Insulin Modulates Cocaine-Sensitive Monoamine Transporter Function and Impulsive Behavior

Abstract

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 cocainesensitive 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.

Effect of insulin deficiency on the rewarding properties of methamphetamine in streptozotocin-induced diabetic rats

“…It has also been proven that insulin signalling regulates DA neurotransmission, affects the ability of psychostimulants in the DA system and facilitates their neurochemical and behavioural outcomes. Schoffelmeer et al (2011) demonstrated that insulin can presynaptically enhance the function of cocaine sensitive monoamine transporters, including DAT, and may decrease impulsive behaviours in rat NAc (Dawset al, 2011). This suggests that insulin receptors may modulate the cocaine-sensitive inhibitory response control by intensifying the monoamine transporter function (Schoffelmeer et al, 2011).…”

“…Schoffelmeer et al (2011) demonstrated that insulin can presynaptically enhance the function of cocaine sensitive monoamine transporters, including DAT, and may decrease impulsive behaviours in rat NAc (Dawset al, 2011). This suggests that insulin receptors may modulate the cocaine-sensitive inhibitory response control by intensifying the monoamine transporter function (Schoffelmeer et al, 2011). In fact, insulin shows CNS specificity in its effects on monoamine transporter function and may provide a novel therapeutic target for inhibitory control of disorders, such as drug addiction and obesity (Daws et al, 2011).…”

“…Streptozotocin (STZ)-induced hypoinsulinaemia depresses the DAreleasing action of AMPH by suppressing downstream signalling of insulin receptors, which further decreases the surface expression and function of DAT in the neural system (Schoffelmeer et al, 2011). Given the fact that psychostimulants target the dopaminergic system, clarifying how DA and other brain reward systems are regulated by insulin may create opportunities to develop new treatments for drug and food addiction (Davis et al, 2010).…”

A Method for Testing Food Preference in Animal Experiments

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The formation of food preference is known to be tightly connected with the level of motivation, which depends on the status of the blood and the calorifi c value of food entering the stomach [9,12,17], and its taste properties, which are mediated via orosensory stimulation when food enters the mouth, as well as from stimulation signaling the physical properties, time of ingestion, and quantity of food received [1,2,6,7,8,15].Studies of food preference and its associated level of food motivation in experiments in different animal species generally involve presenting subjects with a situation in which they can make alternative choices of feeders and foods with different taste properties. Investigators use the two bottle test [10,16], which includes a working chamber fi tted with food reservoirs located outside the chamber, and tubes in the working sector allowing the animals to access test liquid foods with different taste properties or different concentrations of test food substances (saccharine, fructose, etc.).

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“…The formation of food preference is known to be tightly connected with the level of motivation, which depends on the status of the blood and the calorifi c value of food entering the stomach [9,12,17], and its taste properties, which are mediated via orosensory stimulation when food enters the mouth, as well as from stimulation signaling the physical properties, time of ingestion, and quantity of food received [1, 2,6,7,8,15].…”