Topics for this lecture
Drugs - All drugs of abuse induce dopamine release (?)
The anatomy of the reward pathway defines the road to drug abuse
(?)
Cellular adaptations to drugs of abuse - not so impressive - are
they important?
Systems adaptations to drugs of abuse - more impressive - way
more complicated!
Conclusion -
Many drugs of abuse act on receptors that endogenous 'transmitters' also activate
Drug
Endogenous ligands
Action on
Nicotine
THC
Opioids
Acetylcholine
anandamide, 2AG
Enk,ß-endorphin, Dyn
Ligand gated channels
Cannabinoid receptors (GPCRs)
Opioid GPCRs (µ,∂,k)
Cocaine
Amphetamine
MDMA (ecstasy)
5-HT, DA, NA transporters
DA,NA transporters, VMAT
(therefore multiple GPCRs)
5-HT transporters, VMAT
Three classes of drugs act on separate effectors that all increase
the release of dopamine
Class 1: GPCRs - opioids, cannabinoids, GHB
Class 2: Ionotropic receptors/ion channels - nicotine, alcohol
Class 3: Transporters - cocaine, methamphetamine, ecstasy
Class 1: GPCRs - opioids
1.
g-i coupled receptors
2.
Best known acute actions are ALL inhibitory
a. Increase Potassium Conductance
b. Decrease Calcium Conductance
c. Decrease Transmitter Release
By inhibiting neurons that release GABA - opioids can result in excitation
(dis-inhibition) - first described in hippocampus (1979) and is though
to happen in many areas including dopamine cells of the VTA.
3.
4.
Opioids increase dopamine release by dis-inhibiting dopamine neurons!
As with all G-Protein Coupled receptors - There is much more going on with opioid
receptor activation. We will discuss some of the downstream effectors.
Opioid inhibition of GABA IPSCs in different dopamine cells in the VTA
(inhibition of IPSCs results in less inhibition of dopamine cells)
Opioid inhibition of GABA-B IPSCs on different dopamine cells
Class 2: Ionotropic receptors/ion channels - nicotine
1.
2.
3.
4.
5.
Nicotinic acetylcholine receptors - multiple subunits, pentameric
Cation non-selective ion channel
Simple to see how the activation of these receptors will result in
an increase in excitability of dopamine cells.
These receptors are also found on presynaptic terminals, including
the terminals of dopamine cells. Activation of nicotinic receptors
increases dopamine release (transmitters at other terminals too).
One confounding problem in the dopamine system is the fact that
GABA neurons (inter-neurons) also have nicotinic receptors. Thus
under some conditions nicotine can decrease the activity of dopamine
cells by causing an increased release of GABA.
Figure 1.
Wooltorton, J. R. A. et al. J. Neurosci. 2003;23:3176-3185
Figure 6.
Wooltorton, J. R. A. et al. J. Neurosci. 2003;23:3176-3185
Copyright ©2003 Society for Neuroscience
Class 3: Transporters - cocaine, methamphetamine
1.
2.
3.
4.
5.
Cocaine blocks all monoamine transporters - dopamine, noradrenaline, 5-HT
Amphetamine and methamphetamine are substrates for the dopamine and
noradrenaline transporters, different from cocaine.
Amphetamine and methamphetamine are substrates for the vesicular
monoamine transporter - and thus deplete vesicular stores of monoamines.
These simple and straight forward mechanisms lead to VERY complicated
changes in downstream signaling. Think about all the subtypes of
monoamine receptors and how many things would be affected by an
increase in the extracellular levels of all monoamines.
Dopamine release in projection areas is dramatically increased. One
confounding problem is that the extracellular level of dopamine is also
increased in the dopamine cell body region. That results in the activation of
inhibitory dopamine receptors (D2) that decrease the activity of dopamine
cells. How does this line up with an increase in dopamine release in
projection areas??
Cocaine increases the size and the time course of the cloud of dopamine.
Control - localized diffusion
Cocaine - extended diffusion
Dopamine transporter
D2 receptor
Dopamine IPSC on a dopamine cell in the VTA
The dopamine transporter is the primary mechanism that terminates dopamine signaling.
Parts of the endogenous reward pathway and multiple sites that are directly
Affected by drugs of abuse.
Circuitry Mediating Goal-directed Behavior
MDthalamus
Ventral
Pallidum
glutamate
PFCortex
NA Core
GABA
VTA
Basolateral
Amygdala
Dopamine
??
Extended Amygdala
Central amydala
BNST
NA Shell
Circuitry Mediating Goal-directed Behavior
MDthalamus
Ventral
Pallidum
glutamate
PFCortex
NA Core
Amygdala - FEARmotivated behaviors
GABA
VTA
Basolateral
Amygdala
Dopamine
??
Extended Amygdala
Central amydala
BNST
NA Shell
Circuitry Mediating Goal-directed Behavior
MDthalamus
Ventral
Pallidum
glutamate
PFCortex
NA Core
Amygdala - FEARmotivated behaviors
GABA
VTA
Basolateral
Amygdala
Dopamine
??
Nucleus Accumbens - Rewardmotivated behaviors
Extended Amygdala
Central amydala
BNST
NA Shell
Circuitry Mediating Goal-directed Behavior
MDthalamus
Ventral
Pallidum
glutamate
Prefrontal Cortex - Valence of
stimulus
PFCortex
NA Core
Amygdala - FEARmotivated behaviors
GABA
VTA
Basolateral
Amygdala
Dopamine
??
