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The Addicted Synapse Katie Malanson
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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.
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Addiction hijacks Natural Reward Pathways
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Addiction hijacks Natural Reward Pathways
Self Stimulation (Percent) Routtenberg 1978
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From Mice to Men: Reward Pathway in Humans
PFC – Prefrontal Cortex NAc – Nucleus Accumbens VTA – Ventral Tegmental Area PFC PFC VTA NAc NAc VTA
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Cocaine activates the Reward Pathway
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Cocaine activates the Reward Pathway
The Amygdala is important for the emotional aspects of addiction
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Neurotransmitter Transporters
The Synapse Presynaptic Neuron Voltage-Gated Ca2+ Channels AP Ca2+ Postsynaptic Neuron Slowly acting receptors – Ion channel is separate from receptor Slow excitation or Slow inhibition Ion Channel Neurotransmitter Neurotransmitter Transporters Ca2+ Fast excitation Fast acting receptors are ion channels Cl- Fast inhibition
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Neurotransmitter Transporters
The Synapse Presynaptic Neuron Voltage-Gated Ca2+ Channels AP Ca2+ Postsynaptic Neuron Slowly acting receptors – Ion channel is separate from receptor Slow excitation or Slow Inhibition Ion Channel Neurotransmitter Neurotransmitter Transporters Ca2+ Fast excitation Fast acting receptors are ion channels Cl- Fast inhibition
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The Dopamine Synapse Presynaptic Neuron Postsynaptic Neuron AP
Ca2+ Voltage-Gated Ca2+ Channels Dopamine only has slowly acting receptors with ion channel separate from receptor Slow excitation or Slow Inhibition Ion Channel Dopamine Dopamine Transporters
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Drugs of abuse alter dopamine signaling between the VTA and the NAc
Prefrontal Cortex VTA NAc Amygdala Dopamine Glutamate
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VTA Presynaptic Neuron
Effect of Cocaine VTA Presynaptic Neuron NAc Postsynaptic Neuron AP Ca2+ Voltage-Gated Ca2+ Channels Dopamine only has slowly acting receptors with ion channel separate from receptor Ion Channel Dopamine Cocaine X Slow excitation or Slow Inhibition Dopamine Transporters Cocaine blocks the dopamine transporter. More dopamine is available at the synapse. Postsynaptic signaling through the dopamine receptor is increased.
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Drugs of abuse alter dopamine signaling between the VTA and the NAc
Nicotine Prefrontal Cortex Dopamine VTA NAc Amygdala Dopamine Glutamate
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Drugs of abuse alter dopamine signaling between the VTA and the NAc
Ethanol Inhibitory neuron Prefrontal Cortex Dopamine VTA NAc Dopamine
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Drugs of abuse alter dopamine signaling between the VTA and the NAc
Heroin & other opiates Inhibitory neuron Prefrontal Cortex Dopamine VTA NAc Heroin & other opiates Opiate receptors
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Conclusion: Drugs of abuse increase dopamine signaling between the VTA and the NAc.
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Tolerance and Dependence
VTA Presynaptic Neuron AP Ca2+ Ca2+ NAc Postsynaptic Neuron Ion Channel Dopamine Transporters Dopamine Receptors are activated Signaling increases CREB transcription factor is activated Gene transcription increases - Dynorphin
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Tolerance and Dependence
VTA Dynorphin NAc Dopamine The increased Dynorphin is released by the NAc It acts on the VTA to reduce Dopamine release
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Tolerance, Dependence and Relapse: Drugs of Abuse Alter Gene Expression
Drugs of abuse increase dopamine release Transcription factors increase When CREB goes up When Delta FosB goes up Dynorphin decreases Dopamine release from the VTA Cdk5 alters the structure of the NAc neuron
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Drugs of Abuse alter Synaptic Structure: Potential for Relapse
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dopamine release from the VTA
Tolerance, Dependence and Relapse: Drugs of Abuse Alter Gene Expression When CREB goes up When Delta FosB goes up Cdk5 alters the structure of the NAc neuron: Dopamine signaling increases Dynorphin decreases dopamine release from the VTA FAST BUT TRANSIENT SLOW AND SUSTAINED
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dopamine release from the VTA TOLERANCE and DEPENDENCE
Tolerance, Dependence and Relapse: Drugs of Abuse Alter Gene Expression When CREB goes up When Delta FosB goes up Cdk5 alters the structure of the NAc neuron: Dopamine signaling increases Dynorphin decreases dopamine release from the VTA FAST SLOW AND SUSTAINED TOLERANCE and DEPENDENCE SENSITIVITY and RELAPSE
