Enhanced Acquisition of Cocaine Self-Administration in Rats Developmentally Exposed to Lead

1. Enhanced Acquisition of Cocaine Self-Administration in Rats Developmentally Exposed to Lead Angelica Rocha Texas A&M University October 13, 2004

2. Does Lead Remain a Problem Today? Levels of lead in blood remain higher for individuals: • who live in the inner city (>10ug/dl) with a disproportionate number being ethnic minorities (Pellizzari et al., 1999). • who reside in older homes that contain lead-based plumbing and paint (Manuel, 2003)

3. Pictures taken from CDC website 9/04. Lead Effects are Long-Lasting Lead is stored in bone for 20-30 years and is released into blood plasma during pregnancy. • Women raised in the 1970’s before stringent CDC lead regulations are now of childbearing age.

4. Lead Lead is a toxic heavy metal that crosses the placental barrier producing changes in neurotransmission via systems including those that are glutamatergic and dopaminergic.

5. In laboratory settings, a relation between lead-exposure and drug self-administration has been observed.

6. Developmental Lead and Heroin Chronic Presentation Heroin Procedure • Dose Effect Curve (Self-Administration) • Progressive-Ratio (Rocha et al., 2004) Effect Observed Attenuation • In lab settings an interaction between lead exposure and the rewarding effects of drugs of abuse, such as heroin and cocaine have been found.

7. Developmental Lead and Cocaine Chronic Presentation Cocaine Procedure • Dose-Effect Curve (Self-Administration) • Reinstatement (Nation 2003; 2004) Effect Observed Potentiation • Developmental lead exposure alters the effects of psychostimulants to a point where drug reward potency is dramatically altered.

8. Purpose of Study Examine differential rates of drug acquisition in developmentally lead-exposed and control rats devoid of intrusions characteristic of drug-maintenance studies.

9. Adult Female Sprague-Dawleys 30-day exposure regimen via gavage (0, 16 pb) Females bred with non-exposed males Exposure with lead or control solution continued until weaning (PND 21) One male rat per litter was used in testing. Lead ExposurePerinatal (gestation & lactation) Animals: Sprague-Dawley rats [controls (n=7), lead-exposed (n=10)]

10. Operant Chambers Apparatus Two levers: (right- reinforcing; left- no programmed consequence) Infusion pumps: Delivered a .1 ml infusion over a 6-s period concurrently with lighting of stimulus light.

11. Cocaine (.2 mg/kg) acquisition testing lasted 35 days. 1st 3-hours 2nd 3-hours Component Autoshaping Operant Schedule Non/Contingent • Associations of light & lever to be made with infusion of drug. • After 15 sec if no response, automatic infusion administered (10 per hour; total of 30 per day). FR-1 • Active/Contingent responses were required for infusion. Cocaine Acquisition Testing Procedure

12. Acquisition Measures: • Rate to acquire cocaine acquisition criterion (50+ mean infusions over a two-day period during Operant Component). • Mean number of infusions after acquisition criterion was met.

13. Lead Concentrations Atomic Absorption Spectophotometry Dams Exposure Day 30 10 days of gestation Parturition (PND 2) Weaning (PND 21) Littermates PND 2 PND 21 Test Animals Termination

14. Results

15. m m g/dl) g/dl) Blood Lead Concentration ( Blood Lead Concentration ( ___________________________________________________________ _________________________________________________ Group 0 Group 0 - - mg Lead mg Lead Group 16 Group 16 - - mg mg Lead Lead Dams Dams Exposure Day 30 <1.0 <1.0 34.2 (7.0)* 34.2 (7.0)* 10 days of gestation 10 days of gestation <1.0 <1.0 21.0 (3.1)* 21.0 (3.1)* Parturition (PND Parturition (PND 2) <1.0 <1.0 36.4 (3.5)* 36.4 (3.5)* Weaning (PND 21) Weaning (PND 21) <1.0 <1.0 54.0 (3.7)* 54.0 (3.7)* Littermates Littermates PND 2 PND <1.0 <1.0 96.0 (8.1)* 96.0 (8.1)* PND 21 PND 21 <1.0 <1.0 16.0 (.8)* 16.0 (.8)* Test animals Test animals Termination Termination <1.0 <1.0 <1.0 <1.0 Mean (SEM) blood lead concentration values for dams, littermates Mean (SEM) blood lead concentration values for dams, littermates , and test animals. The symbol * indicates that control and lead and test animals. The symbol * indicates that control and lead - exposed animals were significantly different ( exposed animals were significantly different ( p .05). <

16. Rate to Cocaine Acquisition • As assessed by survival analysis, more lead-exposed animals (8 of 10) reached criterion across the testing period (35 days) than controls (3 of 7) [Kaplan-Meier, Breslow statistic (X² = 3.89, df=1, p< .05)].

17. Mean # of Infusions After Acquisition Was Reached • The double-dash hash lines reflect the median value for all animals that reached criterion. Open symbols and closed symbols represent the non-exposed and exposed conditions, respectively, t (9)= 2.22, p > .05).

18. Summary • Vulnerability to self-administer cocaine increased in animals exposed to lead in utero and through lactation. • In the human population, individuals born to mothers with high lead levels may also show a sensitivity to the rewarding potency of cocaine. • Lead accounts for approximately 10-40% of variability when examining behavioral problems (i.e. aggression, violence) [Needleman, 1996]. • Future studies will increase understanding of how environmental risk factors change the neurochemistry and function of the human brain to produce a vulnerabilty to drug abuse, especially in high risk populations.

19. Thank You! Acknowledgements: Fellow Graduate Student: Rodrigo Valles, M.S. Laboratory Technicians: Aaron Cardon, B.S. Carol McNamara, M.S. Undergraduate Assistants: Allison Davidson Avanthi Tayi Prinicipal Investigator: Jack Nation, Ph.D. *Texas Consortium in Behavioral Neuroscience