Interactions Between Reward and Stress Systems
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Marisela Morales NIDA Intramural Research Program Cellular Neurobiology Branch Cellular Neurophysiology Section PowerPoint PPT Presentation

Interactions Between Reward and Stress Systems. Marisela Morales NIDA Intramural Research Program Cellular Neurobiology Branch Cellular Neurophysiology Section. National Advisory Council on Drug Abuse. The Science of Drug Abuse & Addiction.

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Marisela Morales NIDA Intramural Research Program Cellular Neurobiology Branch Cellular Neurophysiology Section

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Interactions Between Reward and Stress Systems

Marisela Morales

NIDA Intramural Research Program

Cellular Neurobiology Branch

Cellular Neurophysiology Section

National Advisory Council on Drug Abuse

The Science of Drug Abuse & Addiction


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Identification of neuronal pathways , neurons and molecules that may be affected or participate in the biology of drugs of abuse

Diversity. Brain is made of neurons with different phenotypes

Connectivity. Different phenotypes of neurons establish functional interactions (synapses) that determine specific neuronal pathways (specific behaviors)

Information. Exchange of information among different neurons in a neuronal pathway is mediated by molecules

Drugs of abuse affect the structure and function of the brain


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Interactions between the stress and reward systems

Different models of stress have shown that it increases vulnerability to addictive drugs

Stressors increase drug self-administration

Prenatal stress increases amphetamine self-administration in the adult rat

Single or repeated exposure to stressful stimuli can augment the motor stimulant action of amphetamine, cocaine, or morphine

Stressors reinstate drug seeking (model of relapse).Recent findings

Foot shock reinstates cocaine seeking, however, transient inhibition of the VTA blocks drug seeking (McFarland, 2004)

Foot shock reinstates cocaine seeking and induces release of CRF, glutamate and DA in VTA of cocaine-experienced rats (Wang, et al., 2005)


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Investigate neuronal pathways , type of neurons and molecules that might mediate functional interactions between stress and reward systems


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Stress responses are mediated by corticotrophin-releasing factor (CRF) originated from different cell types located in several brain areas


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Reward responses are mediated by dopamine (DA) produced by neurons located in the ventral tegmental area (VTA)

Mesocorticolimbic DA system

Hippocampus

Prefrontal cortex

Nucleus accumbens

Ventral Tegmental

Area (VTA)

Olfactory tubercle

Amygdala

Dopamine neurons


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Interactions between stress and reward systems. Brain area?

VTA

(1) Application of CRF into VTA increases locomotor activity(Kalivas et al., 1987

CRF cell

Do CRF target VTA cells?

GABAergic or DAergic neurons?

(2) Footshock induces CRF release in VTA (Wang et al., 2005)

(3) In vivo administration of drugs of abuse or acute stress increase strength at excitatory synapses on DA neurons (Saal et al., 2003)


Do crf cells establish functional interactions synapses with cells located in vta

Do CRF cells establish functional interactions (synapses) with cells located in VTA?

(1) Rat brain sections were incubated with specific antibodies to label neurons containing CRF

(2) VTA ultra thin sections (70 nm in thickness) were obtained from labeled brain tissue

(3) Material was analyzed under the electron microscope


Do crf cells establish functional interactions synapses with cells located in vta1

CRF (-) axonal terminal

CRF (+) axonal terminals

Synapse

Presynaptic

CRF

CRF (-) dendrite

Do CRF cells establish functional interactions (synapses) with cells located in VTA?

Yes

Postsynaptic

dopamine?


Do crf cells establish synapses with dopaminergic neurons in vta

Do CRF cells establish synapses with dopaminergic neurons in VTA?

(1) Rat brain sections were incubated with antibodies against CRF and tyrosine hydroxylase (TH, marker of dopamine neuronsin VTA)

(2) VTA ultra thin sections (70 nm in thickness) were obtained from double labeled brain tissue

(3) Material was analyzed under the electron microscope


Do crf cells establish synapses with dopaminergic neurons in vta1

Symmetrical

synapse

CRF (+) axonal terminals

83 %

TH (+) dendrites

Do CRF cells establish synapses with dopaminergic neurons in VTA?

Yes

17 %

Asymmetrical

synapses

EXCITATORY

INHIBITORY


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Aim:

To investigateneuronal pathways, type of neurons and molecules that might mediate functional interactions between stress and reward

At the molecular level, CRF mediates its biological effects by interacting with three different proteins

  • CRF receptor 1 (CRF-R1)

  • CRF receptor 2 (CRF-R2)

  • CRF binding protein (CRF-BP)

Which of these molecules mediate the functional interactions between CRF and VTA dopaminergic neurons?

  • Are these proteins present in DAergic neurons in VTA?


