Tommy Pattij

The neuropharmacology of impulsive behaviour

Impulsivity is a heterogenous phenomenon encompassing several behavioural phenomena that can be dissociated neuroanatomically as well as pharmacologically. Impulsivity is pathological in several psychiatric disorders including attention-deficit/hyperactivity disorder (ADHD), drug addiction and personality disorders. Pharmacological agents alleviating impulsivity therefore might substantially aid the treatment of these disorders. The availability of preclinical models that measure various forms of impulsivity has greatly increased our understanding of its neuropharmacological substrates. Historically, deficits in central serotonin neurotransmission are thought to underlie impulsivity. Accumulating evidence also points towards an important role of brain dopamine and noradrenaline systems in impulsive behaviour, consistent with the therapeutic efficacy of amphetamine, methylphenidate and atomoxetine in ADHD. However, recent findings also implicate glutamate and cannabinoid neurotransmission in impulsivity. In this review, we will discuss some of the recent developments in the neuropharmacological manipulation of impulsive behaviour.

Impulsive Choice and Impulsive Action Predict Vulnerability to Distinct Stages of Nicotine Seeking in Rats

BACKGROUND Although heavy smoking has been associated with impulsivity in humans, it is not clear whether poor impulse control represents a risk factor in the etiology of nicotine dependence. METHODS To address this issue, rats were selected on the basis of individual differences in impulsivity in the delayed reward task (impulsive choice) and the 5-choice serial reaction time task (impulsive action). Subsequently, rats were subjected to a nicotine self-administration (SA) paradigm tailored to measure the motivational properties of nicotine and nicotine-associated stimuli. In separate groups, differences in electrically evoked dopamine release in slice preparations obtained from several mesolimbic brain regions were determined. RESULTS Impulsive action was associated with an enhanced motivation to initiate and maintain nicotine SA. In contrast, impulsive choice predicted a diminished ability to inhibit nicotine seeking during abstinence and an enhanced vulnerability to relapse upon re-exposure to nicotine cues. Impulsive action was associated with reduced dopamine release in the accumbens core and impulsive choice with reduced dopamine release in accumbens core, shell, and medial prefrontal cortex. CONCLUSIONS The strong association between sub-dimensions of impulsivity and nicotine SA implies that interventions aimed to improve impulse control might help to reduce susceptibility to nicotine dependence and/or lead to successful smoking cessation.

Stress-induced hyperthermia and anxiety: pharmacological validation.

When mammals, including man, are confronted with a stressful event, their core body temperature rises, stress-induced hyperthermia. In mice, the stress-induced hyperthermia procedure has been developed to measure antistress or anxiolytic-like effects of psychoactive drugs. Group-housed and singly housed versions of the stress-induced hyperthermia generate comparable results. Because the number of animals needed to perform an experiment is much lower in the singly housed versus the group-housed procedure, the former is the test of choice for pharmacological testing. A typical stress-induced hyperthermia test starts with an injection 60 min before the first rectal temperature measurement (T(1)), followed by a second temperature measurement (T(2)) 10-15 min later. The difference DeltaT (=T(2)-T(1)) is the stress-induced hyperthermia. The procedure also measures the intrinsic activity of drugs on the basal body temperature and DeltaT is relatively independent from the intrinsic temperature effects of drugs. Anxiolytic drugs (benzodiazepines, 5-HT(1A) receptor agonists, alcohol) reduce DeltaT suggestive of anxiolytic-like effects. Because the parameter measured for anxiety in the stress-induced hyperthermia procedure is not dependent on locomotor activity, like in almost all other anxiety tests, the stress-induced hyperthermia procedure is an attractive addition to tests in the anxiety field. Because the stress-induced hyperthermia is also present with a comparable pharmacological profile in females, this procedure has a wide species and gender validity. The procedure was applied in various genetically modified mice [5-HT(1A) and 5-HT(1B) receptor knockout (KO) mice and corticotropin-releasing hormone overexpressing (CRH-OE) mice] to study phenotypic influences of the various mutations on aspects of anxiety. The stress-induced hyperthermia test in singly housed male and female mice appears a useful and extremely simple test to measure effects of drugs on certain aspects of anxiety or to help to determine phenotypic differences in mutant mice.