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Dopamine Receptors are Not Created Equal
D1 Receptors D2 Receptors Excitatory effects Inhibitory effects Stimulate Addiction Inhibit Addiction
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Tolerance and Relapse VTA Presynaptic Neuron NAc Postsynaptic Neuron
Ca2+ Ca2+ NAc Postsynaptic Neuron D1 and D2 Dopamine receptors D2 Ion Channel Dopamine Transporters D1 Ion Channel Inhibits addiction Stimulates addiction
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Highly impulsive rats have lower levels
“Addictive Personality”: Levels of Dopamine D2 Receptor predict how rats will self administer drugs Low Impulsive High Impulsive Area 1 Highly impulsive rats have lower levels of D2 receptor. Area 2 Dalley et al 2007
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“Addictive Personality”: Levels of Dopamine D2 Receptor predict how rats will self administer drugs
Low Impulsive High Impulsive Area 1 Area 1 Area 2 Area 2 Dalley et al 2007
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Conclusion: Lower levels of D2 receptors are associated with impulsive, addictive behaviors
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Social Stress decreases Dopamine D2 receptors
DA Receptor Levels When monkeys are raised together, subordinate monkeys have fewer D2 receptors. Morgan et al 2002
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Social Stress decreases Dopamine D2 receptors
Dominant Subordinate Cocaine The subordinate monkeys self administered more drugs than their dominant peers. Morgan et al 2002
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Drug use also alters Dopamine D2 Receptor Expression in Humans
Cocaine Abusers have lower levels of Dopamine D2 receptor.
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Addiction as a Disease: Drug use inhibits brain activity like heart disease inhibits heart activity.
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Other influences on the NAc
Cortical development Affects the NAc Hippocampus Prefrontal Cortex Learning affects the NAc VTA NAc Amygdala Emotion affects the NAc
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Maturation of PFC The PFC does not reach maturity until mid 20s.
Loss of Grey Matter Due to Synaptic Pruning 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. MRI Study of 13 children scanned every 2 years Gogtay et al 2004
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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.
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Addiction Overview
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Synaptic Transmission
Presynaptic Neuron Voltage-Gated Ca2+ Channels AP Ca2+ Ca2+ Postsynaptic Neuron Ion Channel Neurotransmitter Receptor: 2nd Messenger Gated 2nd Messenger Signal Cascade Excitatory or Inhibitory Signal DA Transporters Ca2+ Neurotransmitter Receptor: Ligand-Gated Ion Channel Excitatory Signal Cl- Inhibitory Signal Cl-
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Drugs of Abuse Effect Synaptic Transmission Involvement of Glutamate
Hippocampus Prefrontal Cortex VTA NAc Amygdala Dopamine Glutamate
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Tolerance and Dependence: Drugs of Abuse Alter Protein Expression
Change Protein Translation Change Protein Degradation PKA not degraded as quickly after chronic drug exposure, increases activation of cAMP Change Protein Targeting Opiate receptors internalized following chronic exposure to drug
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From Mice to Men: Reward Pathway in Humans
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Tolerance and Dependence: Drugs of Abuse Alter Protein Expression
Change Protein Translation Change Protein Degradation PKA not degraded as quickly after chronic drug exposure, increases activation of cAMP Change Protein Targeting Opiate receptors internalized following chronic exposure to drug
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Genetic Factors Enzymes involved in drug metabolism
Some alleles of alcohol dehydrogenase are protective Certain polymorphisms in cytochrome P-450 2A6 (nicotine metabolism) - protective Polymorphisms in receptors Certain dopamine D2 Receptor polymorphisms – increase vulnerability
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Addiction hijacks Natural Reward Pathways
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The Dopamine Synapse Presynaptic Neuron (the VTA)
Ca2+ Postsynaptic Neuron (the NAc) Dopamine has a slowly acting receptor Ion Channel The ion channel is separate from the receptor Dopamine Transporters Dopamine Ca2+ Dopamine can produce slow excitation or slow Inhibition Ca2+ Fast excitation Cl- Fast inhibition Cl- Postsynaptic Neuron
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Synaptic Transmission
Presynaptic Neuron Voltage-Gated Ca2+ Channels AP Ca2+ Ca2+ Postsynaptic Neuron Ion Channel Neurotransmitter Receptor: 2nd Messenger Gated DA Transporters Neurotransmitter Receptor: Ligand-Gated Ion Channel
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