T. Pattij

Trait Impulsivity Predicts Escalation of Sucrose Seeking and Hypersensitivity to Sucrose-Associated Stimuli

Poor impulse control has been associated with compulsive drug seeking and an enhanced risk of relapse, suggesting that impulsivity is causally related to addiction proneness and relapse vulnerability. However, whether this association is specific to drugs of abuse or whether heightened impulsivity relates to a general increase in sensitivity to rewards and reward-associated stimuli is unknown. To address this issue, the authors selected rats on the basis of individual differences in impulsive action in the 5-choice serial reaction time task, after which they were subjected to an operant sucrose self-administration paradigm. High-impulsive rats displayed a progressive increase in responding on the active hole (including responses emitted during the time-out period) in comparison with low-impulsive rats, which reflects escalation of sucrose-seeking behavior. Once sucrose and sucrose-associated stimuli were omitted (extinction training), nose-poke responding ceased rapidly, an effect that was independent of impulsivity level. In contrast, on reintroduction of sucrose-associated stimuli, sucrose seeking was successfully reinstated in high-impulsive but not in low-impulsive rats. Collectively, the results suggest that impaired response inhibition is associated with enhanced responsiveness to reward-associated stimuli. As such, elevated impulsivity might constitute a risk factor for the initiation and maintenance of addictive behaviors.

Insulin Modulates Cocaine-Sensitive Monoamine Transporter Function and Impulsive Behavior

Because insulin acutely enhances the function of dopamine transporters, the tyrosine kinase receptors activated by this hormone may modulate transporter-dependent neurochemical and behavioral effects of psychoactive drugs. In this respect, we examined the effects of insulin on exocytotic monoamine release and the efficacy of the monoamine transporter blocker cocaine in rat nucleus accumbens. Whereas insulin reduced electrically evoked exocytotic [3H]dopamine release in nucleus accumbens slices, the hormone potentiated the release-enhancing effect of cocaine thereon. The phosphatidylinositol 3-kinase inhibitor LY294002 abolished these effects, indicating the involvement of insulin receptors. Similar insulin effects were observed on the release of [3H]norepinephrine in nucleus accumbens slices, but not on that of [3H]serotonin, and were also apparent in medial prefrontal cortex slices. As might then be expected, insulin also potentiated the dopamine and norepinephrine release-enhancing effects of the selective monoamine uptake inhibitors GBR12909 and desmethylimipramine, respectively. In subsequent behavioral experiments, we investigated the role of insulin in motor impulsivity that depends on monoamine neurotransmission in the nucleus accumbens. Intracranial administration of insulin in the nucleus accumbens alone reduced premature responses in the five-choice serial reaction time task and enhanced the stimulatory effect of peripheral cocaine administration on impulsivity, resembling the observed neurochemical effects of the hormone. In contrast, cocaine-induced locomotor activity remained unchanged by intra-accumbal insulin application. These data reveal that insulin presynaptically regulates cocaine-sensitive monoamine transporter function in the nucleus accumbens and, as a consequence, impulsivity. Therefore, insulin signaling proteins may represent targets for the treatment of inhibitory control deficits such as addictive behaviors.

Mechanismen van impulsiviteit in neurologie en psychiatrie: recente ontwikkelingen in translationeel preklinisch onderzoek

SamenvattingVerhoogde impulsiviteit is een kernsymptoom in verschillende psychiatrische en neurologische aandoeningen en wordt gekenmerkt door verstoringen in cognitieve controle en impulsieve beslissingen. Naast nieuwe toepassingen en mogelijkheden in humaan neuroimagingonderzoek, heeft vooral translationeel preklinisch onderzoek veel opgehelderd over de neurobiologie van impulsiviteit. Farmacologische interventies hebben het belang laten zien van de neurotransmitters serotonine, dopamine en noradrenaline in het reguleren van impulsief gedrag. De intrede van zeer geavanceerde technologieën in de neurowetenschappen, zoals de optogenetica en farmacogenetica, stelt ons in staat om grote sprongen voorwaarts te maken in het ontrafelen van de neurobiologie van impulsiviteit.