New Vistas in the Neurobiology of Alcoholism and Depression: The role of CART peptides

1. New Vistas in the Neurobiology of Alcoholism and Depression: The role of CART peptides Pastor R. Couceyro, Ph.D. Department of Cellular and Molecular Pharmacology Rosalind Franklin University of Medicine and Science

2. addiction anxiety depression

3. CART (Cocaine- and Amphetamine-Regulated Transcript) peptides • The gene was discovered first in a screen for cDNAs that were regulated by acute psychostimulant administration. • CART peptides are expressed by neurons in the brain and gut, the pituitary and the adrenal glands. • In the brain, CART peptides 55-102 and 62-102 predominate. They are heterogeneously distributed in limbic, cortical, hypothalamic and brainstem areas.

4. CART (Cocaine- and Amphetamine-Regulated Transcript) peptides • CART peptides are anorectic, anxiogenic and antinociceptive. • CART peptides are involved in stress responses. • CART peptides are believed to modulate the behavioral effects of psychostimulants and other drugs of abuse.

5. CART KO mouse Mice with a deletion of the CART gene or knockout (KO) were generated. The effects of drugs of abuse in adult CART KO and wild-type (WT) mice were examined in several animal models of drug addiction.

6. CART peptides and Psychostimulants Intravenous cocaine self-administration is attenuated in CART KO mice. (n = 10) (n = 10)

7. Psychostimulant Effects in CART KO mice WT vs. KO mice amphetamine hyperlocomotion WT > KO amphetamine locomotor sensitization WT > KO amphetamine conditioned place preference WT > KO cocaine self-administration (IV) WT > KO sucrose preference similar novel open field activity similar learning (operant response) similar in press, J. Pharm. Exp. Ther.

8. Ethanol Effects in CART KO mice Ethanol induced hyperlocomotion is not observed in CART KO mice. (n = 10) (n = 10) (n = 5) (n = 5)

9. Ethanol Effects in CART KO mice Voluntary oral ethanol consumption and ethanol preference is reduced in CART KO mice. (n = 15) (n = 15)

10. Ethanol Effects in CART KO mice WT vs. KO mice intake (oral) WT > KO preference (oral) WT > KO hyperlocomotion WT > KO sedation similar taste reactivity: sweet (saccharin) similar bitter (quinine) similar clearance similar

11. CART peptides in Depression • Over 40% of alcoholics also suffer from depression. • Depression has multiple etiologies and subpopulations of affected individuals. • One cause of depression is a maladaptive stress response.

12. Hypothesis Insufficient or excessive CART peptide neurotransmission may cause alcoholism and drug addiction, and depression.

13. CART peptides in Depression stress ACTH CRF adrenal glands PVN pituitary sensory cortex CART peptides are found in both central and peripheral sites that mediate stress responses. hippocampus glucocorticoids amygdala adrenal glands spinal cord LC adrenaline

14. CART peptides in Depression • CART peptides are anxiogenic. • CART peptide 55-102 increases anxiety in the elevated plus maze test. • CART peptide 62-102 has no effect on anxiety in the elevated plus maze test.

15. CART peptides in Depression CART peptides inhibit the acoustic startle response. CART peptide 55-102 CART peptide 62-102 J. Pharm. Exp. Ther. (2001) 299, 1021-26.

16. CART peptides in Depression CART KO mice exhibit abnormal social interactions in the resident-intruder test. (WT, n = 6) (KO, n = 6) (WT, n = 7) (KO, n = 7) (WT, n = 6) (KO, n = 6) (WT, n = 6) (KO, n = 6) bold, p< 0.01

17. CART peptides in Depression • CART peptides are found in both central and peripheral sites that mediate stress responses. • CART peptides are anxiogenic. • CART peptides inhibit the acoustic startle response. • CART KO mice exhibit abnormal social interactions.

18. CART peptides in Depression • At least two conditions can be identified with altered CART peptide activity that lead to drug addiction and/or depression. • Increased CART peptide activity may increase anxiety and the susceptibility to alcoholism and drug abuse. • Decreased or absent CART peptide activity may cause depression but reduced liability to alcohol and drug abuse.

19. Conclusions and Future Directions • Dysfunctional CART peptide neurotransmission may contribute to drug addiction, anxiety and depression. • Examine animal models of addiction and depression. • Further define the depression phenotype. • Alter CART peptide levels within specific brain regions and neural circuits and measure their effects in the these models. • Examine alcoholics and depressed populations. • Study single nucleotides polymorphisms of the CART gene. • Study CART expression in brain areas of affected individuals.

20. Anthony de la Cruz Tim D’Alfonso Matt Dube Charity Evans Da Sheng Gu Leila Hagshenas Anna Layung Darrion Mitchell Amgen Anthony Bannon Jim Douglass Audra McKinzie William Richards Acknowledgements Supported by the Shweppe Foundation and NIDA/NIH.