The Addicted Synapse

1. The Addicted Synapse Katie Malanson

2. 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.

3. Addiction hijacks Natural Reward Pathways

4. Addiction hijacks Natural Reward Pathways Self Stimulation (Percent) Routtenberg 1978

5. PFC – Prefrontal Cortex NAc – Nucleus Accumbens VTA – Ventral Tegmental Area From Mice to Men: Reward Pathway in Humans PFC PFC VTA NAc NAc VTA

6. Cocaine activates the Reward Pathway

7. Cocaine activates the Reward Pathway The Amygdala is important for the emotional aspects of addiction

8. The Synapse AP Ca2+ Ca2+ Ca2+ Ca2+ Neurotransmitter Slow excitation or Slow inhibition Ca2+ Ca2+ Fast excitation Fast inhibition Cl- Cl- Presynaptic Neuron Voltage-GatedCa2+ Channels Postsynaptic Neuron Ca2+ Slowly acting receptors – Ion channel is separate from receptor Ion Channel NeurotransmitterTransporters Fast acting receptors are ion channels

9. The Synapse AP Ca2+ Ca2+ Ca2+ Ca2+ Neurotransmitter Slow excitation or Slow Inhibition Ca2+ Ca2+ Fast excitation Fast inhibition Cl- Cl- Presynaptic Neuron Voltage-GatedCa2+ Channels Postsynaptic Neuron Ca2+ Slowly acting receptors – Ion channel is separate from receptor Ion Channel NeurotransmitterTransporters Fast acting receptors are ion channels

10. The Dopamine Synapse AP Ca2+ Ca2+ Ca2+ Ca2+ Dopamine Slow excitation or Slow Inhibition Presynaptic Neuron Postsynaptic Neuron Ca2+ Voltage-GatedCa2+ Channels Dopamine only has slowly acting receptors with ion channel separate from receptor Ion Channel DopamineTransporters

11. Drugs of abuse alter dopamine signaling between the VTA and the NAc PrefrontalCortex VTA NAc Amygdala Dopamine Glutamate

12. Effect of Cocaine AP Ca2+ Ca2+ Ca2+ Ca2+ Dopamine VTAPresynaptic Neuron NAcPostsynaptic Neuron Ca2+ Voltage-GatedCa2+ Channels Dopamine only has slowly acting receptors with ion channel separate from receptor Ion Channel Cocaine X Slow excitation or Slow Inhibition DopamineTransporters • Cocaine blocks the dopamine transporter. • More dopamine is available at the synapse. • Postsynaptic signaling through the dopamine receptor • is increased.

13. Drugs of abuse alter dopamine signaling between the VTA and the NAc Nicotine PrefrontalCortex Dopamine VTA NAc Amygdala Dopamine Glutamate

14. Drugs of abuse alter dopamine signaling between the VTA and the NAc PrefrontalCortex Inhibitory neuron Ethanol Dopamine NAc VTA Dopamine

15. Drugs of abuse alter dopamine signaling between the VTA and the NAc PrefrontalCortex Inhibitory neuron Heroin & other opiates Dopamine NAc VTA Heroin & other opiates Opiate receptors

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

17. AP Ca2+ Ca2+ Ca2+ Ca2+ Tolerance and Dependence VTA Presynaptic Neuron Ca2+ NAc Postsynaptic Neuron Ion Channel Dopamine Transporters • Dopamine Receptors are activated • Signaling increases • CREB transcription factor is activated • Gene transcription increases - Dynorphin

18. Tolerance and Dependence VTA Dynorphin NAc Dopamine The increased Dynorphin is released by the NAc It acts on the VTA to reduce Dopamine release

19. 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

20. Drugs of Abuse alter Synaptic Structure:Potential for Relapse

21. 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

22. 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 SLOW AND SUSTAINED FAST TOLERANCE and DEPENDENCE SENSITIVITY andRELAPSE

23. Dopamine Receptors areNot Created Equal Dopamine D1 Receptors D2 Receptors Excitatory effects Inhibitory effects Stimulate Addiction Inhibit Addiction

24. AP Ca2+ Ca2+ Ca2+ Ca2+ Tolerance and Relapse VTA Presynaptic Neuron Ca2+ NAc Postsynaptic Neuron D1 and D2 Dopamine receptors D2 Ion Channel Dopamine Transporters D1 Ion Channel Inhibits addiction Stimulates addiction

25. “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

26. “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

27. Conclusion:Lower levels of D2 receptorsare associated with impulsive, addictive behaviors

28. Social Stress decreasesDopamine D2 receptors DA Receptor Levels When monkeys are raised together, subordinate monkeys have fewer D2 receptors. Morgan et al 2002

29. Social Stress decreases Dopamine D2 receptors Dominant Subordinate Cocaine The subordinate monkeys self administered more drugs than their dominant peers. Morgan et al 2002

30. Drug use also alters Dopamine D2 Receptor Expression in Humans Cocaine Abusers have lower levels of Dopamine D2 receptor.

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

32. Other influences on the NAc Cortical development Affects the NAc Hippocampus PrefrontalCortex Learning affects the NAc VTA NAc Amygdala Emotion affects the NAc

33. Maturation of PFC 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

34. 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.