University of Texas at El PasoLaura E. O’Dell, Ph.D. Mechanisms of Vulnerability to Tobacco Abuse
Acknowledgements Financial Support from: • Start up funds from The University of Texas at El Paso • National Institute on Drug Abuse (R01-DA-021274) O’Dell Lab
Mechanisms of Vulnerability to Tobacco Abuse: • Age: Adolescence is a unique period of development • Sex: Females are particularly vulnerable • Disease states: Can disease states such as Diabetes influence drug vulnerability?
What is Diabetes? Diabetes is a disease in which the body does not produce or properly use insulin. Insulin is a hormone that is needed to allow glucose to enter the cells and fuel them. • Type 1 diabetesPancreas does not produce insulin. • Type 2 diabetes The body does not properly use insulin (insulin resistance). There is often insulin deficiency. • Gestational diabetes Immediately after pregnancy, 5% to 10% of women are found to have diabetes, usually, type 2. • Pre-diabetes Blood glucose is higher than normal but not high enough for a diagnosis of type 2 diabetes (above 200 mg/dl after a glucose drink).
Diabetes and smoking • People with diabetes are 3 times as likely to die from heart attack or stroke. Diabetic smokers are 11 times more likely to die of a heart attack or stroke. • Smoking increases cholesterol levels, constricts blood vessels, and reduces the amount of oxygen in tissues---all of which compound problems caused by diabetes. • Smoking also raises blood sugar levels and reduces the body's ability to utilize insulin, making it hard to control diabetes. • However, it is unclear whether diabetics are more vulnerable to tobacco abuse.
Experimental Question: • Do diabetic animals display enhanced rewarding effects of nicotine?
Streptozocin (STZ): Animal model of Diabetes • STZ is structurally similar glucose and binds to glucose transporters. • STZ has the highest affinity transporters (GLUT2) that are highly localized in the insulin-producing cells of the pancreas. • STZ alkylates DNA forming DNA cross links and inhibiting DNA synthesis.
Self-administration Paradigm Nicotine -5 days food and water training -Administer STZ (35-50 mg/kg X 2 5 days apart) Water Food -Intravenous catheter implantation -7 days of access to nicotine: Reinforcement Schedule: FR1 Nicotine Dose: 0.03 mg/.1ml infusion
STZ treatment produced High and Low Diabetic rats Controls n=4 Controls n=4 Low n=5 600 High n=6 500 Mean glucose=470 400 Glucose levels (mg/dl; +SEM) 300 Mean glucose=150 200 Mean glucose=127 100 0 1 2 3 4 5 6 7 Test Day
Food Intake was Greater In High Diabetic rats Controls n=4 Low n=6 High n=5 Controls n=4 1200 Low n=6 High n=5 Mean intake=891 1000 Mean intake=700 800 Operant responses (+SEM) Mean intake=684 600 400 200 0 1 2 3 4 5 6 7 Test Day
Water Intake Was Higher In Diabetic rats Controls n=4 Low n=6 8000 High n=5 Mean intake=4,736 6000 Operant responses (+SEM) 4000 Mean intake=1,317 2000 Mean intake=710 0 1 2 3 4 5 6 7 Test Day
Nicotine Intake Was Higher In Diabetic rats Controls n=4 controls Low n=6 intermediate 120 High n=5 100 80 Operant responses (+SEM) Mean intake=77 60 40 Mean intake=45 Mean intake=30 20 0 1 2 3 4 5 6 7 Test Day
SUMMARY • STZ-treated rats respond more for food and water, as expected in diabetic animals. • However, STZ-treated rats also displayed enhanced nicotine intake. • These data suggest that the rewarding effects of nicotine are facilitated in diabetic rats.
Potential confound • STZ-treated rats displayed enhanced operant responding for food, water and nicotine. • Are STZ-treated rats more active?
Inactive Lever Pressing was Similar Across Treatment Conditions Controls n=4 controls controls Low n=6 intermediate intermediate 120 High n=5 100 80 Operant responses (+SEM) 60 Mean intake=24 40 Mean intake=19 20 Mean intake=16 0 1 2 3 4 5 6 7 Test Day
Future Studies • It is possible that the higher levels of nicotine self-administration in diabetic rats is due to enhanced responding for IV fluids. Do STZ-treated rats respond more for IV saline? • The question of whether diabetic rats display enhanced sensitivity to nicotine reward can be addressed using place preference procedures. • Do dopamine systems mediate enhanced sensitivity to nicotine reward in diabetic rats?
STZ-treated rats lost more weight Controls n=4 Intermediate n=6 450 High n=5 Mean weight=370 400 Mean weight=344 350 Operant responses ( SEM) Mean weight=325 300 250 200 1 2 3 4 5 6 7 Test Day
Insulin and Dopamine • Enhanced Insulin===>Enhanced dopamine • Hypoinsulemia--- Decreased dopamine synthesis, turnover, behavioral responses to dopamine agonists DRUGS OF ABUSE: Insulin receptors are highly localized in mesolimbic system STZ treated rats decreased amphetamine self-administration (but increased methamphet CPP) Reduction of insulin in VTA decreases cocaine-CPP Chronic exposure to drugs causes a downregulation of insulin receptors and signaling