control. Some previous reports demonstrated that Ca2+/CaM-sensitive AC activity in membranes from postmortem human brain reflected the function of AC-I. Therefore, the downregulation of AC-I in TC plays an important role in the molecular mechanism of chronic opiate addiction in human brain.
Subject(s)
Brain Chemistry/drug effects , Brain/drug effects , Cyclic AMP/metabolism , Heroin Dependence/metabolism , Heroin/adverse effects , Narcotics/adverse effects , Signal Transduction/drug effects , Adenylyl Cyclases/metabolism , Adult , Age Factors , Brain/metabolism , Brain/physiopathology , Brain Chemistry/physiology , Calcium/metabolism , Calcium/pharmacology , Calmodulin/metabolism , Calmodulin/pharmacology , Cell Membrane/drug effects , Cell Membrane/metabolism , Colforsin/metabolism , Colforsin/pharmacology , Female , Freezing , Heroin Dependence/physiopathology , Humans , Immunohistochemistry , Male , Manganese/metabolism , Manganese/pharmacology , Neurons/drug effects , Neurons/metabolism , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Nucleus Accumbens/physiopathology , Signal Transduction/physiology , Subcellular Fractions/drug effects , Subcellular Fractions/metabolism , Temporal Lobe/drug effects , Temporal Lobe/metabolism , Temporal Lobe/physiopathologyABSTRACT
In animal and culture cell experiments, the upregulation of cAMP-related signal transduction after chronic opioid administration has been hypothesized to be an adaptive change of the molecular mechanism to maintain homeostasis in intracellular signals downstream from opioid receptors. Herein, we have examined the quantitative changes of three adenylyl cyclase (AC) subtypes (I, II, and V/VI) in temporal cortex membranes from brains of heroin addicts and age-matched controls by immunoblotting. The immunoreactivity of AC-I decreased significantly (p < 0.05) in heroin addicts, compared with controls; whereas those of AC-II and AC-V/VI were not changed. The present findings indicate that differential regulation of AC subtypes occurs and that AC-I may play an important role in the signal transduction for opiate-induced tolerance and dependence mechanisms in human brain cortex.
Subject(s)
Adenylyl Cyclases/metabolism , Brain/drug effects , Heroin Dependence/pathology , Heroin/adverse effects , Isoenzymes/metabolism , Adult , Brain/enzymology , Brain/pathology , Drug Tolerance , Female , Heroin Dependence/enzymology , Humans , Immunoblotting , Male , Reference Values , Second Messenger Systems/drug effects , Synaptic Membranes/drug effects , Synaptic Membranes/enzymology , Synaptic Membranes/pathology , Temporal Lobe/drug effects , Temporal Lobe/enzymology , Temporal Lobe/pathologyABSTRACT
Glutamyltranspeptidase binding (G) proteins play an important role in intracellular signal transduction downstream from many receptors, including opioid receptors. Moreover, it was recently reported that the beta-subunits of G proteins, in addition to the alpha-subunits, regulate effector pathways. In this study, membrane G protein immunoreactivity was estimated by Western blotting with polyclonal antibodies (RM/1, AS/7, GC/2, QL, and SW/1) against specific G proteins (G alpha S, G alpha i-1,2, G alpha o, G alpha q, and G beta, respectively) in postmortem temporal cortex obtained from 6 heroin addicts and 6 control subjects without a history of drug abuse. Immunoreactivities of the G beta-subunit increased significantly (p < 0.05) in heroin addicts, compared with controls, and that of G alpha i-1,2 tended to increase in heroin addicts. Present findings suggest that the alterations in G protein-mediated signal transduction may be involved in the mechanism of opiate addiction.
Subject(s)
Brain/pathology , GTP-Binding Proteins/metabolism , Heroin Dependence/pathology , gamma-Glutamyltransferase/metabolism , Adult , Cerebral Cortex/pathology , Female , Humans , Male , Signal Transduction/physiologyABSTRACT
We had a case of psychiatric evidence who was homeless and exhibited severe abulia and autism on detention for assault and battery. It was thought that his past history of chronic methamphetamine abuse and his familial history played some part in his showing such symptoms. His mother was alcohol dependent. He was an ACOA (adult child of alcoholics), which might have led to his chronic abuse of methamphetamine. On the other hand, it is well-known fact that the amotivational syndrome induced by marijuana abuse is typified by a diminution of ambition, productivity, and motivation. However, it has been contended that amotivational syndrome is induced not only by marijuana but also by amphetamine and its analogs, cocaine and volatile solvents. Since we positively support this view, we diagnosed the case as amotivational syndrome after long-term methamphetamine abuse. This was also a rare criminal case of amotivational state without hallucinations and delusions after methamphetamine abuse. We suggested that the crime committed in this case was closely related to crime induced by economic problems in residual states of schizophrenic offenders. This could be a case of both ACOA and methamphetamine dependence. There were unresolved alcohol- and drug-related problems in this case. Therefore, careful early intervention in a crisis, cooperation with the authorities and the institutions concerned, and comprehensive rehabilitation should be employed to resolve such alcohol- and drug-related problems.
