Gene Expression Profiling of the Rewarding Effect Caused by Methamphetamine in the Mesolimbic Dopamine System
Moon Hee YangMinsuk JungMin-Joo LeeKyung Hyun YooYeon Joo YookEun Young ParkSeo Hee ChoiYoung Ju SuhKee-Won KimJong Hoon Park
19
Citation
22
Reference
10
Related Paper
Citation Trend
Abstract:
Methamphetamine, a commonly used addictive drug, is a powerful addictive stimulant that dramatically affects the CNS. Repeated METH administration leads to a rewarding effect in a state of addiction that includes sensitization, dependence, and other phenomena. It is well known that susceptibility to the development of addiction is influenced by sources of reinforcement, variable neuroadaptive mechanisms, and neurochemical changes that together lead to altered homeostasis of the brain reward system. These behavioral abnormalities reflect neuroadaptive changes in signal transduction function and cellular gene expression produced by repeated drug exposure. To provide a better understanding of addiction and the mechanism of the rewarding effect, it is important to identify related genes. In the present study, we performed gene expression profiling using microarray analysis in a reward effect animal model. We also investigated gene expression in four important regions of the brain, the nucleus accumbens, striatum, hippocampus, and cingulated cortex, and analyzed the data by two clustering methods. Genes related to signaling pathways including G-protein-coupled receptor-related pathways predominated among the identified genes. The genes identified in our study may contribute to the development of a gene modeling network for methamphetamine addiction.Keywords:
Methamphetamine
Neurochemical
Stimulant
The objective of this study was to investigate and analyze the behavioral and neurochemical effects of monosodium glutamate (MSG) injections at various and subsequent dosages on male Wistar rats during the neonatal period.In order to determine the behavioral and neurochemical effects of MSG, the experiment was implemented on neonatal male Wistar rats and the test was repeated for various MSG dosages. After completing the experiment, additionally, levels of dopamine, GABA, catecholamine (dopamine, noradrenaline, and adrenaline) and glutamate in the brain cells of the decapitated rats were also measured using the ELISA method.Considering the results of the behavioral test, when we compared the test values of the control group with the values of the MSG-injected groups we noted that there were significant differences in the statistical figures obtained. Additionally, we found that the statistical figures of some neurochemical parameters were also significantly different when we compared the values of the MSG group with the control values.MSG injection has a clear effect on the neurochemical parameters, learning memory, and locomotor activities of rats.
Neurochemical
Monosodium glutamate
Dose
Microdialysis
Cite
Citations (15)
Neurochemical
Human brain
Cite
Citations (0)
Neurochemical
Neurochemistry
Neurophysiology
Cite
Citations (38)
For the identification and quantitative analysis of methamphetamine and its metabolites in the urine from a habitual user of the stimulant, the combined method of gas chromatography and mass fragmentgraphy was developed. The proportion of methamphetamine and its metabolites to the excreted matter is as follows : amphetamine 7.5%, p-hydroxymethamphetamine 6.45%, p-hydroxyamphetamine 0.35%, and norephedrine 0.23% respectively.
Methamphetamine
Stimulant
Cite
Citations (5)
The neurotoxic organochlorine insecticide chlordecone (Kepone) was examined in several in vitro and in vivo neurochemical systems in an attempt to identify neurochemical alterations that might be relevant to the central nervous system manifestations of chlordecone toxicity in humans. In vitro, chlordecone was a remarkably potent inhibitor of brain mitochondrial oxidative phosphorylation and associated Ca2+ transport (Ki congruent to 10(-7) M). At a high concentration of chlordecone (10(-5) M), destabilization of biological membranes was observed. Both of these effects appeared to contribute to inhibition of synaptosomal Ca2+ uptake, which was accompanied by a pronounced, although paradoxical, stimulation of neurotransmitter release. Studies of the disposition of [14C]chlordecone revealed that the concentrations that elicited neurochemical changes in vitro were comparable to the brain tissue chlordecone concentrations achieved with a 40 mg/kg tremorigenic dose in intact animals. However, no neurochemical correlates of chlordecone toxicity were observed in studies of dopamine and norepinephrine turnover in chlordecone-intoxicated animals. These findings are discussed in relation to the development of neurochemical assays appropriate for investigating neurotoxic agents.
Neurochemical
Neurotoxicity
Neurotoxin
Cite
Citations (21)
Electrochemistry is one of the most advanced techniques for monitoring neurochemical activities in the living brain because electrochemical approaches bear the advantageous features of high spatial and temporal resolutions, which facilitate its tremendous potential in investigating the highly spatially heterogeneous brain system and the fast dynamics of neurochemical activities. On the other hand, since brain is the most complicated organ in the sense of its numerous kinds of neurochemical species, high selectivity is always required for any analytical methods that approach the brain. In this review, we will discuss various electrochemical methodologies to achieve selective detection of neurochemicals in mammalian brain and the strategies developed mainly by our group towards selective monitoring of both electrochemically active and inactive neurochemicals. At the end, we will discuss possible solutions towards brain mapping of neurochemical species and combination of neurochemical detection strategy with electrophysiology as the direction of future development of electroanalysis in living brain.
