Mesolimbic Reward Circuit Research Articles

GLP-1 analog attenuates cocaine reward

GLP-1 analog attenuates cocaine reward

Association of V89L SRD5A2 polymorphism with craving and serum leptin levels in male alcohol addicts

A causal role of sex hormones in the onset and course of alcohol dependence is well established. We recently demonstrated that the genetics of the androgen receptor and aromatase relate to craving in alcohol addicts during withdrawal. This relationship involves the modulation of leptin, which affects the mesolimbic dopamine reward circuit. The steroid 5-α reductase 2 (SRD5A2) converts testosterone to dihydrotestosterone and thereby causes increased androgenic potency. In this study, we explored whether functionally relevant genetic polymorphisms in SRD5A2 (V89L, A49T, [TA](n)) are linked to alcohol addiction and craving. We investigated 118 male alcohol-addicted inpatients admitted for withdrawal treatment and compared them to 50 healthy age- and body mass index-matched controls. The two groups did not differ in their allelic distributions. Subsequent analyses revealed an association between the V89L genotype and alcohol craving within the patient group (p < 0.05). Leptin accounted for 55 % of this relationship. Compared to VL and VV carriers, LL carriers had reduced serum leptin levels (p < 0.05) and lower levels of craving (p < 0.01). Furthermore, we observed an interaction between the V89L and the TTTAn aromatase polymorphisms (p < 0.05). No effects were found for A49T or (TA)(n). These findings further support a crucial role of sex hormone biosynthetic genes and signaling in alcohol withdrawal. Craving is an accepted risk factor for alcohol relapse. Hence, these results might be helpful in predicting the outcomes of alcohol addicts after detoxification. With SRD5A2 inhibitors already in clinical use worldwide, this study may also guide future preventive and therapeutic strategies.

Anhedonia and Reward System: Psychobiology, Evaluation, and Clinical Features

Anhedonia can be defined as a condition in which the hedonic capacity is totally or partially lost. From a psychobiological perspective, several researchers proposed that anhedonia has a putative neural substrate, the dopaminergic mesolimbic and mesocortical reward circuit, which involves the ventral tegmental area, the ventral striatum and part of the prefrontal cortex. Anhedonia is, besides depressed mood, one of the two core symptoms of depression; furthermore it is one of the most important negative symptom in schizophrenia. Anhedonia is also present in substance use disorders as part of the abstinence symptomatology, and interrelations between hedonic capability, craving and protracted withdrawal have been found, particularly in opiate-dependent subjects. Although anhedonia is regarded as an important symptom in psychopathology, so far it has received relatively little attention. In general, two main approaches have been utilized to investigate and assess anhedonia or hedonic capacity: laboratory-based measures and questionnaires. Among measurement scales, the most commonly used are the Snaith-Hamilton Pleasure Scale (SHAPS), the Fawcett-Clark Pleasure Scale (FCPS), and the Revised Chapman Physical Anhedonia Scale (CPAS). Nevertheless, other measurement scales, particularly used within broader psychopathological dimensions, are the Anhedonia-Asociality subscale (SANSanh) of the Scale for the Assessment of Negative Symptoms (SANS) and the Bech-Rafaelsen Melancholia Scale (BRMS). In this paper we analyze these different scales, individuating their strengths and limits and their current clinical applications.

Protein Kinase Mζ Is Necessary for Cocaine-Induced Synaptic Potentiation in the Ventral Tegmental Area

