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1.  Cannabinoids and value-based decision making: implications for neurodegenerative disorders 
Basal ganglia  2012;2(3):131-138.
In recent years, disturbances in cognitive function have been increasingly recognized as important symptomatic phenomena in neurodegenerative diseases, including Parkinson’s Disease (PD). Value-based decision making in particular is an important executive cognitive function that is not only impaired in patients with PD, but also shares neural substrates with PD in basal ganglia structures and the dopamine system. Interestingly, the endogenous cannabinoid system modulates dopamine function and subsequently value-based decision making. This review will provide an overview of the interdisciplinary research that has influenced our understanding of value-based decision making and the role of dopamine, particularly in the context of reinforcement learning theories, as well as recent animal and human studies that demonstrate the modulatory role of activation of cannabinoid receptors by exogenous agonists or their naturally occurring ligands. The implications of this research for the symptomatology of and potential treatments for PD are also discussed.
PMCID: PMC3496267  PMID: 23162787
cannabinoid; cognition; decision making; dopamine; Parkinson’s disease; reinforcement learning
2.  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
3.  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
4.  Endocannabinoids shape accumbal encoding of cue-motivated behavior via CB1 receptor activation in the ventral tegmentum 
Neuron  2012;73(2):360-373.
Transient increases in nucleus accumbens (NAc) dopamine concentration are observed when animals are presented with motivationally salient stimuli and are theorized to energize reward seeking. They arise from high frequency firing of dopamine neurons in the ventral tegmental area (VTA), which also results in the release of endocannabinoids from dopamine cell bodies. In this context, endocannabinoids are thought to regulate reward seeking by modulating dopamine signaling, although a direct link has never been demonstrated. To test this, we pharmacologically manipulated endocannabinoid neurotransmission in the VTA while measuring transient changes in dopamine concentration in the NAc during reward seeking. Disrupting endocannabinoid signaling dramatically reduced, whereas augmenting levels of the endocannabinoid 2-arachidonoylglycerol (2AG) increased, cue-evoked dopamine concentrations and reward seeking. These data suggest that 2AG in the VTA regulates reward seeking by sculpting ethologically relevant patterns of dopamine release during reward-directed behavior.
PMCID: PMC3269037  PMID: 22284189
5.  On the Role of Cannabinoid CB1- and μ-Opioid Receptors in Motor Impulsivity 
Previous studies using a rat 5-choice serial reaction time task have established a critical role for dopamine D2 receptors in regulating increments in motor impulsivity induced by acute administration of the psychostimulant drugs amphetamine and nicotine. Here we investigated whether cannabinoid CB1 and/or μ-opioid receptors are involved in nicotine-induced impulsivity, given recent findings indicating that both receptor systems mediate amphetamine-induced motor impulsivity. Results showed that the cannabinoid CB1 receptor antagonist SR141716A, but not the opioid receptor antagonist naloxone, reduced nicotine-induced premature responding, indicating that nicotine-induced motor impulsivity is cannabinoid, but not opioid receptor-dependent. In contrast, SR141716A did not affect impulsivity following a challenge with the dopamine transporter inhibitor GBR 12909, a form of drug-induced impulsivity that was previously found to be dependent on μ-opioid receptor activation. Together, these data are consistent with the idea that the endogenous cannabinoid, dopamine, and opioid systems each play important, but distinct roles in regulating (drug-induced) motor impulsivity. The rather complex interplay between these neurotransmitter systems modulating impulsivity will be discussed in terms of the differential involvement of mesocortical and mesolimbic neurocircuitry.
PMCID: PMC3371578  PMID: 22701425
5-choice serial reaction time task; endocannabinoid system; endogenous opioid system; inhibitory response control; mesocortical dopamine system; mesolimbic dopamine system; nicotine; rat
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.  Cannabinoid CB1 Receptor Activation Mediates the Opposing Effects of Amphetamine on Impulsive Action and Impulsive Choice 
PLoS ONE  2011;6(10):e25856.
