University of Texas at El Paso Laura E. O’Dell, Ph.D.

1. University of Texas at El PasoLaura E. O’Dell, Ph.D. Mechanisms of Vulnerability to Tobacco Abuse

2. 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

3. 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?

4. 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).

5. 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.

6. Experimental Question: • Do diabetic animals display enhanced rewarding effects of nicotine?

7. 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.

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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.

14. Potential confound • STZ-treated rats displayed enhanced operant responding for food, water and nicotine. • Are STZ-treated rats more active?

15. 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

16. 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?

17. Questions? Questions?

18. 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

19. 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

21. Insulin regulation of glucose levels