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1.  A Sustained Depressive State Promotes a Guanfacine Reversible Susceptibility to Alcohol Seeking in Rats 
Neuropsychopharmacology  2013;39(5):1115-1124.
High rates of comorbidity between alcohol use disorder (AUD) and major depressive disorder (MDD) are reported. Preclinical models examining effects of primary depression on secondary AUD are currently absent, preventing adequate testing of drug treatment. Here, we combined social defeat-induced persistent stress (SDPS) and operant alcohol self-administration (SA) paradigms to assess causality between these two neuropsychiatric disorders. We then exploited guanfacine, an FDA-approved adrenergic agent reported to reduce drug craving in humans, against SDPS-induced modulation of operant alcohol SA. Wistar rats were socially defeated and isolated for a period of ⩾9 weeks, during which depression-like symptomatology (cognitive and social behavioral symptoms) was assessed. Subsequently, animals were subjected to a 5-month operant alcohol SA paradigm, examining acquisition, motivation, extinction, and cue-induced reinstatement of alcohol seeking. The effects of guanfacine on motivation and relapse were measured at >6 months following defeat. SDPS rats exhibited significant disruption of social and cognitive behavior, including short-term spatial and long-term social memory, several months following defeat. Notably, SDPS increased motivation to obtain alcohol, and cue-induced relapse vulnerability. Guanfacine reversed the SDPS-induced effects on motivation and relapse. Together, our model mimics core symptomatology of a sustained depressive-like state and a subsequent vulnerability to alcohol abuse. We show that SDPS is strongly associated with an enhanced motivation for alcohol intake and relapse. Finally, we show that the clinically employed drug guanfacine has potential as a novel treatment option in comorbid patients, as it effectively reduced the enhanced sensitivity to alcohol and alcohol-associated stimuli.
PMCID: PMC3957105  PMID: 24192553
Addiction & Substance Abuse; alcohol use disorder; Animal models; Comorbidity; cue-induced reinstatement; Depression; Unipolar/Bipolar; motivation; Psychopharmacology; social defeat-induced persistent stress; comorbidity; alcohol use disorder; prolonged social defeat stress; motivation; cue-induced reinstatement; adrenergic agonist
2.  Glutamate Mechanisms Underlying Opiate Memories 
As the major excitatory neurotransmitter in the brain, glutamate plays an undisputable integral role in opiate addiction. This relates, in part, to the fact that addiction is a disorder of learning and memory, and glutamate is required for most types of memory formation. As opiate addiction develops, the addict becomes conditioned to engage in addictive behaviors, and these behaviors can be triggered by opiate-associated cues during abstinence, resulting in relapse. Some medications for opiate addiction exert their therapeutic effects at glutamate receptors, especially the NMDA receptor. Understanding the neural circuits controlling opiate addiction, and the locus of glutamate’s actions within these circuits, will help guide the development of targeted pharmacotherapeutics for relapse.
Opiate drugs exert their primary addictive effects on the μ opioid receptor. But glutamate receptors (e.g., NMDA), which are involved in most types of memory formation, are also critical for opiate reward.
PMCID: PMC3426813  PMID: 22951449
3.  Characterization of the Effects of Reuptake and Hydrolysis Inhibition on Interstitial Endocannabinoid Levels in the Brain: An in Vivo Microdialysis Study 
ACS Chemical Neuroscience  2012;3(5):407-417.
The present experiments employed in vivo microdialysis to characterize the effects of commonly used endocannabinoid clearance inhibitors on basal and depolarization-induced alterations in interstitial endocannabinoid levels in the nucleus accumbens of rat brain. Compounds targeting the putative endocannabinoid transporter and hydrolytic enzymes (FAAH and MAGL) were compared. The transporter inhibitor AM404 modestly enhanced depolarization-induced increases in 2-arachidonoyl glycerol (2-AG) levels but did not alter levels of N-arachidonoyl-ethanolamide (anandamide, AEA). The transport inhibitor UCM707 did not alter dialysate levels of either endocannabinoid. The FAAH inhibitors URB597 and PF-3845 robustly increased AEA levels during depolarization without altering 2-AG levels. The MAGL inhibitor URB602 significantly enhanced depolarization-induced increases in 2-AG, but did not alter AEA levels. In contrast, the MAGL inhibitor JZL184 did not alter 2-AG or AEA levels under any condition tested. Finally, the dual FAAH/MAGL inhibitor JZL195 significantly enhanced depolarization-induced increases in both AEA and 2-AG levels. In contrast to the present observations in rats, prior work in mice has demonstrated a robust JZL184-induced enhancement of depolarization-induced increases in dialysate 2-AG. Thus, to further investigate species differences, additional tests with JZL184, PF-3845, and JZL195 were performed in mice. Consistent with prior reports, JZL184 significantly enhanced depolarization-induced increases in 2-AG without altering AEA levels. PF-3845 and JZL195 produced profiles in mouse dialysates comparable to those observed in rats. These findings confirm that interstitial endocannabinoid levels in the brain can be selectively manipulated by endocannabinoid clearance inhibitors. While PF-3845 and JZL195 produce similar effects in both rats and mice, substantial species differences in JZL184 efficacy are evident, which is consistent with previous studies.
