The Addicted Synapse

Katie Malanson

Objectives, Part 2• Name the brain structures of the reward

pathway.• Describe the connections between the brain

structures in the reward pathway• Describe how drugs of abuse alter synaptic

transmission.• Describe the molecular biology behind

tolerance, dependence, and relapse.• Explain the benefit derived from increased

expression of dopamine D2 receptors.

Addiction hijacks Natural Reward Pathways

Addiction hijacks Natural Reward Pathways

Routtenberg 1978

Se

lf S

timu

latio

n

(Pe

rce

nt)

From Mice to Men: Reward Pathway in Humans

PFC – Prefrontal Cortex

NAc – Nucleus Accumbens

VTA – Ventral Tegmental Area

VTANAc

PFCVTANAc

PFC

Cocaine activates the Reward Pathway

Cocaine activates the Reward Pathway

The Amygdala is important for the emotional aspectsof addiction

The SynapsePresynaptic Neuron

NeurotransmitterTransporters

AP

Fast acting receptors are ion channels

Slowly acting receptors – Ion channel is separate from receptor

Ion Channel

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Postsynaptic Neuron

Neurotransmitter

Ca2+

Fast excitationCa2+

Cl- Fast inhibitionCl-

Slow excitation or Slow inhibition

Voltage-GatedCa2+ Channels

The SynapsePresynaptic Neuron

AP

Slowly acting receptors – Ion channel is separate from receptor

Ion Channel

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Postsynaptic Neuron

Neurotransmitter

Ca2+

Fast excitationCa2+

Cl- Fast inhibitionCl-

Slow excitation or Slow Inhibition

Fast acting receptors are ion channels

Voltage-GatedCa2+ Channels

NeurotransmitterTransporters

The Dopamine Synapse

Presynaptic Neuron

DopamineTransporters

AP

Dopamine only has slowly acting receptors with ion channel separate from receptor

Ion Channel

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Postsynaptic Neuron

Dopamine

Slow excitation or Slow Inhibition

Voltage-GatedCa2+ Channels

VTAVTA

NAc

Dopamine

Drugs of abuse alter dopamine signaling between the VTA and the NAc

PrefrontalCortex

Amygdala

Glutamate

Effect of CocaineVTAVTA

Presynaptic Neuron

DopamineTransporters

AP

Dopamine only has slowly acting receptors with ion channel separate from receptor

Ion Channel

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

NAcNAcPostsynaptic Neuron

Dopamine Slow excitation or Slow Inhibition

Voltage-GatedCa2+ Channels

XCocaine

1. Cocaine blocks the dopamine transporter.2. More dopamine is available at the synapse.3. Postsynaptic signaling through the dopamine receptor

is increased.

VTAVTA

NAc

Dopamine

Drugs of abuse alter dopamine signaling between the VTA and the NAc

PrefrontalCortex

Amygdala

Glutamate

Nicotine

Dopamine

VTAVTA

Dopamine

PrefrontalCortex

Ethanol

Dopamine

Inhibitoryneuron

Drugs of abuse alter dopamine signaling between the VTA and the NAc

VTAVTA

Opiate receptors

PrefrontalCortex

Heroin &other opiates

Dopamine

Inhibitoryneuron

Heroin &other opiates

Drugs of abuse alter dopamine signaling between the VTA and the NAc

Conclusion:

Drugs of abuse increase dopamine signaling between the VTA and the NAc.

Dopamine Transporters

AP

Ca2+

Ion Channel

Ca2+

Ca2+

Ca2+

Ca2+

Presynaptic Neuron

Postsynaptic Neuron

Tolerance and DependenceVTA

NAc

1. Dopamine Receptors are activated2. Signaling increases3. CREB transcription factor is activated4. Gene transcription increases - Dynorphin

Tolerance and Dependence

VTA

NAc

Dynorphin

Dopamine

The increased Dynorphin is released by the NAcIt acts on the VTA to reduce Dopamine release

Tolerance, Dependence and Relapse: Drugs of Abuse Alter Gene Expression

Drugs of abuse increase dopamine release

Transcription factors increase

Dynorphin decreasesDopamine release from

the VTA

When CREB goes up When Delta FosB goes up

Cdk5 alters the structure of the NAc neuron

Drugs of Abuse alter Synaptic Structure:Potential for Relapse

Tolerance, Dependence and Relapse: Drugs of Abuse Alter Gene Expression

Dynorphin decreasesdopamine release from

the VTA

When CREB goes up When Delta FosB goes up

Cdk5 alters the structure of the NAc neuron:

Dopamine signaling increases

FAST BUT TRANSIENT SLOW AND SUSTAINED

Tolerance, Dependence and Relapse: Drugs of Abuse Alter Gene Expression

Dynorphin decreasesdopamine release from

the VTA

When CREB goes up When Delta FosB goes up

Cdk5 alters the structure of the NAc neuron:

Dopamine signaling increases

FAST SLOW AND SUSTAINED

TOLERANCE and

DEPENDENCE

SENSITIVITY and

RELAPSE

Dopamine Receptors areNot Created Equal

Dopamine

D1 Receptors D2 Receptors

Stimulate Addiction Inhibit Addiction

Excitatory effects Inhibitory effects

Dopamine Transporters

AP

Ca2+

D1 and D2 Dopamine receptors

D2 Ion Channel

Ca2+

Ca2+

Ca2+

Ca2+

Presynaptic Neuron

Postsynaptic Neuron

Tolerance and RelapseVTA

NAc

D1 Ion Channel

Stimulates addiction

Inhibits addiction

“Addictive Personality”:Levels of Dopamine D2 Receptor predict how

rats will self administer drugs

Low Impulsive High Impulsive

Dalley et al 2007

Area 1

Area 2

Highly impulsive rats have lower

levelsof D2 receptor.

“Addictive Personality”:Levels of Dopamine D2 Receptor predict how

rats will self administer drugs

Low Impulsive High Impulsive

Dalley et al 2007

Area 1

Area 2

Area 1

Area 2

Conclusion:

Lower levels of D2 receptorsare associated with impulsive, addictive

behaviors

Social Stress decreasesDopamine D2 receptors

DA

Rec

epto

r Le

vels

Morgan et al 2002

When monkeys are raised together, subordinate monkeys have fewer D2 receptors.

Social Stress decreases Dopamine D2 receptors

Morgan et al 2002

Dominant

Subordinate

The subordinate monkeys self administered more drugs than their dominant peers.

Cocaine

Drug use also alters Dopamine D2 Receptor Expression in Humans

Cocaine Abusers have lower levels

of Dopamine D2 receptor.

Addiction as a Disease:Drug use inhibits brain activity like heart

disease inhibits heart activity.

VTAVTA

Other influences on the NAc

PrefrontalCortex

Hippocampus

Amygdala

Learning affects the NAc

Emotion affects the NAc

Cortical developmentAffects the NAc

Maturation of PFC

Gogtay et al 2004

MRI Study of 13 children scanned every 2 years

• The PFC does not reach maturity until mid 20s.

• Elimination extra synapses• Myelination of remaining synapses

• Drugs of abuse taken during maturation of brain drastically change the maturation process, having long lasting effects.

Loss of Grey Matter Due to Synaptic Pruning

Objectives, Part 2• Name the brain structures of the reward

pathway.• Describe the connections between the brain

structures in the reward pathway• Describe how drugs of abuse alter synaptic

transmission.• Describe the molecular biology behind

tolerance, dependence, and relapse.• Explain the benefit derived from increased

expression of dopamine D2 receptors.