Method

Method

DNA

mRNA

Protein

(Double in situ hybridization)

  • Brain sections were hybridized with a non-radioactive anti-sense TH riboprobeto label DAergic neurons

  • Same sections were hybridized with a radioactive anti-sense CRF-R1,CRF-R2andCRF-BP riboprobes to determine expression of any of these molecules within DAergic neurons

Results

CRF-R2 mRNA was not detected in VTA neurons

CRF-R1 and CRF-BP mRNA were detected in VTA neurons


Expression of crf receptor 1 crf r1 mrna in the ventral tegmental area

VTA

VTA

SNC

SNC

Expression of CRF Receptor 1 (CRF-R1) mRNA in the Ventral Tegmental Area

Regional Distribution

TH mRNA

CRF-R1 mRNA

Hybridization with non radioactive antisense RNA probes to detect TH mRNA

Hybridization with radioactive antisense RNA probes to detect CRF-R1 mRNA

VTA = Ventral Tegmental Area

SNC = Substantia Nigra Compacta


Expression of crf receptor 1 crf r1 mrna in dopaminergic neurons in the vta

Expression of CRF receptor 1 (CRF-R1) mRNA in dopaminergic neurons in the VTA

Hybridization with non radioactive antisense RNA probes to detect TH mRNA

Hybridization with radioactive antisense RNA probes to detect CRF-R1 mRNA

TH mRNA

CRF-R1 mRNA

Arrows indicate cellular co-expression of TH (dark color) and CRF-R1 (green grains) in VTA

71.46% of all CRF-R1expressing neurons aredopaminergic in VTA


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At the molecular level, CRF mediates its biological effects by interacting with three different proteins

  • CRF receptor 1 (CRF-R1)

  • CRF receptor 2 (CRF-R2)

  • CRF binding protein (CRF-BP)

CRF binding protein

  • Peripheral CRF-BP plays a role in lowering free circulating CRF levels

  • CRF-BP is expressed in different type of cells in many brain regions

    • (What is the role of CRF-BP in the brain?)

  • Studies with mouse midbrain slices indicates that CRF-BP is required for CRF to potentiate synaptic transmission by N-MDA (N-methyl-D-aspartate) receptors in VTA dopaminergic neurons


Expression of crf binding protein crf bp mrna in the ventral tegmental area

VTA

VTA

SNC

SNC

Expression of CRF Binding protein (CRF-BP) mRNA in the Ventral Tegmental Area

Regional Distribution

TH mRNA

CRF-BP mRNA

Hybridization with non radioactive antisense RNA probes to detect TH mRNA

Hybridization with radioactive antisense RNA probes to detect CRF-BP mRNA

VTA = Ventral Tegmental Area

SNC = Substantia Nigra Compacta


Expression of crf binding protein crf bp mrna in vta dopaminergic neurons

Expression of CRF Binding Protein (CRF-BP) mRNA in VTA Dopaminergic Neurons

CRF-BP mRNA

TH mRNA

Hybridization with non radioactive antisense RNA probes to detect TH mRNA

Hybridization with radioactive antisense RNA probes to detect CRF-BP mRNA


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Expression of CRF Binding Protein (CRF-BP) mRNA in VTA Dopaminergic Neurons

TH mRNA

CRF-BP mRNA


Summary

Summary

  • Within the VTA, CRF axonal terminals establish mainly asymmetrical (presumably excitatory) synapses with dopaminergic dendrites

Implications:

Following stress, synaptical release of CRF in VTA may directly activate dopaminergic neurons, inducing release of dopamine within the mesocorticolimbic system

  • Within the VTA, CRF-R1 and CRF-BP are preferentially expressed in dopaminergic neurons

Implications:

At the cellular level, CRF may affect dopaminergic neurotransmition by interacting with CRF-R1 and CRF-BP located with VTA dopaminergic cell bodies

  • We suggest CRF excitatory synapses on dopaminergic dendrites as a locus for the known interaction of stress mechanisms and themesocorticolimbic dopamine system (a system implicated in addiction, a number of stress-related psychiatric syndromes) and co-morbidity between the two


Why is this important

Why is this important?

We provide evidences indicating that stress system may directly activate the reward system through CRF-R1 and CRF-BP

New targets for medication development

CRF-BP is a molecule that interacts with CRF and is selectively present in DAergic neurons involved in the rewarding effects of drugs of abuse


Current and future studies

Current and future studies

(1) Brain circuitry involved in the direct interaction between stress and reward systems

Identification of CRF neurons that synapse on VTA dopaminergic neurons [brain distribution, cellular phenotype (receptors, neurotransmitters, etc.), afferents, etc.]

Determination the neurotransmitters (glutamate, GABA) present in CRF axonal terminals, and establish at the ultratructural level the distribution of CRF-R1 and CRF-BP

(2) Evaluation of effects of drugs of abuse on the CRF, CRF-R1 and CR-BP system

  • (3) Evaluation of the participation of CRF, CRF-R1 and CRF-BP system in cocaine and methamphetamine induced behaviors (collaboration with Dr. Roy Wise)

  • (4) Set up in vitro studies to determine functional molecular interactions among CRF, CRF-R1 and CRF-BP


Acknowledgement

Acknowledgement

  • Patricia Tagliaferro Ph.D.

    • (Ultrastructural studies)

  • Emma Roach

    • (In situ hybridization studies)

Support: NIDA IRP


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