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Mesolimbic Dopamine System (mesolimbic + dopamine_system)
Selected AbstractsPRECLINICAL STUDY: FULL ARTICLE: Altered architecture and functional consequences of the mesolimbic dopamine system in cannabis dependenceADDICTION BIOLOGY, Issue 3 2010Saturnino Spiga ABSTRACT Cannabinoid withdrawal produces a hypofunction of mesencephalic dopamine neurons that impinge upon medium spiny neurons (MSN) of the forebrain. After chronic treatment with two structurally different cannabinoid agonists, ,9 -tetrahydrocannabinol and CP55 940 (CP) rats were withdrawn spontaneously and pharmacologically with the CB1 antagonist SR141716A (SR). In these two conditions, evaluation of tyrosine hydroxylase (TH)-positive neurons revealed significant morphometrical reductions in the ventrotegmental area but not substantia nigra pars compacta of withdrawn rats. Similarly, confocal analysis of Golgi,Cox-stained sections of the nucleus accumbens revealed a decrease in the shell, but not the core, of the spines' density of withdrawn rats. Administration of the CB1 antagonist SR to control rats, provoked structural abnormalities reminiscent of those observed in withdrawal conditions and support the regulatory role of cannabinoids in neurogenesis, axonal growth and synaptogenesis by acting as eu-proliferative signals through the CB1 receptors. Further, these measures were incorporated into a realistic computational model that predicts a strong reduction in the excitability of morphologically altered MSN, yielding a significant reduction in action potential output. These pieces of evidence support the tenet that withdrawal from addictive compounds alters functioning of the mesolimbic system and provide direct morphological evidence for functional abnormalities associated with cannabinoid dependence at the level of dopaminergic neurons and their postsynaptic counterpart and are coherent with recent hypothesis underscoring a hypodopaminergic state as a distinctive feature of the ,addicted brain'. [source] PRECLINICAL STUDY: Proteomic analysis of methamphetamine-induced reinforcement processes within the mesolimbic dopamine systemADDICTION BIOLOGY, Issue 3-4 2008Moon Hee Yang ABSTRACT Methamphetamine (MAP) is a commonly used, addictive drug, and a powerful stimulant that dramatically affects the central nervous system. In this study, we used the conditioned place preference (CPP) paradigm in order to study the reinforcing properties of MAP and the herewith associated changes in proteins within the mesolimbic dopamine system. A CPP was induced by MAP after three intermittent intraperitoneal injections (1 mg/kg) in rats and protein profiles in the nucleus accumbens, striatum, prefrontal cortex, cingulate cortex and hippocampus were compared with a saline-treated control group. In addition, a group of animals was run through extinction and protein profiles were compared with a non-extinguished group. Protein screening was conducted using two-dimensional electrophoresis analysis which identified 27 proteins in the group that showed MAP-induced CPP. Some of the proteins were confirmed by Western lot analysis. Identified proteins had functions related to the cytoskeleton, transport/endocytosis or exocytosis (e.g. profilin-2 and syntaxin-binding protein), and signal transduction, among others. [source] PRECLINICAL STUDY: Morphine withdrawal decreases responding reinforced by sucrose self-administration in progressive ratioADDICTION BIOLOGY, Issue 2 2007Dengke Zhang ABSTRACT Previous studies have shown that withdrawal from psychostimulant drugs such as d -amphetamine or methamphetamine decreases motivation to work for a natural reinforcement, which is thought to be associated with the withdrawal-induced depressive state and hypofunction of the mesolimbic dopamine system. However, to our knowledge, studies exploring the effect of morphine withdrawal on motivation for a natural reinforcement are lacking. The purpose of the present study was to examine whether motivation to work for a natural reinforcement changes during morphine withdrawal. Three groups of male Sprague,Dawley rats were trained to respond on a nose poke for a 4% sucrose solution under a progressive ratio schedule and were subsequently administered a 10-day regimen of injection of high or low dose of morphine or saline. Their duration of break point and withdrawal symptoms were assessed. The finding showed that break points were significantly reduced on day 1 and persisted to at least day 10 of withdrawal without change in locomotor activity. There were hardly any differences bear mentioning when comparing the magnitude of the decrease between the high- and the low-dose group, whereas the withdrawal scales were significant greater in the high-dose group than in the low-dose group. The results suggest that the morphine withdrawal resulted in decreased motivation to obtain the natural reinforcement. The progressive ratio procedure may be a useful technique for evaluation of changes in motivation for natural reinforcing stimuli following withdrawal from opiates. [source] PRECLINICAL STUDY: Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbensADDICTION BIOLOGY, Issue 1 2007Elisabet Jerlhag ABSTRACT Ghrelin stimulates appetite, increases food intake and causes adiposity by mechanisms that include direct actions on the brain. Previously, we showed that intracerebroventricular administration of ghrelin has stimulatory and dopamine-enhancing properties. These effects of ghrelin are mediated via central nicotine receptors, suggesting that ghrelin can activate the acetylcholine,dopamine reward link. This reward link consists of cholinergic input from the laterodorsal tegmental area (LDTg) to the mesolimbic dopamine system that originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens. Given that growth hormone secretagogue receptors (GHSR-1A) are expressed in the VTA and LDTg, brain areas involved in reward, the present series of experiments were undertaken to examine the hypothesis that these regions may mediate the stimulatory and dopamine-enhancing effects of ghrelin, by means of locomotor activity and in vivo microdialysis in freely moving mice. We found that local administration of ghrelin into the VTA (1 µg in 1 µl) induced an increase in locomotor activity and in the extracellular concentration of accumbal