PMCID: PMC3382459  PMID: 22860210
Endocannabinoid transporter; FAAH; in vivo microdialysis; MAGL; nucleus accumbens; endogenous cannabinoid system
4.  Trait Impulsive Choice Predicts Resistance to Extinction and Propensity to Relapse to Cocaine Seeking: A Bidirectional Investigation 
Neuropsychopharmacology  2012;37(6):1377-1386.
Despite the strong association between impulsivity and addiction in humans, it is still a matter of debate whether impulsive choice predisposes to, or results from, drug dependence. Furthermore, it is unknown whether treating impulsivity can protect against relapse propensity. Therefore, this study explored the bidirectional relationship between impulsive choice and cocaine taking and seeking in rat behavioral models. In experiment 1, to determine whether impulsive choice predisposes to cocaine taking or seeking, rats were selected based on trait impulsivity in a delayed reward task and subsequently compared on various stages of cocaine self-administration (SA). To examine the consequence of cocaine intake on impulsive choice, impulsivity was monitored once a week throughout various stages of cocaine SA. To determine whether treating impulsive choice can protect against relapse propensity, in experiment 2, impulsive choice was manipulated by pharmacological interventions and cocaine-associated contextual cues. Trait impulsive choice as determined in experiment 1 predicted high extinction resistance and enhanced propensity to context-induced relapse in the cocaine SA model, whereas cocaine intake did not alter impulsive choice. Furthermore, acute changes in impulsive choice were not related to rates of context-induced relapse. Taken together, the current data indicate that trait impulsive choice predicts persistent cocaine seeking during extinction and enhanced propensity to relapse, whereas acute manipulations of impulsive choice had no favorable outcomes on relapse measures. These observations suggest that trait impulsivity can be used as a predictive factor for addiction liability, but treating this impulsivity does not necessarily protect against relapse.
PMCID: PMC3327843  PMID: 22318198
impulsivity; cocaine; addiction; methylphenidate; SCH-23390; reinstatement; addiction & substance abuse; animal models; cognition; psychostimulants; impulsivity; cocaine; methylphenidate; SCH-23390; reinstatement
5.  Enhanced alcohol self-administration and reinstatement in a highly impulsive, inattentive recombinant inbred mouse strain 
Deficits in executive control have frequently been associated with alcohol use disorder. Here we investigated to what extent pre-existing genetically encoded levels of impulsive/inattentive behavior associate with motivation to take alcohol and vulnerability to cue-induced reinstatement of alcohol seeking in an operant self-administration paradigm. We took advantage of BXD16, a recombinant inbred strain previously shown to have enhanced impulsivity and poor attentional control. We compared BXD16 with C57BL/6J mice in a simple choice reaction time task (SCRTT) and confirmed its impulsive/inattentive phenotype. BXD16 mice were less active in a novel open field (OF), and were equally active in an automated home cage environment, showing that increased impulsive responding of BXD16 mice could not be explained by enhanced general activity compared to C57BL/6J mice. After training in a sucrose/alcohol fading self-administration procedure, BXD16 showed increased motivation to earn 10% alcohol solution, both under fixed ratio (FR1) and progressive ratio (PR2) schedules of reinforcement. Responding on the active lever readily decreased during extinction training with no apparent differences between strains. However, upon re-exposure to alcohol-associated cues, alcohol seeking was reinstated to a larger extent in BXD16 than in C57BL/6J mice. Although further studies are needed to determine whether impulsivity/inattention and alcohol seeking depend on common or separate genetic loci, these data show that in mice enhanced impulsivity coincides with increased motivation to take alcohol, as well as relapse vulnerability.