Much progress has been made in our understanding of brain regions and specific receptors that are involved in the action of cocaine addiction. Although long-term modifications of mesolimbic reward circuit following cocaine exposure are responsible for cocaine-addicted behaviors, the underlying molecular mechanism at the cellular level is still obscure. Here, we investigated the possible participation of protein kinase Mζ (PKMζ) in synaptic potentiation following cocaine exposure. Spontaneous and evoked synaptic activity of glutamate synapse in saline- and cocaine-treated rats were examined by preparing acute brain slices and performing whole-cell voltage-clamp recordings from individual dopamine neurons in the ventral tegmental area (VTA). We also assessed the role of PKMζ on the behavioral responses by cocaine conditioned place preference. Chelerythrine, an inhibitor of PKMζ, reversed the cocaine-induced facilitation of spontaneous synaptic transmission in the VTA. PKMζ inhibition by chelerythrine or myristoylated ζ inhibitory peptide significantly attenuated the cocaine exposure-induced enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor ratio. Myristoylated ζ inhibitory peptide had no effect on spike timing-dependent long-term potentiation in rats previously injected with saline but remarkably restored spike timing-dependent long-term potentiation in VTA dopamine neurons in slices prepared from rats that received single or multiple cocaine exposure. Western blot analyses showed that both single and five consecutive cocaine injections induced a significant increase in PKMζ level. Furthermore, intracranial infusion of myristoylated ζ inhibitory peptide in the VTA disrupted cocaine conditioned place preference. Our results suggest that persistent activity of PKMζ is a requisite for cocaine-induced enhancement of synaptic plasticity in the VTA and cocaine conditioned place preference.

P02-330 - Food-cue evoked activation of reward pathways is modulated by the satiety factor leptin: An fMRI study in obese and normal weight subjects

IntroductionMechanisms contributing to the development and maintenance of obesity remain to be elucidated especially regarding the interaction between appetite regulating hormones and mesolimbic reward circuits. Leptin was recently suggested to attenuate dopamine release in mesolimbic reward pathways. We now test the functional relevance assessing whether leptin plasma concentration affects the BOLD-response following the presentation of food cues.Methods21 obese and 23 normal weight subjects were investigated. Visual food cues and neutral stimuli were presented in a block design during fMRI. Blood-samples were collected immediately prior to the scan to assess plasma leptin concentration. Using linear regression analyses, the association between BOLD response to food cues and the body mass index (BMI) as well as plasma leptin concentration was examined.ResultsFood-cues elicited activation of large cortical and subcortical networks, whereas only in obese patients food cues activated the left ventral and right dorsal striatum. Mean plasma concentration of leptin was significantly increased in obese subjects compared to normal weight controls. We found a significant positive correlation between the food cue-induced BOLD signal change in the ventral striatum and leptin plasma concentration. Furthermore, ventral and dorsal striatum BOLD response to food cues was significantly positive associated with the body mass index (BMI).ConclusionsThese findings suggest a physiological role of the satiety factor leptin in modulating responsivity of reward pathways towards food cues. Altered homeostatic feedback regulation of the mesolimbic brain reward circuit might explain the inability of obese patients to adapt their food intake according to physiologically needs.

Anhedonia and Substance Dependence: Clinical Correlates and Treatment Options

Anhedonia is a condition in which the capacity of experiencing pleasure is totally or partially lost, and it refers to both a state symptom in various psychiatric disorders and a personality trait. It has a putative neural substrate, originating in the dopaminergic mesolimbic and mesocortical reward circuit. Anhedonia frequently occurs in mood disorders, as a negative symptom in schizophrenia, and in substance use disorders. In particular, we focus our attention on the relationships occurring between anhedonia and substance use disorders, as highlighted by many studies. Several authors suggested that anhedonia is an important factor involved in relapse as well as in the transition from recreational use to excessive drug intake. In particular, anhedonia has been found to be a frequent feature in alcoholics and addicted patients during acute and chronic withdrawal as well as in cocaine, stimulant, and cannabis abusers. Furthermore, in subjects with a substance dependence disorder, there is a significant correlation between anhedonia, craving, intensity of withdrawal symptoms, and psychosocial and personality characteristics. Therefore treating anhedonia in detoxified alcohol-dependent subjects could be critical in terms of relapse prevention strategies, given its strong relationship with craving.