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

RationaleImpaired inhibitory control over behavior is a key feature in various psychiatric disorders, and recent studies indicated an important role for dopamine D1 and D2 receptors and the nucleus accumbens (Acb) in this respect.ObjectiveThe present experiments were designed to study the role of dopamine D1 and D2 receptors in the Acb in inhibitory response control.MethodsRats 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 D1 and D2 receptor antagonists, respectively). Subsequently, the effects of systemic amphetamine on inhibitory response control were examined.ResultsEticlopride 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.ConclusionOur data provide evidence for the involvement of dopamine D1 and D2 receptors in the Acb core and shell in inhibitory response control and attentional performance.

The relationship between impulsive choice and impulsive action: a cross-species translational study.

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.

Individual differences in male rat ejaculatory behaviour: searching for models to study ejaculation disorders.

In addition to investigating sexual function in rats that display normal ejaculatory behaviour, studying rats that are either ‘hyposexual’ or ‘hypersexual’ may provide important insights into the aetiology of ejaculatory dysfunctions in men, such as premature and retarded ejaculation. To this end, rats were matched into groups of ‘sluggish’, ‘normal’ and ‘rapid’ ejaculators based on their ejaculation frequencies displayed in a series of weekly sexual behaviour tests. Selecting rats on this parameter revealed large and stable differences in other parameters of sexual behaviour as well, including ejaculation latency and mount frequency but not intromission frequency and mount latency, putative indices of sexual motivation. Neuroanatomically, Fos immunoreactivity as a measure of neuronal activation was increased in rapid ejaculators compared with sluggish ejaculators in ejaculation‐related brain areas, presumably associated with the differences in ejaculatory behaviour. Although the total number of oxytocin neurones within subregions of the hypothalamus did not differ between groups, in the supraoptic nucleus of the hypothalamus more oxytocin neurones were activated in rapid ejaculators compared with the other groups. Apart from the differences observed in ejaculatory behaviour, groups did not differ with respect to their locomotor activity and approach‐avoidance behaviour as measured in the elevated plus‐maze. Finally, apomorphine‐induced stereotypy was similar in sluggish and rapid ejaculators, suggesting no large differences in dopamine susceptibility. Altogether, the present results suggest stable differences in male rat ejaculatory behaviour. Further exploring the neurobiological mechanisms underlying these differences may be a promising approach to gain insights into the aetiology of sexual dysfunctions such as premature, retarded or an‐ejaculation.

Long-lasting cognitive deficits resulting from adolescent nicotine exposure in rats.

Adolescence is a developmental period, during which the brain and particularly medial prefrontal cortical (mPFC) regions thereof have not fully matured. Because epidemiological data have suggested that adolescent nicotine use may result in disturbances in cognitive function in adulthood, we investigated the long-term effects of adolescent nicotine exposure in rats. Male Wistar rats were exposed to either nicotine (three times daily, 0.4 mg/kg s.c.) or saline for 10 days during (postnatal day (PND) 34–43) or following (PND 60–69) adolescence. After 5 weeks during adulthood, separate groups of animals were tested in operant paradigms taxing attention and distinct measures of impulsivity. Visuospatial attention and impulsive action were tested in the five-choice serial reaction time task, whereas impulsive choice was assessed in the delayed reward task. Our data show that adolescent, but not postadolescent, nicotine exposure affects cognitive performance in adulthood and results in diminished attentional performance and increments in impulsive action, while leaving impulsive choice intact. This altered cognitive performance appeared to be associated with enhanced releasability of dopamine in the mPFC. Together, these data suggest that adolescence is a time window during which the brain is vulnerable to long-lasting cognitive disturbances resulting from nicotine exposure.

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.

Cannabinoid modulation of executive functions

Executive functions are higher-order cognitive processes such as attention, behavioural flexibility, decision-making, inhibitory control, planning, time estimation and working memory that exert top-down control over behaviour. In addition to the role of cannabinoid signaling in other cognitive functions such as mnemonic processes, interest in its involvement in executive functions has arisen more recently. Here, we will briefly review some of the recent findings indicating a modulatory role of cannabinoid action on executive functioning. In addition, a growing body of evidence suggests that in particular adolescents are more vulnerable for the deleterious effects of drugs of abuse such as cannabis on cognitive functioning. Therefore, in this paper we will also briefly discuss some recent developments in this research field.

Endocannabinoids Shape Accumbal Encoding of Cue-Motivated Behavior via CB1 Receptor Activation in the Ventral Tegmentum

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.