Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The successful generation and functional expression of a series of recombinant chimeric transporters, in which distinct functional properties of NET and DAT are exchanged, have allowed the assignment of a number of important functional properties of MPP+ and antidepressant-sensitive catecholamine transporters to specific domains within their primary structure. These studies are the first comprehensive structure-function analysis of members of the rapidly growing superfamily of Na+/Cl- carriers using chimeric transporters. This represents the first step in identifying the specific structural or regulatory determinants that differentiate NET and DAT. An appreciation of the potentially distinct sites for substrate recognition, translocation, and transport inhibition of NET and DAT may facilitate the development of more selective drugs for the treatment of stimulant addiction, human depression, and other affective disorders.
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PMID:Discrete structural domains and cell-specific expression determine functional selectivity of the dopamine and norepinephrine transporters. 878 50

Zero-order correlational and simultaneous regression analyses were performed to ascertain the comparative validity of four measures of antisociality for predicting the initial 7 months treatment response of 193 male methadone maintenance (MM) patients. Predictor variables were the number of childhood conduct disorder (CD) behaviors, number of adult antisocial personality disorder (A-APD) behaviors, the revised Psychopathy Checklist (PCL-R) score and the revised California Psychological Inventory-Socialization (CPI-So) scale score. The outcome measures were completion/noncompletion of 7 months of treatment, percent positive during-treatment of cocaine, opiate and benzodiazepine urine toxicologies, and change from baseline to 7 months follow-up in seven Addiction severity index (ASI) composite scores (CSs). All four measures of antisociality were significantly correlated with treatment noncompletion, although only the PCL-R score was significant in the predictor model. The PCL-R predicted more positive cocaine urines. At the individual level, both PCL-R and CPI-So were associated with more positive benzodiazepine urines, but neither contributed a significant amount of variance when both were entered in the model. None of the predictors were significantly associated with self reported improvement in the CSs. The PCL-R and CPI-So were more successful in predicting outcomes than the two behavior-based measures.
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PMID:Prediction of 7 months methadone maintenance treatment response by four measures of antisociality. 957 86

The Psychopathy Checklist-Revised (PCL-R; R. D. Hare, 1991) is an often-used device for assessment of adult antisociality. This research examined generalizability by replicating the 2-factor model for a sample of 326 male prisoners and assessing its congruence and relative reliability and specificity among 620 substance-dependent patients. Generality was assessed also across addiction subtypes (opioid, cocaine, and alcohol), age, gender, and ethnicity. The 2-factor model was found inappropriate for the substance-dependent samples, whereas a unidimensional model represented by the PCL-R total score was found generalizable across prison and substance-dependent samples.
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PMID:Generality of Psychopathy Checklist-Revised factors over prisoners and substance-dependent patients. 1071 Aug 54

The five manual-guided treatment models tested in the Cannabis Youth Treatment study funded by the Center for Substance Abuse Treatment are described. The five models include (a) a 6-week intervention consisting of two sessions of individual motivational enhancement therapy plus three sessions of group cognitive behavioral therapy (MET/CBT5); (b) a 12-week intervention consisting of two sessions of motivational enhancement therapy plus 10 sessions of group cognitive behavioral therapy treatment (MET/CBT12); (c) a 12-week intervention consisting of MET/CBT12 plus the family support network (FSN), a multi-component intervention that includes parent education, family therapy and case management; (d) a 12-week intervention based on the adolescent community reinforcement approach (ACRA), an individual behavioral treatment approach designed to help adolescents and their parents reshape their environment and learn new skills; and (e) multi-dimensional family therapy (MDFT), a multi-faceted, developmentally and contextually oriented family-based model targeting individual, family and social systems. For each model, we describe the treatment background and/or its empirical support, its theoretical underpinnings, its goals and proposed treatment mechanism and the structure and content of each treatment. Procedures used for maintaining treatment fidelity and monitoring quality assurance are also described. These interventions represent the first readily available, manual-guided interventions to be evaluated in a large randomized field study for this population. Consequently, these manuals have the potential to advance treatment and research for adolescents with substance use disorders.
Addiction 2002 Dec
PMID:Five outpatient treatment models for adolescent marijuana use: a description of the Cannabis Youth Treatment Interventions. 1246 Jan 30

