[Advanced findings on the molecular mechanisms for behavioral sensitization to psychostimulants].
Repeated administration of psychostimulants like methamphetamine and cocaine induce behavioral sensitization, which is recognized as an animal model for dependence and psychoses. Many previous studies have proved two major cascades play a crucial roles for molecular mechanisms underling sensitization. The first one is activation of D1 dopamine receptors by robust increase of dopamine release, followed by activation of adenylyl cyclase, increase of cyclic AMP, activation of protein kinase A (PKA) and phosphorylation of proteins by PKA. The second one is activation of NMDA receptor by enhanced release of glutamine, followed by increased intracellular Ca2+ concentration, formation of Ca2+/calmodulin complex, and phosphorylation of several proteins such as calcineurin, CaM-K II and nitric oxide synthase. Recent advanced findings on sensitization mechanisms were reviewed from three different aspects: 1) Studies using knockout mice offered quite amazing findings that D1DA-receptor-lacking mice or dopamine-transporter-lacking mice can develop sensitization and dependence, which were not consistent with the previously established hypotheses based on behavioral pharmacology. In addition, those data showed the important roles of vesicular monoamine transporter 2, 5HT1B receptors and delta FosB. 2) Research on neural-plasticity-related sensitization revealed the involvement of several molecules such as tissue plasminogen activator, arc (activity-regulated, cytoskeleton-associated), synaptophysin and stathmin. Increased expression of these genes may participate in the rearrangement of neural networks with synaptogenesis and expansion of dendrites 3) Trials to discover novel-genes-involved sensitization phenomenon using differential display or subtraction cloning found some candidate genes, mrt-1, NAC-1 and CART. Although in these areas are still in progress, accumulating findings will elucidate the details of the molecular mechanism of behavioral sensitization and dependence.
Department of Neuropsychiatry, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. hujike@cc.okayama-u.ac.jp
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D000818:Animals; D001426:Bacterial Proteins; D000697:Central Nervous System Stimulants / Q000009:adverse effects*; D003042:Cocaine / Q000009:adverse effects; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009473:Neuronal Plasticity; D009479:Neuropeptides; D016760:Proto-Oncogene Proteins c-fos; D011605:Psychoses, Substance-Induced / Q000235:genetics*; D044302:Receptor, Serotonin, 5-HT1B; D017447:Receptors, Dopamine D1 / Q000235:genetics; D011985:Receptors, Serotonin; D012097:Repressor Proteins; D019966:Substance-Related Disorders / Q000235:genetics*; D016708:Synaptophysin; D010959:Tissue Plasminogen Activator; D014157:Transcription Factors; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
D001426:Bacterial Proteins; D000697:Central Nervous System Stimulants; C483819:Fosb protein, mouse; C483820:Fosb protein, rat; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C484605:Nacc1 protein, mouse; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D016760:Proto-Oncogene Proteins c-fos; D044302:Receptor, Serotonin, 5-HT1B; D017447:Receptors, Dopamine D1; D011985:Receptors, Serotonin; D012097:Repressor Proteins; D016708:Synaptophysin; D014157:Transcription Factors; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D008694:Methamphetamine; D010959:Tissue Plasminogen Activator; D003042:Cocaine