Insulin in the ventral tegmental area reduces cocaine‐evoked dopamine in the nucleus accumbens in vivo

Abstract

Mesolimbic dopamine circuits, implicated in incentive motivation, are sensitive to changes in metabolic state such as weight loss and diet‐induced obesity. These neurons are important targets for metabolic hormones such as leptin, glucagon‐like peptide‐1, ghrelin and insulin. Insulin receptors are located on dopamine neurons in the ventral tegmental area (VTA) and we have previously demonstrated that insulin induces long‐term depression of excitatory synapses onto VTA dopamine neurons. While insulin can decrease dopamine concentration in somatodendritic regions, it can increase dopamine in striatal slices. Whether insulin directly targets the VTA to alter dopamine release in projection areas, such as the nucleus accumbens (NAc), remains unknown. The main goal of the present experiments was to examine NAc dopamine concentration following VTA administration of insulin. Using in vivo FSCV to detect rapid fluctuations in dopamine concentration, we showed that intra‐VTA insulin via action at insulin receptors reduced pedunculopontine nucleus‐evoked dopamine release in the NAc. Furthermore, intra‐VTA insulin reduced cocaine‐potentiated NAc dopamine. Finally, intra‐VTA or intranasal insulin decreased locomotor responses to cocaine, an effect blocked by an intra‐VTA administered insulin receptor antagonist. Together, these data demonstrate that mesolimbic dopaminergic projections are important targets of the metabolic hormone, insulin.

Insulin enhances presynaptic glutamate release via opioid receptor-mediated disinhibition

“…Furthermore, the involvement of opioid receptor activation in insulinreceptor mediated increases in glutamate release found here is consistent with the ability of opioids in the NAc to enhance food intake and hedonic responses to palatable foods (Zhang and Kelley, 2000;Katsuura and Taha, 2013;Richard et al, 2013;Castro and Bruchas, 2019), and with conditioned increases in insulin in anticipation of palatable food consumption (Teff, 2011). Thus, results here have broad implications for the regulation of foodseeking and eating behavior by insulin, as well as motivation for non-essential reinforcers like cocaine (Naef et al, 2018) that also relies on NAc excitatory transmission. Finally, the NAc receives inhibitory input from GABAergic neurons in the VTA (Van Bockstaele and Pickel, 1995), in addition to local collateralization of MSNs and aspiny GABAergic interneurons (Smith and Bolam, 1990;Kawaguchi, 1993;Planert et al, 2010).…”

“…Insulin modulates dopamine systems at the level of VTA dopamine neurons (Mebel et al, 2012;Labouebe et al, 2013;Liu et al, 2013) and at dopamine terminals within the NAc (Stouffer et al, 2015;Naef et al, 2018). Within VTA, relatively high concentrations of insulin (100-500 nM) reduce presynaptic glutamate release onto VTA dopamine neurons (Labouebe et al, 2013;, while within the NAc 30 nM, but not 100 nM, insulin enhances dopamine release by increasing cholinergic interneuron firing (Stouffer et al, 2015).…”

Metabolic and Addiction Indices in Patients on Opioid Agonist Medication-Assisted Treatment: A Comparison of Buprenorphine and Methadone

“…www.nature.com/scientificreports www.nature.com/scientificreports/ Marginally higher (i.e., trend significance) addiction severity in OUD comorbidity with MetS would support this sort of an interaction regardless of the primary index event. Of note, insulin mediates the homeostatic and reward systems' cross-talk (impairment of which might underlie the chronically relapsing nature of addictive disorders) and it has been successfully tried in nicotine 116,117 and cocaine 118 addiction. It would be of interest to test whether insulin is also able to improve metabolic and reward dysfunction in patients with OUD.…”

Addiction in focus: molecular mechanisms, model systems, circuit maps, risk prediction and the quest for effective interventions

“…Preclinical studies also explore novel treatment approaches. For example, insulin in the VTA reduced cocaine‐evoked DA in the nucleus accumbens in vivo (Naef et al ., ) with other data highlighting the mechanistic underpinnings of R‐modafinil and its bis(F) analogs as pharmacological tools to guide the discovery of novel medications to treat psychostimulant use disorders (Keighron et al ., ). However, one has to be cognizant of the evidence suggesting that DA agonists may precipitate de novo impulse control disorders, although this response can partially be attenuated by the beta‐adrenoceptor antagonist propranolol (Cocker et al ., ).…”