RESUMO
A major goal of drug abuse research is to identify and understand drug-induced changes in brain function that are common to many or all drugs of abuse. As these may underlie drug dependence and addiction, the purpose of the present study was to examine if different drugs of abuse effect changes in gene expression that converge in common molecular pathways. Microarray analysis was employed to assay brain gene expression in postmortem anterior prefrontal cortex (aPFC) from 42 human cocaine, cannabis and/or phencyclidine abuse cases and 30 control cases, which were characterized by toxicology and drug abuse history. Common transcriptional changes were demonstrated for a majority of drug abuse cases (N = 34), representing a number of consistently changed functional classes: Calmodulin-related transcripts (CALM1, CALM2, CAMK2B) were decreased, while transcripts related to cholesterol biosynthesis and trafficking (FDFT1, APOL2, SCARB1), and Golgi/endoplasmic reticulum (ER) functions (SEMA3B, GCC1) were all increased. Quantitative PCR validated decreases in calmodulin 2 (CALM2) mRNA and increases in apolipoprotein L, 2 (APOL2) and semaphorin 3B (SEMA3B) mRNA for individual cases. A comparison between control cases with and without cardiovascular disease and elevated body mass index indicated that these changes were not due to general cellular and metabolic stress, but appeared specific to the use of drugs. Therefore, humans who abused cocaine, cannabis and/or phencyclidine share a decrease in transcription of calmodulin-related genes and increased transcription related to lipid/cholesterol and Golgi/ER function. These changes represent common molecular features of drug abuse, which may underlie changes in synaptic function and plasticity that could have important ramifications for decision-making capabilities in drug abusers.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/genética , Abuso de Maconha/genética , Abuso de Fenciclidina/genética , Transcrição Gênica , Adulto , Autopsia , Calmodulina/genética , Estudos de Casos e Controles , Colesterol/metabolismo , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Retículo Endoplasmático/genética , Feminino , Complexo de Golgi/genética , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Abuso de Maconha/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Abuso de Fenciclidina/metabolismo , Reação em Cadeia da Polimerase , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto JovemRESUMO
We investigated the molecular mechanisms of development to phencyclidine (PCP)-induced rewarding effect by using tyrosine hydroxylase (TH) heterozygous (TH(+/-)) mice. PCP (8 mg/kg) induced the place preference in wild-type mice pretreated with PCP (10 mg/kg/day for 28 days). The place preference induced by PCP is attenuated by 6-hydroxydopamine, a dopaminergic neurotoxin, and (+) SCH-23390, a dopamine-D1 receptor antagonist, but not by DSP-4, a noradrenergic neurotoxin, and (-) sulpiride, a dopamine-D2 receptor antagonist. In TH(+/-) mice pretreated with PCP (10 mg/kg/day for 28 days), no PCP (8 mg/kg)-induced place preference was observed. In wild-type mice pretreated with PCP, the levels of cAMP, cAMP response element binding protein (CREB), and c-fos mRNA in the nucleus accumbens were increased. The levels of cAMP, CREB, and c-fos mRNA in the nucleus accumbens were not increased by the same treatment schedule of PCP in TH(+/-) mice. These findings suggest that changes in dopaminergic and/or cAMP signal cascades induced by repeated PCP treatment play an important role in the development of PCP-induced rewarding effect.