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University of Texas at El Paso Laura 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

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university of texas at el paso laura e o dell ph d
University of Texas at El PasoLaura E. O’Dell, Ph.D.

Mechanisms of Vulnerability to Tobacco Abuse

acknowledgements
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
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
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
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
Experimental Question:
  • Do diabetic animals display enhanced rewarding effects of nicotine?
streptozocin stz animal model of diabetes
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.
slide8

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

slide9

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

slide10

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

slide11

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

slide12

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
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.
slide14

Potential confound

  • STZ-treated rats displayed enhanced operant responding for food, water and nicotine.
  • Are STZ-treated rats more active?
slide15

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
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?
slide18

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
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