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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. addiction. anxiety. depression.

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new vistas in the neurobiology of alcoholism and depression the role of cart peptides

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

slide2

addiction

anxiety

depression

cart cocaine and amphetamine regulated transcript peptides
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.
cart cocaine and amphetamine regulated transcript peptides4
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.
cart ko mouse
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.

cart peptides and psychostimulants
CART peptides and Psychostimulants

Intravenous cocaine self-administration is attenuated

in CART KO mice.

(n = 10)

(n = 10)

psychostimulant effects in cart ko mice
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.

ethanol effects in cart ko mice
Ethanol Effects in CART KO mice

Ethanol induced hyperlocomotion is not observed in CART KO mice.

(n = 10)

(n = 10)

(n = 5)

(n = 5)

ethanol effects in cart ko mice9
Ethanol Effects in CART KO mice

Voluntary oral ethanol consumption and ethanol preference is reduced in CART KO mice.

(n = 15)

(n = 15)

ethanol effects in cart ko mice10
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

cart peptides in depression
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.
hypothesis
Hypothesis

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

cart peptides in depression13
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

cart peptides in depression14
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.
cart peptides in depression15
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.

cart peptides in depression16
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

cart peptides in depression17
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.
cart peptides in depression18
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.
conclusions and future directions
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.
acknowledgements
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.