Neurochemical
Brain chemistry
Cite
Citations (13)
Monoamine releasers such as d-methamphetamine (d-MA) can reduce cocaine use in laboratory studies and have been forwarded for the management of cocaine use disorder (CUD). However, the proven abuse liability of d-MA has limited enthusiasm for clinical use. The levorotatory isomer of MA, l-MA, appears to have lesser stimulant effects, possibly due to its preferential norepinephrine-releasing properties compared with dopamine. The present study evaluated the abuse potential of l-MA by comparing its reinforcing effects with known stimulant drugs of abuse in nonhuman primates. Adult rhesus macaques (N = 4) responded for intravenous injections of cocaine, d-MA, methcathinone (MCAT), or l-MA under a fixed-ratio (FR) schedule of reinforcement; reinforcing effectiveness was evaluated using behavioral economic demand procedures. In a separate cohort (N = 9), daily activity and food-reinforced responding were assessed during 100 days of treatment with daily dosages of l-MA (2.3 mg/kg per day, i.v.) or d-MA (0.74 mg/kg per day, i.v.) previously shown to decrease cocaine self-administration. Results show that all drugs maintained self-administration, with peak injections reaching ∼100 inj per session for cocaine, MCAT, and d-MA and ∼50 inj per session for l-MA . In demand studies, self-administration of each drug gradually decreased as FR size increased. The exponential model of demand indicated that the reinforcing effectiveness of l-MA was significantly less than the other drugs studied. Chronic l-MA treatment did not appreciably alter daily activity and only transiently suppressed food-reinforced responding. These data, coupled with previous findings that l-MA effectively reduces stimulant self-administration, suggest that l-MA, or other norepinephrine-preferring releasers, may serve as agonist medication for CUD with lesser abuse liability than common psychostimulants.
SIGNIFICANCE STATEMENT
Development of pharmacotherapies for cocaine use disorder remains a formidable challenge. Agonist-based therapies show promise, but enthusiasm is tempered by the abuse liability of previously proposed medications. This study evaluated the abuse liability and chronic treatment effects of methamphetamine's levorotatory isomer (l-MA). l-MA demonstrated lower abuse liability compared with commonly abused stimulants and produced few untoward effects. In the context of recent studies demonstrating that l-MA attenuates stimulant self-administration, these findings support l-MA's potential as a pharmacotherapy for stimulant addiction.Methamphetamine
Stimulant
Cite
Citations (0)
Abstract A new generation of novel cathinone compounds has been developed as stimulant substitutes to avoid drug control laws and detection of use by blood tests. Dipentylone, N ‐ethylhexedrone, 4‐chloroethcathinone (4‐CEC), and 4′‐methyl‐α‐pyrrolidinohexiophenone (MPHP) were tested for in vivo psychostimulant‐like effects to assess their abuse liability. Locomotor activity was assessed in an open‐field assay using Swiss–Webster mice to screen for locomotor stimulant effects and to identify behaviorally‐active dose ranges, times of peak effect, and durations of action. Discriminative stimulus effects were assessed in separate groups of Sprague–Dawley rats trained to discriminate cocaine or methamphetamine from vehicle. Dipentylone, N ‐ethylhexedrone, 4‐CEC, and MPHP dose‐dependently increased locomotor activity. Dipentylone, N ‐ethylhexedrone, and MPHP produced maximal stimulant effects similar to cocaine and methamphetamine. 4‐CEC was less efficacious, producing peak stimulant effects of about 74% of that of methamphetamine. The compounds were less potent than methamphetamine and approximately equipotent with cocaine. The doses of cocaine, methamphetamine, dipentylone, and 4‐CEC that produced peak effects lasted 2 to 3 h, the peak dose of N ‐ethylhexedrone lasted 4 h, and the peak dose of MPHP lasted 6 h. All four compounds fully substituted for the discriminative stimulus effects of methamphetamine and cocaine, although full substitution by 4‐CEC occurred at doses that substantially decreased response rate. Only 4‐CEC fully substituted for MDMA. These data provide evidence that the novel cathinone compounds dipentylone, N ‐ethylhexedrone, 4‐CEC, and MPHP demonstrate potential for abuse as psychostimulants, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of methamphetamine and cocaine.
Stimulant
Methamphetamine
Cathinone
Locomotor activity
MDMA
Dextroamphetamine
Cite
Citations (21)
Neurochemical
Microdialysis
Cite
Citations (0)
The interpretation of neurochemical studies of attention deficit disorder (ADD) with hyperactivity is complicated by the variability in diagnosis and by the limitations of single neurochemical measures--whose levels may be compensated by chronic feedback mechanisms. This article reviews previous neurochemical studies of ADD and proposes the use of single-dose neurochemical probes. Administration of a provocative agent with subsequent sequential measures of plasma levels of neurotransmitters, their metabolites, and hormones may help define the responsivity of neurochemical systems. Blood levels of drugs and neurotransmitters following single doses of methylphenidate and clonidine are studied as a strategy to explore the responsivity of dopaminergic and noradrenergic mechanisms in ADD.
Neurochemical
Neurochemistry
Cite
Citations (22)