PMCID: PMC3812782  PMID: 24198771
BXD; inhibitory control; intra-individual variability; executive function; reinstatement; ethanol; 5csrt; addiction
6.  The Relationship between Impulsive Choice and Impulsive Action: A Cross-Species Translational Study 
PLoS ONE  2012;7(5):e36781.
Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.
PMCID: PMC3344935  PMID: 22574225
7.  Extracellular Matrix Plasticity and GABAergic Inhibition of Prefrontal Cortex Pyramidal Cells Facilitates Relapse to Heroin Seeking 
Neuropsychopharmacology  2010;35(10):2120-2133.
Successful treatment of drug addiction is hampered by high relapse rates during periods of abstinence. Neuroadaptation in the medial prefrontal cortex (mPFC) is thought to have a crucial role in vulnerability to relapse to drug seeking, but the molecular and cellular mechanisms remain largely unknown. To identify protein changes that contribute to relapse susceptibility, we investigated synaptic membrane fractions from the mPFC of rats that underwent 21 days of forced abstinence following heroin self-administration. Quantitative proteomics revealed that long-term abstinence from heroin self-administration was associated with reduced levels of extracellular matrix (ECM) proteins. After extinction of heroin self-administration, downregulation of ECM proteins was also present in the mPFC, as well as nucleus accumbens (NAc), and these adaptations were partially restored following cue-induced reinstatement of heroin seeking. In the mPFC, these ECM proteins are condensed in the perineuronal nets that exclusively surround GABAergic interneurons, indicating that ECM adaptation might alter the activity of GABAergic interneurons. In support of this, we observed an increase in the inhibitory GABAergic synaptic inputs received by the mPFC pyramidal cells after the re-exposure to heroin-conditioned cues. Recovering levels of ECM constituents by metalloproteinase inhibitor treatment (FN-439; i.c.v.) prior to a reinstatement test attenuated subsequent heroin seeking, suggesting that the reduced synaptic ECM levels during heroin abstinence enhanced sensitivity to respond to heroin-conditioned cues. We provide evidence for a novel neuroadaptive mechanism, in which heroin self-administration-induced adaptation of the ECM increased relapse vulnerability, potentially by augmenting the responsivity of mPFC GABAergic interneurons to heroin-associated stimuli.
PMCID: PMC3055295  PMID: 20592718
addiction; reinstatement; mPFC; proteomics; synaptic plasticity; cognition and behavior; addiction & substance abuse; molecular & cellular neurobiology; plasticity; opioids; addiction; reinstatement; mPFC; proteomics; synaptic plasticity
8.  Unidirectional relationship between heroin self-administration and impulsive decision-making in rats 
Psychopharmacology  2011;219(2):443-452.
There is growing clinical evidence for a strong relationship between drug addiction and impulsivity. However, it is not fully clear whether impulsivity is a pre-existing trait or a consequence of drug abuse. Recent observations in the animal models show that pre-existing levels of impulsivity predict cocaine and nicotine seeking. Whether such relationships also exist with respect to non-stimulant drugs is largely unknown.
We studied the relationship between impulsive choice and vulnerability to heroin taking and seeking.
Materials and methods
Rats were selected in the delayed reward task based on individual differences in impulsive choice. Subsequently, heroin intravenous self-administration behaviour was analysed, including acquisition of heroin intake, motivation, extinction and drug- and cue-induced reinstatement. Throughout the entire experiment, changes in impulsive choice were monitored weekly.
Results and discussion
High impulsivity did not predict measures of heroin taking. Moreover, high impulsive rats did not differ from low impulsive rats in extinction rates or heroin- and cue-induced reinstatement. However, both groups became more impulsive as heroin self-administration continued. During abstinence, impulsivity levels returned towards baseline (pre-heroin) levels. Our results indicate that, in contrast to psychostimulants, impulsive choice does not predict vulnerability to heroin seeking and taking.
These data implicate that different neural mechanisms may underlie the vulnerability to opiate and psychostimulant dependence. Moreover, our data suggest that elevated impulsivity levels as observed in heroin-dependent subjects are a consequence of heroin intake rather than a pre-existing vulnerability trait.
PMCID: PMC3249213  PMID: 21887498
Impulsivity; Heroin; Opiate; Addiction; Delayed reward task; Self-administration
9.  Chronic Loss of Melanin-Concentrating Hormone Affects Motivational Aspects of Feeding in the Rat 
PLoS ONE  2011;6(5):e19600.
