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 [(3)H]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 [(3)H]norepinephrine in nucleus accumbens slices, but not on that of [(3)H]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.

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.

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.

Exocytotic release of creatine in rat brain.

The guanidino compound creatine has been shown to occur throughout the brain affecting energy metabolism and mental performance and to act at central GABAA receptors as a partial agonist. Therefore, we examined the possibility that creatine may in fact represent a neuromodulator that is released in the brain in an action-potential dependent manner. To that end, we studied the uptake of [3H]creatine and its electrically evoked release from superfused rat brain slices as well as the evoked release of endogenously synthesized creatine. [3H]creatine was accumulated in neocortex slices in a Na+-dependent manner, consistent with the involvement of the Na+-dependent SLC6A8 creatine transporter. Most importantly, the electrically evoked release of [3H]creatine from neocortex slices (like that from caudate putamen and hippocampus slices) as well as the evoked release of endogenous (unlabeled) creatine was abolished when Ca2+ was omitted from the superfusion medium or in the presence of the Na+-channel blocker tetrodotoxin (TTX). Moreover, blockade of K+-channels by 4-aminopyridine (4-AP) strongly enhanced the electrically evoked release of [3H]creatine as well as that of endogenous creatine. These in vitro data indicate that creatine is not only synthesized and taken up by central neurons, but also released in an action-potential dependent (exocytotic) manner, providing strong evidence for its role as a neuromodulator in the brain.