Smoking-Related Cue-Induced Brain Activation in Adolescent Light Smokers

To examine using functional magnetic resonance imaging whether adolescents with low levels of nicotine exposure (light smokers) display neural activation in areas shown to be involved with addiction in response to smoking-related stimuli. A total of 12 adolescent light smokers (aged 13-17, who smoked 1-5 cigarettes per day) and 12 nonsmokers (ages 13-17, never smoked a cigarette) from the San Francisco Bay Area underwent functional magnetic resonance imaging scanning. During scanning, the adolescents were shown photographic blocks of smoking and control cues. Smoking cues comprised pictures of individuals smoking cigarettes and smoking-related objects such as lighters and ashtrays. Neutral cues comprised images of everyday objects and individuals engaged in daily activities. For smokers, smoking cues elicited greater activation than neutral cues in the mesolimbic reward circuit (left anterior cingulate: t = 7.04, p < .001; right hippocampus: t = 6.37, p < .001). We found activation from smoking cues versus neutral cues within both the left and right frontal medial orbital regions (t = 5.09, p < .001 and t = 3.94, p = .001, respectively). Nonsmokers showed no significant difference in activation between smoking-related cues and neutral cues. Our finding that smoking cues produced activation in adolescent light smokers in brain regions, similar to that seen in adult and teenage heavy smokers, suggests that adolescents exhibit heightened reactivity to smoking cues even at low levels of smoking. This article adds to the existing published data by suggesting that nicotine dependence may begin with exposure to low levels of nicotine, thus underscoring the need for early intervention among adolescent smokers.

Attenuation of cue-induced smoking urges and brain reward activity in smokers treated successfully with bupropion

Twenty-two regular smokers (15+ cigarettes per day) were treated with bupropion and group therapy for 2 months. Subjects underwent positron emission tomography (PET) studies using measures of brain global and regional glucose metabolism (regional cerebral metabolic rates of glucose [rCMRglc]) with [18F]-Fluorodeoxyglucose (FDG) twice, after watching a videotape showing smoking scenes and after watching a control movie in counter-balanced order. A questionnaire of smoking urges (QSU) was filled in before and after watching both the movies. Changes in brain metabolic rates of FDG were analysed using Statistical Parametric Maps (SPM 2) in 11 smokers who abstained from smoking in comparison with 11 smokers who continued to smoke during the second month of treatment. Still-smokers had higher craving scores after watching the videotape showing smoking scenes compared with non-smokers. Second, watching the videotape showing smoking scenes compared with the control videotape in still-smokers resulted in increased metabolic rates in the striatum, thalamus and midbrain. Third, the ratings of the urge to smoke cigarettes while watching the videotape showing smoking scenes in still-smokers were associated with brain metabolic activity in the ventral striatum, anterior cingulate, orbitofrontal cortex, middle temporal lobe, hippocampus, insula, midbrain and thalamus. In conclusion, successfully treated smokers showed attenuated craving and reduced activity in the mesolimbic reward circuit.

The circadian clock and mood-related behavior

Over many years evidence accumulated that circadian rhythms are related to psychiatric disorders.1-3 However, a mechanistic relationship between the circadian clock and mood related behaviors remained enigmatic. Now, we have reported that monoamine oxidase A (MAOA), a mitochondrial enzyme degrading catecholamines including dopamine, is regulated by components of the circadian clock .4 Interestingly, this regulation is variable depending on cell type, indicating the presence of cell type specific factors modulating BMAL1/NPAS2 or BMAL1/CLOCK dependent transcription. In the mesolimbic dopaminergic reward circuit, including the ventral tegmental area (VTA) and the ventral striatum/nucleus accumbens (NAc) we found a positive influence of Period 2 (PER2) on transcriptional activation of Maoa using mice mutant in the Per2 gene. These animals show less Maoa mRNA expression and MAO activity compared to wild type littermates. This is probably the reason for the observed increase in dopamine levels in the striatum of Per2 mutant mice what leads to alteration in despair-based behavioral tests. These results suggest that clock components can influence dopamine metabolism and mood-related behaviors.Addendum to:Hampp G, Ripperger JA, Houben T, Schmutz I, Blex C, Perreau-Lenz S, Brunk I, Spanagel R, Ahnert-Hilger G, Meijer JH, Albrecht U. Regulation of monoamine oxidase a by circadian-clock components implies clock influence on mood. Curr Biol 2008;18:678-83.