Nucleus Accumbens - Rewardmotivated behaviors
Extended Amygdala
Central amydala
BNST
NA Shell
Circuitry Mediating Goal-directed Behavior
MDthalamus
glutamate
GABA
Ventral
Pallidum
Prefrontal Cortex - Valence of
stimulus
PFCortex
NA Core
Amygdala - FEARmotivated behaviors
Expression
of motivated
behavior
VTA
Basolateral
Amygdala
Dopamine
??
Nucleus Accumbens - Rewardmotivated behaviors
Extended Amygdala
Central amydala
BNST
NA Shell
Circuitry Mediating Goal-directed Behavior
MDthalamus
glutamate
GABA
Ventral
Pallidum
Prefrontal Cortex - Valence of
stimulus
PFCortex
NA Core
Amygdala - FEARmotivated behaviors
Expression
of motivated
behavior
VTA
Basolateral
Amygdala
Dopamine
??
Nucleus Accumbens - Rewardmotivated behaviors
Extended Amygdala
Central amydala
BNST
NA Shell
Extended Amygdala - Stressorinduced behaviors
Circuitry Mediating Goal-directed Behavior
MDthalamus
Ventral
Pallidum
glutamate
PFCortex
NA Core
GABA
VTA
Dopamine from the VTA goes to each
part of the circuit.
1. Alerts to novel stimulus
2. Alerts to learned associations
Basolateral
Amygdala
??
Extended Amygdala
Central amydala
BNST
NA Shell
Drug Seeking = Disruption of the Motive Circuit
Components critical for craving and drug seeking
Final common pathway
Ventral
Pallidum
PFCortex
NA Core
cue
VTA
stress
Basolateral
Amygdala Extended Amygdala
Central amydala
BNST
NA Shell
How were the disruptions studied
1. Inactivation of specific nuclei
2. Testing for reinstatement of drug seeking
3. Examining cerebral blood flow/O2 utilization
Drug Seeking = Disruption of the Motive Circuit
Components critical for craving and drug seeking
Final common pathway
Ventral
Pallidum
PFCortex
NA Core
cue
VTA
stress
Basolateral
Amygdala Extended Amygdala
Central amydala
BNST
NA Shell
Three general principles
1. Final common pathway - AMPA receptor in N.Accumbens
2. Modality-dependent stimuli - Cue/Stress/Drug induced
3. Mesocorticolimbic dopamine release
Drug Seeking = Disruption of the Motive Circuit
Components critical for craving and drug seeking
Final common pathway
Ventral
Pallidum
PFCortex
NA Core
cue
VTA
stress
Basolateral
Amygdala Extended Amygdala
Central amydala
BNST
NA Shell
Stages of addiction
1. Acute Drug Effects - this is what we know the MOST about
2. Transition to Addiction - transcriptional regulators - protein expression
3. End-Stage Addiction - enduring changes ??
Acute actions of opioids on neurons
Increase Potassium Conductance
Decrease Calcium Conductance
Decrease Transmitter Release
Long-term actions of opioids on neurons
Acute desensitization
Receptor down regulation
How do the acute and long-term actions of opioids result in addiction?
Acute - receptor desensitization/internalization
Chronic - receptor down regulation
If the decline was ONLY
the result of desensitization
The after-reaction is the result of counter-adaptation(s) someplace beyond the receptor.
When the agonist is removed the counter-adaptation takes time to re-adjust.
During the re-adjustment time the system is not at baseline (withdrawal).
There are MANY stages of withdrawal from drugs - some last forever
Simple case - One receptor - MANY effectors
Changes induced after prolonged receptor activation (red arrows)
Pre-synaptic inhibition by morphine is increased during withdrawal
WHY??
Chronic morphine treatment Up-regulates
an opioid sensitive adenylyl cyclase.
The increased cAMP increases transmitter
release.
The increased transmitter release is sensitive
to morphine
During withdrawal morphine inhibits transmission
by two mechanisms
What are the links from the acute cellular effects of drugs and the
development of addiction?
With repeated administration of drugs - there is a rewiring of key
synapses. Could this be mediated by the same processes that
underlie learning and memory (Synaptic plasticity - LTP/LTD)??
Dopamine cells in the VTA
The ratio of currents induced by AMPA and NMDA receptors can be used as an
indication of a change in synaptic plasticity.
The AMPA/NMDA is low in dopamine cells in control animals.
After treatment of animals with drugs the ratio is increased.
The results suggests that the drug treatment resulted in a LTP type change in transmission.
The same result was obtained after treatment of animals with MANY drugs of abuse.
What does this mean for the activity of dopamine cells?
What are potential mechanisms that would account of this result?
Animals will self-administer drugs
Results obtained from animals that
self-administer drugs
can be compared with animals that
receive the same drug given passively
This experiment will distinguish pure
pharmacology from the systems level
desire for the drug.
Bed Nucleus of the Stria Terminals is a site
known to be involved in relapse to drug seeking
Behavior.
The AMPA/NMDA was increased ONLY in
animals that self-administered either cocaine
or a food reward.
Drug abuse
A lot is known about how individual drugs of abuse act.
1. Which receptors
2. What second messengers
3. How gene expression may be changed
Some drugs of abuse are also used therapeutically (examples)
There are only theories about why these are drugs of abuse.
Theories by big names in the field - Wise, Koob
1. Some take drugs to feel good (activating endogenous reward)
2. Some take drugs to stop feeling bad (correct a neurochemical deficit)
Most people can use drugs with little or no long-lasting problems
The lives of some are dominated by drugs of abuse.
Why are some people affected in others not?
Is it the pharmacology of that drug in that person that is different?
Is it the brain neurochemistry/neurobiology that is different?