It is well known that acute challenges with psychostimulants such as amphetamine affect impulsive behavior. We here studied the pharmacology underlying the effects of amphetamine in two rat models of impulsivity, the 5-choice serial reaction time task (5-CSRTT) and the delayed reward task (DRT), providing measures of inhibitory control, an aspect of impulsive action, and impulsive choice, respectively. We focused on the role of cannabinoid CB1 receptor activation in amphetamine-induced impulsivity as there is evidence that acute challenges with psychostimulants activate the endogenous cannabinoid system, and CB1 receptor activity modulates impulsivity in both rodents and humans. Results showed that pretreatment with either the CB1 receptor antagonist/inverse agonist SR141716A or the neutral CB1 receptor antagonist O-2050 dose-dependently improved baseline inhibitory control in the 5-CSRTT. Moreover, both compounds similarly attenuated amphetamine-induced inhibitory control deficits, suggesting that CB1 receptor activation by endogenously released cannabinoids mediates this aspect of impulsive action. Direct CB1 receptor activation by Δ9-Tetrahydrocannabinol (Δ9-THC) did, however, not affect inhibitory control. Although neither SR141716A nor O-2050 affected baseline impulsive choice in the DRT, both ligands completely prevented amphetamine-induced reductions in impulsive decision making, indicating that CB1 receptor activity may decrease this form of impulsivity. Indeed, acute Δ9-THC was found to reduce impulsive choice in a CB1 receptor-dependent way. Together, these results indicate an important, though complex role for cannabinoid CB1 receptor activity in the regulation of impulsive action and impulsive choice as well as the opposite effects amphetamine has on both forms of impulsive behavior.
PMCID: PMC3189229  PMID: 22016780
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.  On the improvement of inhibitory response control and visuospatial attention by indirect and direct adrenoceptor agonists 
Psychopharmacology  2011;219(2):327-340.
The clinical efficacy of the monoamine and noradrenaline transporter inhibitors methylphenidate and atomoxetine in attention deficit/hyperactivity disorder implicates noradrenergic neurotransmission in modulating inhibitory response control processes. Nonetheless, it is unclear which adrenoceptor subtypes are involved in these effects.
The present study aimed at investigating the effects of adrenoceptor agonists on inhibitory response control as assessed in the rodent 5-choice serial reaction time task, a widely used translational model to measure this executive cognitive function.
Consistent with the previous reported effects of atomoxetine, the noradrenaline transporter inhibitor desipramine improved inhibitory response control, albeit the effect size was smaller compared to that of atomoxetine. Methylphenidate exerted a bimodal effect on inhibitory response control. Interestingly, the preferential β2-adrenoceptor agonist clenbuterol improved inhibitory response control. Moreover, clenbuterol improved visuospatial attention in the task, an effect that was also observed with the preferential β1-adrenoceptor agonist dobutamine. By contrast, although the preferential α1-adrenoceptor and α2-adrenoceptor agonists (phenylephrine and clonidine, respectively) and the non-selective β-adrenoceptor agonist (isoprenaline) were found to alter inhibitory response control, this was probably secondary to the simultaneous increments in response latencies and omissions observed at effective doses.
Taken together, these findings further strengthen the notion of noradrenergic modulation of inhibitory response control and attentional processes and particularly reveal the involvement of β2-adrenoceptors therein.
PMCID: PMC3249209  PMID: 21769568
Adrenoceptors; Attention; Clenbuterol; Impulsive behaviour; Noradrenaline; Rat
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.  Acute effects of morphine on distinct forms of impulsive behavior in rats 
Psychopharmacology  2009;205(3):489-502.
Disturbances in impulse control are key features of substance abuse disorders, and conversely, many drugs of abuse are known to elicit impulsive behavior both clinically and preclinically. To date, little is known with respect to the involvement of the opioid system in impulsive behavior, although recent findings have demonstrated its involvement in delay discounting processes. The aim of the present study was to further investigate the role of the opioid system in varieties of impulsivity.
Materials and methods
To this end, groups of rats were trained in the five-choice serial reaction time task (5-CSRTT) and stop-signal task (SST), operant paradigms that provide measures of inhibitory control and response inhibition, respectively. In addition, another group of rats was trained in the delayed reward paradigm, which measures the sensitivity towards delay of gratification and as such assesses impulsive choice.
Results and discussion
Results demonstrated that morphine, a selective µ-opioid receptor agonist, primarily impaired inhibitory control in the 5-CSRTT by increasing premature responding. In addition, in keeping with previous data, morphine decreased the preference for the large over small reward in the delayed reward paradigm. The effects of morphine on measures of impulsivity in both the 5-CSRTT and delayed reward paradigm were blocked by naloxone, a µ-opioid receptor antagonist. Naloxone by itself did not alter impulsive behavior, suggesting limited involvement of an endogenous opioid tone in impulsivity. Response inhibition measured in the SST was neither altered by morphine nor naloxone, although some baseline-dependent effects of morphine on response inhibition were observed.
In conclusion, the present data demonstrate that acute challenges with morphine modulate distinct forms of impulsive behavior, thereby suggesting a role for the opioid system in impulsivity.
PMCID: PMC2712067  PMID: 19436995
Cognition; Inhibitory control; Impulsive choice; Morphine; Naloxone
12.  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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