Current epidemic obesity levels apply great medical and financial pressure to the strenuous economy of obesity-prone cultures, and neuropeptides involved in body weight regulation are regarded as attractive targets for a possible treatment of obesity in humans. The lateral hypothalamus and the nucleus accumbens shell (AcbSh) form a hypothalamic-limbic neuropeptide feeding circuit mediated by Melanin-Concentrating Hormone (MCH). MCH promotes feeding behavior via MCH receptor-1 (MCH1R) in the AcbSh, although this relationship has not been fully characterized. Given the AcbSh mediates reinforcing properties of food, we hypothesized that MCH modulates motivational aspects of feeding.
Here we show that chronic loss of the rat MCH-precursor Pmch decreased food intake predominantly via a reduction in meal size during rat development and reduced high-fat food-reinforced operant responding in adult rats. Moreover, acute AcbSh administration of Neuropeptide-GE and Neuropeptide-EI (NEI), both additional neuropeptides derived from Pmch, or chronic intracerebroventricular infusion of NEI, did not affect feeding behavior in adult pmch+/+ or pmch−/− rats. However, acute administration of MCH to the AcbSh of adult pmch−/− rats elevated feeding behavior towards wild type levels. Finally, adult pmch−/− rats showed increased ex vivo electrically evoked dopamine release and increased limbic dopamine transporter levels, indicating that chronic loss of Pmch in the rat affects the limbic dopamine system.
Our findings support the MCH-MCH1R system as an amplifier of consummatory behavior, confirming this system as a possible target for the treatment of obesity. We propose that MCH-mediated signaling in the AcbSh positively mediates motivational aspects of feeding behavior. Thereby it provides a crucial signal by which hypothalamic neural circuits control energy balance and guide limbic brain areas to enhance motivational or incentive-related aspects of food consumption.
PMCID: PMC3088702  PMID: 21573180
10.  Varenicline attenuates cue-induced relapse to alcohol, but not nicotine seeking, while reducing inhibitory response control 
Psychopharmacology  2011;216(2):267-277.
Treatment of the most widely abused drugs, nicotine and alcohol, is hampered by high rates of relapse. Varenicline tartrate, an α4β2 nicotinic receptor partial agonist, is currently prescribed as a smoking cessation aid. However, there is emerging evidence that it may also modulate alcohol seeking and cognitive functioning in rats.
As preclinical data on alcohol taking and relapse are limited, we used a self-administration–reinstatement model to evaluate the effects of varenicline on operant responding for alcohol (12%, v/v), intravenous nicotine (40 μg/kg/inf.), sucrose (10%, w/v) and on cue-induced relapse to alcohol and nicotine seeking in rats. At the cognitive level, we assed varenicline's effects on 5-choice serial reaction time task (5-CSRTT) performance with a focus on correct responses (attention) and premature responding (impulsivity), modalities that have previously been associated with addictive behaviour.
Varenicline, at doses of 1.5 and 2.5 mg/kg, reduced alcohol and nicotine self-administration and enhanced operant responding for sucrose. At these doses, varenicline reduced cue-induced relapse to alcohol, but not nicotine seeking. In contrast, at 0.5 mg/kg, varenicline facilitated cue-induced nicotine seeking. Similar to nicotine, varenicline increased premature responding at low doses, but had no effect on any of the other behavioural parameters in the 5-CSRTT.
Our data indicate that varenicline specifically reduced responding for nicotine and alcohol, but not for natural reinforcers such as sucrose. Interestingly, varenicline strongly attenuated cue-induced relapse to alcohol seeking, but not nicotine seeking. Varenicline may therefore be a promising aid in the treatment of alcohol addiction.
PMCID: PMC3121941  PMID: 21331520
Varenicline; Self-administration; Relapse; 5-CSRTT; Nicotine; Alcohol
11.  Disruption of Long-Term Alcohol-Related Memory Reconsolidation: Role of β-Adrenoceptors and NMDA Receptors 
Disrupting reconsolidation of drug-related memories may be effective in reducing the incidence of relapse. In the current study we examine whether alcohol-related memories are prone to disruption by the β-adrenergic receptor antagonist propranolol (10 mg/kg) and the NMDA receptor antagonist MK801 (0.1 mg/kg) following their reactivation. In operant chambers, male Wistar rats were trained to self-administer a 12% alcohol solution. After 3 weeks of abstinence, the animals were placed in the self-administration cages and were re-exposed to the alcohol-associated cues for a 20-min retrieval period, immediately followed by a systemic injection of either propranolol, MK801 or saline. Rats were tested for cue-induced alcohol seeking on the following day. Retrieval session, injection and test were repeated on two further occasions at weekly intervals. Both propranolol and MK801 administration upon reactivation did not reduce alcohol seeking after the first reactivation test. However, a significant reduction of alcohol seeking was observed over three post-training tests in propranolol treated animals, and MK801 treated animals showed a strong tendency toward reduced alcohol seeking (p = 0.06). Our data indicate that reconsolidation of alcohol-related memories can be disrupted after a long post-training interval and that particularly β-adrenergic receptors may represent novel targets for pharmacotherapy of alcoholism, in combination with cue-exposure therapies.