dopamine. In addition, local administration of ghrelin into the LDTg (1 µg in 1 µl) caused a locomotor stimulation and an increase in the extracellular levels of accumbal dopamine. Taken together, this indicates that ghrelin might, via activation of GHSR-1A in the VTA and LDTg, stimulate the acetylcholine,dopamine reward link, implicating that ghrelin is a part of the neurochemical overlap between the reward systems and those that regulate energy balance. [source] The acute anti-craving effect of acamprosate in alcohol-preferring rats is associated with modulation of the mesolimbic dopamine systemADDICTION BIOLOGY, Issue 3 2005Michael Cowen Acamprosate (Campral ?) is a drug used clinically for the treatment of alcoholism. In order to examine further the time-course and mechanism of action of acamprosate, the effect of acute and repeated acamprosate administration was examined on (i) operant ethanol self-administration and (ii) voluntary home cage ethanol consumption by alcohol-preferring Fawn-Hooded, iP and Alko Alcohol (AA) rats. Acutely, acamprosate was shown to cause a significant decrease in operant ethanol self-administration by Fawn-Hooded and alcohol-preferring iP rats in part by decreasing the motivational relevance of a specific ethanol cue; however, repeated injection of acamprosate led to tolerance to this effect. Voluntary alcohol consumption in the home cage in Fawn-Hooded and AA rats was also reduced by an acute acamprosate injection; however, again tolerance developed to repeated injections. In a separate experiment, the effect of acamprosate on markers of the dopaminergic system was examined. Interestingly, acute acamprosate was also shown to cause increased dopamine transporter density and decreased dopamine D2-like receptor density within the nucleus accumbens but not in the caudate-putamen, suggesting a link between the decreased motivational salience of the ethanol cue and altered dopaminergic signalling within the nucleus accumbens. With repeated injections of acamprosate, markers of the dopaminergic system returned to steady state levels with a similar temporal profile to the development of tolerance in the behavioural studies. Along with previous studies, our findings indicate that acamprosate modulates the mesolimbic dopaminergic system and may thereby decrease ethanol reinforcement processes; however, these effects undergo tolerance in alcohol-preferring rats and may in part explain the fact why some subjects are non-responders to chronic acamprosate treatment. [source] Effects of nicotine in the dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptorsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2003L. M. Marubio Abstract The mesostriatal dopaminergic system influences locomotor activity and the reinforcing properties of many drugs of abuse including nicotine. Here we investigate the role of the ,4 nicotinic acetylcholine receptor (nAChR) subunit in mediating the effects of nicotine in the mesolimbic dopamine system in mice lacking the ,4 subunit. We show that there are two distinct populations of receptors in the substantia nigra and striatum by using autoradiographic labelling with 125I ,-conotoxin MII. These receptors are comprised of the ,4, ,2 and ,6 nAChR subunits and non-,4, ,2, and ,6 nAChR subunits. Non-,4 subunit-containing nAChRs are located on dopaminergic neurons, are functional and respond to nicotine as demonstrated by patch clamp recordings. In vivo microdialysis performed in awake, freely moving mice reveal that mutant mice have basal striatal dopamine levels which are twice as high as those observed in wild-type mice. Despite the fact that both wild-type and ,4 null mutant mice show a similar increase in dopamine release in response to intrastriatal KCl perfusion, a nicotine-elicited increase in dopamine levels is not observed in mutant mice. Locomotor activity experiments show that there is no difference between wild-type and mutant mice in basal activity in both habituated and non-habituated environments. Interestingly, mutant mice sustain an increase in cocaine-elicited locomotor activity longer than wild-type mice. In addition, mutant mice recover from depressant locomotor activity in response to nicotine at a faster rate. Our results indicate that ,4-containing nAChRs exert a tonic control on striatal basal dopamine release, which is mediated by a heterogeneous population of nAChRs. [source] Glycine Receptors in the Nucleus Accumbens Involved in the Ethanol Intake-Reducing Effect of AcamprosateALCOHOLISM, Issue 1 2010PeiPei Chau Background:, We have previously demonstrated that strychnine-sensitive glycine receptors (GlyRs) in the nucleus accumbens (nAc) and nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area are involved in mediating ethanol (EtOH)-induced elevation of dopamine in the rat mesolimbic dopamine system. This neuronal circuitry was also demonstrated to mediate dopamine elevation in the nAc after both taurine, an endogenous agonist of GlyRs, and acamprosate, a synthetic derivate of homotaurine. The aim of this study was to investigate whether the EtOH intake-reducing effect of acamprosate involves accumbal GlyRs. Methods:, For this purpose, we used a voluntary EtOH consumption model where EtOH medium- and high-preferring rats were implanted with guide cannulae in the nAc. The animals received daily injections of acamprosate or 0.9% NaCl before accessing a bottle of 6% EtOH and a bottle of water. After 2 days, a microinjection of strychnine or vehicle preceded the daily systemic injection and bottle-access period. Results:, Acamprosate, but not saline, decreased EtOH intake. Pretreatment with Ringer in the nAc did not influence EtOH intake in saline or acamprosate-treated animals. Pretreatment with strychnine had no effect on EtOH intake in saline-treated animals, whereas it completely reversed the EtOH intake-reducing effect of acamprosate. Conclusions:, Based on current and previous results, we suggest that acamprosate primarily interacts with accumbal GlyRs and secondarily with ventral tegmental nAChRs, in a similar manner to that previously observed with EtOH and taurine. The interaction between acamprosate and GlyRs does not only influence dopamine output in the nAc but also EtOH consumption, giving further support for our hypothesis that GlyRs are of importance in EtOH reinforcement. [source] | ||||||||||