The successful dissemination of empirically supported addiction therapies to community providers requires an appreciation of the characteristics of those practitioners who might be willing participants in this process of technology transfer. Clinicians (N = 66) from 11 community treatment programs associated with six research-clinic partnerships of the National Drug Abuse Clinical Trials Network volunteered to be trained in Motivational Interviewing or Motivational Enhancement Therapy (MET/MI) and were assessed prior to training. The sample of clinicians was heterogeneous in education and credentials, had a high level of counseling experience, reported using a wide range of counseling techniques and orientations, but had limited prior exposure to MET/MI or to the use of treatment manuals of empirically supported therapies. In general, many of the clinicians reported beliefs and techniques that were consistent with their stated theoretical orientation and recovery status. Relatively few participants reported relying on one dominant orientation or set of techniques.
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PMID:Characteristics, beliefs, and practices of community clinicians trained to provide manual-guided therapy for substance abusers. 1249 92

Little is known about the cellular effects induced by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), although changes in gene expression have been observed following treatments with other psychostimulants. Thus, the aim of this study was to investigate in mice, the relationships between the ras-dependent protein kinase ERK and MDMA-induced reinforcement using the conditioned place preference (CPP) and locomotor activity measurements. This was completed using real-time quantitative PCR method by a study of immediate early-genes (IEGs) transcription known to be involved in neuronal plasticity. A significant CPP was observed after repeated MDMA treatment in CD-1 mice at a dose of 9 mg kg-1 i.p. but not at 3 and 6 mg kg-1. This rewarding effect was abolished by the selective inhibitor of ERK activation, SL327 (50 mg kg-1; i.p.). Similar results were obtained on MDMA-induced locomotor activity, clearly suggesting a role of ERK pathway in these behavioral responses. Following acute i.p. injection, MDMA induced a strong c-fos transcription in brain structures, such as caudate putamen, nucleus accumbens and hippocampus, whereas egr-1 and egr-3 transcripts were only increased in the caudate putamen. MDMA-induced IEGs transcription was selectively suppressed by SL327 in the caudate putamen, suggesting a role for other signaling pathways in regulation of IEGs transcription in the other brain structures. In agreement with these results, MDMA-induced c-fos protein expression was blocked by SL327 in the caudate putamen. This study confirms and extends to mice the reported role of ERK pathway in the development of addiction-like properties of MDMA. This could facilitate studies about the molecular mechanism of this process by using mutant mice.
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PMID:Importance of ERK activation in behavioral and biochemical effects induced by MDMA in mice. 1451 76

Opiate addiction involves the development of chronic adaptive changes in micro -opioid receptors and associated pathways (e.g. cAMP signalling) which lead to neuronal plasticity in the brain. This study assessed the status of cAMP and mitogen-activated protein kinase (MAPK) pathways in brains (pre-frontal cortex) of chronic opiate addicts. In these subjects (n = 24), the immunodensities of adenylyl cyclase-I, PKA Calpha, total and phosphorylated CREB were not different from those in sex-, age- and PMD-matched controls. Moreover, the ratio pCREB/tCREB was similar in opiate addicts (0.74) and controls (0.76), further indicating that opiate addiction in humans is not associated with an upregulation of several key components of cAMP signalling in the pre-frontal cortex. In contrast, the components of MAPK cascade (Ras/c-Raf-1/MEK/ERK) were decreased in the same brains. Notably, pronounced downregulations of phosphorylated MEK (85%) and ERK1/2 (pERK1: 81%; pERK2: 80%) were quantitated in brains of opiate addicts. Chronic morphine treatment in rats (10-100 mg/kg for 5 days) was also associated with decreases of pERK1/2 (59-68%) in the cortex. In SH-SY5Y cells, morphine also stimulated the activity of pERK1/2 (2.5-fold) and the MEK inhibitor PD98059 blocked this effect (90%). The abnormalities of MAPK signalling might have important consequences in the long term development of various forms of neural plasticity associated with opiate addiction in humans.
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PMID:Long-term regulation of signalling components of adenylyl cyclase and mitogen-activated protein kinase in the pre-frontal cortex of human opiate addicts. 1519 81

