the addicted synapse
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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.
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