Regulation of Monoamine Oxidase A by Circadian-Clock Components Implies Clock Influence on Mood

The circadian clock has been implicated in addiction and several forms of depression [1, 2], indicating interactions between the circadian and the reward systems in the brain [3-5]. Rewards such as food, sex, and drugs influence this system in part by modulating dopamine neurotransmission in the mesolimbic dopamine reward circuit, including the ventral tegmental area (VTA) and the ventral striatum (NAc). Hence, changes in dopamine levels in these brain areas are proposed to influence mood in humans and mice [6-10]. To establish a molecular link between the circadian-clock mechanism and dopamine metabolism, we analyzed the murine promoters of genes encoding key enzymes important in dopamine metabolism. We find that transcription of the monoamine oxidase A (Maoa) promoter is regulated by the clock components BMAL1, NPAS2, and PER2. A mutation in the clock gene Per2 in mice leads to reduced expression and activity of MAOA in the mesolimbic dopaminergic system. Furthermore, we observe increased levels of dopamine and altered neuronal activity in the striatum, and these results probably lead to behavioral alterations observed in Per2 mutant mice in despair-based tests. These findings suggest a role of circadian-clock components in dopamine metabolism highlighting a role of the clock in regulating mood-related behaviors.

Increased Ethanol Resistance and Consumption in Eps8 Knockout Mice Correlates with Altered Actin Dynamics

Dynamic modulation of the actin cytoskeleton is critical for synaptic plasticity, abnormalities of which are thought to contribute to mental illness and addiction. Here we report that mice lacking Eps8, a regulator of actin dynamics, are resistant to some acute intoxicating effects of ethanol and show increased ethanol consumption. In the brain, the N-methyl-D-aspartate (NMDA) receptor is a major target of ethanol. We show that Eps8 is localized to postsynaptic structures and is part of the NMDA receptor complex. Moreover, in Eps8 null mice, NMDA receptor currents and their sensitivity to inhibition by ethanol are abnormal. In addition, Eps8 null neurons are resistant to the actin-remodeling activities of NMDA and ethanol. We propose that proper regulation of the actin cytoskeleton is a key determinant of cellular and behavioral responses to ethanol.

Involvement of the endogenous cannabinoid system in the effects of alcohol in the mesolimbic reward circuit: electrophysiological evidence in vivo

Several lines of evidence indicate that the endogenous cannabinoid system is involved in the pharmacological and behavioural effects of alcohol. The mesolimbic dopaminergic (DA) system and the nucleus accumbens (NAc) process rewarding properties of drugs of abuse, including alcohol and cannabinoids, whereas endocannabinoids in these regions modulate synaptic function and mediate short- and long-term forms of synaptic plasticity. The present study was designed to investigate the contribution of the endogenous cannabinoid system in alcohol electrophysiological effects in the mesolimbic reward circuit. We utilized extracellular single cell recordings from ventral tegmental area (VTA) DA and NAc neurons in anesthetized rats. DA neurons were antidromically identified as projecting to the shell of NAc, whereas NAc putative medium spiny neurons were identified by their evoked responses to basolateral amygdala (BLA) stimulation. Alcohol stimulated firing rate of VTA DA neurons and inhibited BLA-evoked NAc neuron spiking responses. The cannabinoid type-1 receptor (CB1) antagonist rimonabant (SR141716A) fully antagonized alcohol effect in both regions. In the NAc, either inhibition of the major catabolic enzyme of the endocannabinoid anandamide, the fatty-acid amyd hydrolase, with URB597 or a pretreatment with the CB1 receptor agonist WIN55212-2 significantly depressed alcohol-induced effects in the NAc. These results corroborate the notion of the involvement of endocannabinoids and their receptors in the actions of alcohol and highlight the endocannabinoid system as a valuable target in the therapy for alcoholism.