Behavioral studies have demonstrated that chronic food restriction augments the rewarding and motor-activating effects of centrally injected psychostimulants and direct dopamine (DA) receptor agonists. Recently, it has been shown that intracerebroventricular (i.c.v.) injection of the D-1 DA receptor agonist, SKF-82958, produces an enhanced locomotor-activating effect as well as increased activation of striatal ERK 1/2 MAP kinase, CaM kinase II, CREB, and c-fos in food-restricted (FR) relative to ad libitum fed (AL) rats. Striatal neurons that express the D-1 DA receptor coexpress dynorphin and substance P, and CREB is known to couple D-1 DA receptor stimulation to preprodynorphin (ppD) gene expression. The purpose of the present study was to examine possible genomic consequences of FR using real-time quantitative RT-PCR to measure striatal neuropeptide gene expression 3 h after i.c.v. injection of SKF-82958 (20 microg). Results indicate that, in nucleus accumbens (NAc), basal levels of ppD and preprotachykinin (ppT) mRNA are lower in FR than AL rats. This may reflect a decrease in tonic DA transmission during FR which precedes the compensatory upregulation of postsynaptic D-1 DA receptor-mediated cell signaling. In response to SKF-82958 challenge, however, FR subjects displayed greater levels of ppD and ppT mRNA in NAc than did AL subjects. A similar trend was seen in caudate-putamen (CPu). SKF-82958 also increased preproenkephalin (ppE) mRNA in Nac, but not CPu, with no difference between feeding groups. The present findings regarding ppD and ppT are consistent with prior findings of increased behavioral and cellular responses to acute D-1 DA agonist challenge in FR rats. The functional consequences of increased neuropeptide gene expression in response to acute drug challenge remain to be investigated but may include modulation of behavioral effects that emerge with repeated drug exposure, including sensitization, tolerance, and addiction.
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PMID:Comparison of basal and D-1 dopamine receptor agonist-stimulated neuropeptide gene expression in caudate-putamen and nucleus accumbens of ad libitum fed and food-restricted rats. 1625 73

In forensic practice there is an urgent need for criteria which separate personalities with a high risk for violent behaviour from those less likely to cause complications upon discharge or relaxed enforcement. Based upon a sample of over 64 expert opinions on conditional discharge from imprisonment, especially violent offenders and the diagnostic groups of personality disorders and substance abuse were investigated. Dangerousness and risk assessment was based on the criteria of the Psychopathy-Check-List (PCL-SV). Psychopathy has a high coincidence with addiction, hyperkinetical disorders and antisocial behaviour. In our sample of 64 offenders a standardized psychophysiological stress test (with a visuo-acoustic startle stimulus) was administered. Physiological indices consisted of skin conductance, pulse frequency, skin temperature and muscle tension (frontalis). Significant correlations between physiological data and cognitive and personality variables based upon extensive psychodiagnostic assessment are reported. Individual differences in stress reactivity with regard to psychopathy (Hare) and implications for therapy are further discussed.
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PMID:[Personality disorders: psychophysiological and neuropsychological correlates of risk]. 1639 23

The ability of cocaine to produce lasting neural adaptations in mesocorticolimbic brain regions is thought to promote drug seeking and facilitate addiction in humans. The Ras-controlled Raf-MEK-ERK protein kinase signaling cascade has been implicated in the behavioral and neurobiological actions of cocaine in animals. However, these pharmacological studies have not been able to determine the specific role of the two predominant isoforms of ERK (ERK1 and ERK2) in these processes. We report here that deletion of the ERK1 isoform, which leads to increased ERK2 stimulus-dependent signaling, facilitates the development of cocaine-induced psychomotor sensitization and the acquisition of a cocaine conditioned place preference. Conversely, pharmacological blockade of ERK signaling attenuates the development of psychomotor sensitization to cocaine. Finally, cocaine-evoked gene expression in mesocorticolimbic brain regions is potentiated in ERK1-deficient mice. Thus, alterations in ERK signaling influence both the neurobiological impact of cocaine and its ability to produce enduring forms of drug experience-dependent behavioral plasticity. Our results suggest that enhanced ERK2 signaling following repeated drug exposure may facilitate the development of forms of cocaine-induced plasticity that contribute to addiction.
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PMID:Knockout of ERK1 enhances cocaine-evoked immediate early gene expression and behavioral plasticity. 1640 94


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