Dopamine receptor D1/D5 gene expression in the medial prefrontal cortex predicts impulsive choice in rats.

A neuropsychological hallmark of attention deficit/hyperactivity disorder (ADHD) is the reduced ability to tolerate delay of reinforcement, leading to impulsive choice. Genetic association studies have implicated several genes involved in dopaminergic neurotransmission in ADHD. In this study, we investigated whether differences in the expression level of these dopamine-related genes of rats predict the individual level of impulsive choice. Among all frontostriatal brain regions tested, only in the medial prefrontal cortex (mPFC), we observed significant positive correlations between impulsive choice and transcript levels of the dopamine receptor D(1), the dopamine receptor D(5) and calcyon. Local mPFC infusions of the D(1)/D(5) receptor antagonist SCH 23390 and agonist SKF 38393 resulted in increased impulsive choice, in agreement with the idea that endogenous receptor D(1)/D(5) stimulation in the mPFC promotes the choice of large delayed rewards. Together, these data indicate that this class of dopamine receptors in the mPFC plays a pivotal role in impulsive choice, and aberrancies thereof might contribute to ADHD symptomatology.

Involvement of dopamine D1 and D2 receptors in the nucleus accumbens core and shell in inhibitory response control.

RATIONALE: Impaired inhibitory control over behavior is a key feature in various psychiatric disorders, and recent studies indicated an important role for dopamine D(1) and D(2) receptors and the nucleus accumbens (Acb) in this respect. OBJECTIVE: The present experiments were designed to study the role of dopamine D(1) and D(2) receptors in the Acb in inhibitory response control. METHODS: Rats were trained in a five-choice serial reaction time task and received bilateral infusions into the Acb core or shell of either SCH 23390 or eticlopride (representing selective dopamine D(1) and D(2) receptor antagonists, respectively). Subsequently, the effects of systemic amphetamine on inhibitory response control were examined. RESULTS: Eticlopride into either the Acb core or shell did not affect premature responding, a measure for inhibitory response control, but increased reaction time and errors of omission. In contrast, SCH 23390 into both regions reduced premature responding, slightly improved attentional performance in the core and increased errors of omission in the shell. Amphetamine robustly increased premature responding which was dose-dependently blocked by eticlopride in the Acb core and attenuated by eticlopride in the shell. In addition, amphetamine slightly decreased accuracy and reaction time, and these effects were inhibited by eticlopride in both regions. SCH 23390 infusion into the Acb core or shell did not alter amphetamine's effects. CONCLUSION: Our data provide evidence for the involvement of dopamine D(1) and D(2) receptors in the Acb core and shell in inhibitory response control and attentional performance.

Effects of the cannabinoid CB1 receptor antagonist rimonabant on distinct measures of impulsive behavior in rats.

RATIONALE: 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. OBJECTIVES: As recent findings have suggested involvement of the brain cannabinoid system in impulsivity, the present study aimed at further elucidating the role of cannabinoid CB(1) receptor activation in distinct measures of impulsive behavior. MATERIALS AND METHODS: The effects of the selective cannabinoid CB(1) 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. RESULTS: 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 CB(1) 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. CONCLUSIONS: 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.

Suppression of conditioned nicotine and sucrose seeking by the cannabinoid-1 receptor antagonist SR141716A.

The present study shows that the selective cannabinoid CB1 receptor antagonist SR141716A attenuated responding for both nicotine- and sucrose-associated stimuli in a long-term extinction-reinstatement model. The results suggest that endocannabinoids play a general role in modulating cue reactivity or conditioned reinforcement following prolonged abstinence of both drug and natural reinforcers. In line with previous preclinical and recent clinical observations, our results provide a strong rationale for the use of CB1 antagonists in the treatment of addictive behaviors.

Acute effects of morphine on distinct forms of impulsive behavior in rats.

RATIONALE: 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 micro-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 micro-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. CONCLUSION: 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.

Serotonin transporter deficiency in rats improves inhibitory control but not behavioural flexibility.

Impulsivity and aggression have been suggested to inversely correlate with central serotonin (5-HT) levels in a trait-like manner. However, this relationship is far from straightforward. In the present study we addressed the effect of lifelong reduced or absent serotonin transporter (SERT) function, which is associated with constitutively increased extracellular 5-HT levels, on impulsivity and aggression. We used unique SERT knockout rats in a resident-intruder test, five-choice serial reaction time task and serial reversal learning task to assay aggression, inhibitory control and behavioural flexibility, respectively. Homozygous SERT knockout rats (SERT( -/-)) displayed reduced aggression and improved inhibitory control, but unchanged behavioural flexibility. The behavioural phenotype of heterozygous SERT knockout rats (SERT( +/-)) was not different from that of wild-type controls in any of the behavioural paradigms. We determined monoamine (metabolite) tissue levels in the medial prefrontal cortex, orbitofrontal cortex, lateral hypothalamus, raphe nuclei and cerebrospinal fluid, and found that the 5-HT levels, but not other monoamine tissue levels, were reduced in SERT( -/-) rats. In addition, the 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio in cerebrospinal fluid was increased in these rats. In conclusion, our data show that the absence of the SERT affects aggression and inhibitory control, but not behavioural flexibility, characteristics that may reflect the trait-like consequences of constitutive changes in central 5-HT levels.