Telling good from bad news: ADHD differentially affects processing of positive and negative feedback during guessing

Neuroimaging studies on ADHD suggest abnormalities in brain regions associated with decision-making and reward processing such as the anterior cingulate cortex (ACC) and orbitofrontal cortex. Recently, event-related potential (ERP) studies demonstrated that the ACC is involved in processing feedback signals during guessing and gambling. The resulting negative deflection, the ‘feedback-related negativity’ (FRN) has been interpreted as reflecting an error in reward prediction. In the present study, ERPs elicited by positive and negative feedback were recorded in children with ADHD and normal controls during guessing. ‘Correct’ and ‘incorrect’ guesses resulted in respectively monetary gains and losses. The FRN amplitude to losses was more pronounced in the ADHD group than in normal controls. Positive and negative feedback differentially affected long latency components in the ERP waveforms of normal controls, but not ADHD children. These later deflections might be related to further emotional or strategic processing. The present findings suggest an enhanced sensitivity to unfavourable outcomes in children with ADHD, probably due to abnormalities in mesolimbic reward circuits. In addition, further processing, such as affective evaluation and the assessment of future consequences of the feedback signal seems to be altered in ADHD. These results may further help understanding the neural basis of decision-making deficits in ADHD.

Persistent Antagonism of Methamphetamine-Induced Dopamine Release in Rats Pretreated with GBR12909 Decanoate

Methamphetamine abuse is a serious global health problem, and no effective treatments for methamphetamine dependence have been developed. In animals, the addictive properties of methamphetamine are mediated via release of dopamine (DA) from nerve terminals in mesolimbic reward circuits. At the molecular level, methamphetamine promotes DA release by a nonexocytotic diffusion-exchange process involving DA transporter (DAT) proteins. We have shown that blocking DAT activity with high-affinity DA uptake inhibitors, such as 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl) piperazine (GBR12909), can substantially reduce amphetamine-induced DA release in vivo. In the present study, we examined the ability of a long-acting depot formulation of GBR12909 decanoate (GBR-decanoate) to influence neurochemical actions of methamphetamine in the nucleus accumbens of rats. Rats received single injections of GBR-decanoate (480 mg/kg i.m.) and were subjected to in vivo microdialysis testing 1 and 2 weeks later. Pretreatment with GBR-decanoate produced modest elevations in basal extracellular levels of DA, but not 5-hydroxytryptamine (5-HT), at both time points. GBR-decanoate nearly eliminated the DA-releasing ability of methamphetamine (0.3 and 1.0 mg/kg i.v.) for 2 weeks, whereas methamphetamine-induced 5-HT release was unaffected. Autoradiographic analysis revealed that GBR-decanoate caused long-term decreases in DAT binding in the brain. Our data suggest that GBR-decanoate, or similar agents, may be useful adjuncts in treating methamphetamine dependence. This therapeutic strategy would be especially useful for noncompliant patient populations.

Pain-Induced Analgesia Mediated by Mesolimbic Reward Circuits

We tested the hypothesis that noxious stimuli induce pain modulation by activation of supraspinal structures. We found that intense noxious stimuli (i.e., subdermal injection of capsaicin or paw immersion in hot water) induced profound attenuation of the jaw-opening reflex in the anesthetized rat; forepaw subdermal capsaicin also elevated the mechanical hindpaw-withdrawal threshold in the awake rat. These antinociceptive effects were blocked by previous injection of either a dopamine antagonist (flupentixol) or an opioid antagonist (naloxone) into the nucleus accumbens. Additional experiments in anesthetized animals showed that the antinociceptive effect of noxious stimulation by either capsaicin (>/=100 micrograms) or hindpaw immersion in hot water (>/=45 degrees C for 4 min) correlated with the intensity of the stimulus. The maximal antinociceptive effect of capsaicin was similar in magnitude to that of a high dose of morphine (10 mg/kg) injected subcutaneously. Injection of the GABA(A)-receptor agonist muscimol, but not naloxone, into the rostroventral medulla, a major component of descending pain modulation systems, blocked capsaicin-induced antinociception. Although it is widely thought that painful stimuli may induce analgesia by activating forebrain structures, this is the first demonstration that such a mechanism exists. Furthermore, this mechanism can be engaged by naturalistic stimuli in awake animals. These observations imply that painful stimuli might under certain conditions be rewarding.