PMCID: PMC2998860  PMID: 21152256
alcohol; β-adrenergic receptor; instrumental learning; memory reconsolidation; NMDA receptor; propranolol
12.  Methylphenidate Disrupts Social Play Behavior in Adolescent Rats 
Methylphenidate is the first-choice treatment for attention-deficit/hyperactivity disorder (ADHD), but its mechanism of action is incompletely understood. The cognitive effects of methylphenidate have been extensively studied, but little is known about its effects on spontaneous social behavior. During adolescence, rats display a characteristic, highly vigorous form of social behavior, termed social play behavior, which is of critical importance for social and cognitive development. We investigated the neurobehavioral mechanisms by which methylphenidate affects social play behavior in rats. Methylphenidate (0.3-3.0 mg/kg, s.c. or p.o.) abolished social play behavior, without altering general social interest. This effect of methylphenidate did not depend upon the baseline level of social play and was not secondary to changes in locomotion. Furthermore, the play-suppressant effect of methylphenidate was not subject to tolerance or sensitization. Methylphenidate blocked both the initiation to play and the responsivity to play initiation. The effect of methylphenidate was mimicked by the noradrenaline reuptake inhibitor atomoxetine, which is also used for the treatment of ADHD, and was blocked by an α-2 adrenoceptor antagonist. In addition, combined administration of subeffective doses of methylphenidate and atomoxetine suppressed social play. However, blockade of α-1 adrenoceptors, β-adrenoceptors, or dopamine receptors did not alter the effect of methylphenidate. These data show that methylphenidate selectively blocks the most vigorous part of the behavioral repertoire of adolescent rats through a noradrenergic mechanism. We suggest that the effect of methylphenidate on social play is a reflection of its therapeutic effect in ADHD, that is, improved behavioral inhibition. However, given the importance of social play for development, these findings may also indicate an adverse side effect of methylphenidate.
PMCID: PMC2580804  PMID: 18305462
social behavior; adolescent; methylphenidate; atomoxetine; α-2 adrenoceptor; behavioral inhibition
13.  Effects of the cannabinoid CB1 receptor antagonist rimonabant on distinct measures of impulsive behavior in rats 
Psychopharmacology  2007;193(1):85-96.
Pathological impulsivity is a prominent feature in several psychiatric disorders, but detailed understanding of the specific neuronal processes underlying impulsive behavior is as yet lacking.
As recent findings have suggested involvement of the brain cannabinoid system in impulsivity, the present study aimed at further elucidating the role of cannabinoid CB1 receptor activation in distinct measures of impulsive behavior.
Materials and methods
The effects of the selective cannabinoid CB1 receptor antagonist, rimonabant (SR141716A) and agonist WIN55,212-2 were tested in various measures of impulsive behavior, namely, inhibitory control in a five-choice serial reaction time task (5-CSRTT), impulsive choice in a delayed reward paradigm, and response inhibition in a stop-signal paradigm.
In the 5-CSRTT, SR141716A dose-dependently improved inhibitory control by decreasing the number of premature responses. Furthermore, SR141716A slightly improved attentional function, increased correct response latency, but did not affect other parameters. The CB1 receptor agonist WIN55,212-2 did not change inhibitory control in the 5-CSRTT and only increased response latencies and errors of omissions. Coadministration of WIN55,212-2 prevented the effects of SR141716A on inhibitory control in the 5-CSRTT. Impulsive choice and response inhibition were not affected by SR141716A at any dose, whereas WIN55,212-2 slightly impaired response inhibition but did not change impulsive choice.
The present data suggest that particularly the endocannabinoid system seems involved in some measures of impulsivity and provides further evidence for the existence of distinct forms of impulsivity that can be pharmacologically dissociated.
PMCID: PMC1915592  PMID: 17387457
Cannabinoid; Cognition; Inhibitory control; Impulsive choice; Response inhibition; SR141716A; WIN55,212-2

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