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. 2019 May;44(6):1141-1151.
doi: 10.1038/s41386-018-0306-3. Epub 2019 Jan 7.

Insulin modulates the strong reinforcing effects of nicotine and changes in insulin biomarkers in a rodent model of diabetes

Bryan Cruz  1 , Rodolfo J Flores  1 , Kevin P Uribe  1 , Evangelina J Espinoza  1 , Charles T Spencer  2 , Katherine M Serafine  1 , Arbi Nazarian  3 , Laura E O'Dell  4
Affiliations

Insulin modulates the strong reinforcing effects of nicotine and changes in insulin biomarkers in a rodent model of diabetes

Bryan Cruz et al. Neuropsychopharmacology. 2019 May.

Abstract

This study examined whether the strong reinforcing effects of nicotine and changes in insulin biomarkers observed in diabetic rats are modulated via insulin. A model of diabetes was employed involving administration of streptozotocin (STZ), which produces hypoinsulinemia in rats. The present study included vehicle- or STZ-treated rats that received sham surgery or insulin pellets. Two weeks later, the rats were given extended access to intravenous self-administration (IVSA) of saline or nicotine. Concomitant changes in food intake, water responses, and body weight were assessed during 12 days of IVSA. After the last session, plasma levels of insulin, leptin, amylin, and glucagon-like peptide-1 (GLP-1) were assessed using Luminex® technology. In a separate cohort, phosphorylated insulin receptor substrate-2 (pIRS-2) and insulin growth factor-1 receptor β (IGF-1Rβ) were assessed in the nucleus accumbens (NAc) and ventral tegmental area (VTA) of vehicle- or STZ-treated rats that received sham surgery or an insulin pellet. STZ-treated rats displayed an increase in glucose levels, a decrease in body weight, and an increase in nicotine, food, and water intake relative to controls. STZ-treated rats also displayed a decrease in plasma insulin and leptin levels and an increase in amylin and GLP-1 levels relative to controls. Importantly, all of the STZ-induced changes in behavior and insulin biomarkers were prevented by insulin supplementation. STZ-treated rats also displayed a decrease in pIRS-2 and IGF-1Rβ in the NAc (but not VTA), an effect that was also prevented by insulin. These data suggest that insulin systems in the NAc modulate the strong reinforcing effects of nicotine in male diabetic rats.

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Figures

Fig. 1
Fig. 1
Mean (±SEM) nicotine intake (A), nicotine infusions (B), active lever presses (C), and inactive lever presses (D) during each day (left panels) and averaged across days (right panels). The group sizes were as follows: vehicle-treated/saline IVSA (n = 10), vehicle-treated/nicotine IVSA (n = 17), STZ-treated/nicotine IVSA (n = 16), STZ-treated + insulin/nicotine IVSA (n = 13), and vehicle-treated + insulin/nicotine IVSA (n = 8). The asterisks (*) denote a significant difference from vehicle-treated/saline IVSA rats, and the daggers (†) denote a difference from all other groups (p ≤ 0.05)
Fig. 2
Fig. 2
Mean (±SEM) food intake (A), water responses (B), and weight change (C) during each day (left panels) and averaged across days (right panels). The group sizes were as follows: vehicle-treated/saline IVSA (n = 10), vehicle-treated/nicotine IVSA (n = 17), STZ-treated/nicotine IVSA (n = 16), STZ-treated + insulin/nicotine IVSA (n = 13), and vehicle-treated + insulin/nicotine IVSA (n = 8). The asterisks (*) denote a significant difference from vehicle-treated/saline IVSA rats, and the daggers (†) denote a difference from all other groups (p ≤ 0.05)
Fig. 3
Fig. 3
Mean (±SEM) plasma levels of insulin (A), leptin (B), amylin (C), and GLP-1 (D) collected after the last IVSA session. The daggers (†) denote a significant difference from all other groups (p ≤ 0.05), and the number signs (#) denote a difference from vehicle-treated rats that pressed for nicotine
Fig. 4
Fig. 4
Mean (±SEM) protein levels of pIRS-2 (A, B) and IGF-1Rβ (C, D) in the NAc (left panels) and VTA (right panels). The group sizes were as follows: vehicle-treated (n = 6), STZ-treated (n = 6), and STZ-treated + insulin (n = 5). The asterisks (*) denote a significant difference from vehicle-treated rats, and the daggers (†) denote a difference from all other groups (p ≤ 0.05)
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