Enhanced nicotine self-administration and suppressed dopaminergic systems in a rat model of diabetes

Abstract

Patients with diabetes display a heightened propensity to use tobacco; however, it is unclear whether they experience enhanced rewarding effects of nicotine. Thus, this study examined the reinforcing effects of nicotine in a rodent model of diabetes involving administration of streptozotocin (STZ), a drug that is toxic to pancreatic insulin-producing cells. The first study compared STZ- and vehicle-treated rats that had 23-hour access to intravenous self-administration (IVSA) of nicotine or saline and concomitant access to food and water. In order to examine the contribution of dopamine to our behavioral effects, dopamine transporter (DAT), D1 and D2 receptor levels were compared in the nucleus accumbens (NAc) following 10 days of nicotine or saline IVSA. Dopamine levels in the NAc were also compared following nicotine administration. Lastly, nicotine metabolism and dose-dependent effects of nicotine IVSA were assessed. The results revealed that STZ-treated rats displayed enhanced nicotine intake and a robust increase in food and water intake relative to controls. Protein analysis revealed an increase in DAT and a decrease in D1 receptor levels in the NAc of STZ- versus vehicle-treated rats regardless of IVSA condition. STZ-treated rats also displayed suppressed NAc dopamine levels during baseline and in response to nicotine. STZ treatment did not alter our assessment of nicotine metabolism. Furthermore, STZ treatment increased nicotine IVSA in a dose-dependent manner. Our findings suggest that STZ-treatment increased the rewarding effects of nicotine. This suggests that strong reinforcing effects of nicotine may contribute to greater tobacco use in patients with diabetes.

Enhanced vulnerability to tobacco use in persons with diabetes: A behavioral and neurobiological framework

“…The STZ model generally represents the etiology of type 1 diabetes or advanced stages of type 2 diabetes (Bell Jr. and Hye, 1983). The STZ model has been extensively studied and used to assess the complications of type 1 diabetes (Badalzadeh et al, 2015;Piculo et al, 2014), learning and memory (Bellush and Rowland, 1989;Flood et al, 1990), natural hedonic processing and drug reward (Carr, 1994;Carr et al, 2000;Galici et al, 2003b;O'Dell et al, 2014). Thus, the STZ model represents a common method of inducing diabetes via disruptions in insulin signaling.…”

“…To study nicotine reward, a model involving 23-hour access to intravenous self-administration of nicotine was used (O'Dell et al, 2014). The latter study also compared nicotine metabolism and dose-dependent effects of nicotine self-administration across groups.…”

“…This review paper extends prior work by presenting a neurobiological hypothesis that diabetes enhances nicotine reward via a disruption in insulin signaling that suppresses dopamine systems. This hypothesis was developed from pre-clinical work showing that the rewarding effects of nicotine are enhanced in rodent models of type 1 (O'Dell et al, 2014) and type 2 (Richardson et al, 2014) diabetes. Below, we summarize studies that relate to our hypothesis regarding tobacco use in persons with diabetes.…”

Insight into the Potential Factors That Promote Tobacco Use in Vulnerable Populations

“…Previous studies have shown that STZtreated rats display a profound suppression of dopamine release and D1 receptors in the NAcc [62]. Also, STZ-treated rats display a suppression of dopamine release in the dorsal striatum [90][91][92][93][94].…”

“…The HFD model of diabetes produces insulin resistance and hyperglycemia following chronic exposure to a HFD regimen. Pre-clinical studies have revealed that STZ-treated rats display higher levels of nicotine IVSA as compared to healthy controls [62]. A subsequent study revealed that insulin resistance, produced by HFD regimen, potentiates CPP produced by nicotine [63].…”