Recent experiments on mice are giving us interesting information on addiction, and suggesting that l-dopa may be able to control/mitigate addiction. This lecture about how dopamine works in addiction using a mouse model (poor mice) blew me away. The mice fell into two categories: maintenance users and vulnerable addict rats. The study of the dopamine postulates a reason for the difference.

20th Annual Drug Conference Washington State from 2019

Notes from lecture 3: Paul Phillips PhD
Dopamine Neurotransmission in Substance Use Disorders: from Preclinical studies

For a long time there were no agreed upon animal models: rats don’t steal money from other rats to buy drugs. However, rats do get addicted and this can be studied.

There are features in rats, rat behavior and rat brains that might translate to humans.

1. Basic discoveries about dopamine neurotransmission in substance use disorders is discussed.
A neurotransmitter study checking every ten minutes in brain examines two areas: dorsal and ventral striatum. Dopamine is increased in the area between cells from the administration of substances “first time use” in animal models: cocaine, alcohol, methadone, cannabinoids, nicotine, amphetamine, morphine. This is the first clue re addictive drugs, whether there is an increase in dopamine intraneuronally. The endpoint is that direct effect on dopamine receptors, which has a different brain mechanism for each drug. Cocaine blocks the receptor that reuptakes the drug into the neuron. Methamphetamines and amphetamines reverse the reuptake pump, makes the receptor spit it out. Gaba neurons act to inhibit dopamine neurons, normally mu receptors on the gaba interneurons and the opioids block those. Ethanol has another mechanism of action. It changes inhibitory activity, lowering the inhibition of the gaba interneurons. Nicotine REALLY messes with multiple receptors and multiple cells, but main effect is increase of dopamine in the striatum.
Increased dopamine in human brain relates to the feeling of being high: brain PET scans show amphetamine and dopamine bound less, reduction in the binding. Subjects were substance abusers. Subjective questioning of how high they felt correlated with the amount of dopamine released on the PET scan. Methylphenidate was used in that study. Canada study: cocaine increases dopamine in human brain by PET scan.
Addiction does lead to changes in the brain, on both PET scans and functional MRIs.
PET scans measuring dopamine binding in the brain show that the baseline in brains of substance abusers differs from non-abusers. The levels of dopamine receptors is lower in the substance overuses and there is lower binding than controls: heroin, alcohol, meth, cocaine (and obesity and ADHD…..). (This has been known for opioid overuse and chronic use for a while: the brain cells withdraw receptors, so the same dose does not reduce pain because there are less receptors. The change in receptors appears to vary in different subjects. Recovery is very slow.)
The role of dopamine has been confusing. It is known that it is involved in the cue evoking cocaine “craving”, but is also involved with — satiety. This has been confusing and contradictory — what does dopamine do but also the dynamic structural signaling.

2. The animal studies demonstrate that the dopamine signals are phasic.
Rat studies measure changes in dopamine minute to minute electrochemistry for sub-second dopamine detection in vivo, which means we can measure changes in dopamine in real time. There is an identified output signature for dopamine levels, measure in 8.5 millisecond, ten measures per second.
The rats were voluntarily taking cocaine. The cocaine was available in a liquid with a light that would come on when it was available, for two hours daily. The animal presses a lever when the light cue is on and gets an infusion of drug. With the ten measures per second, the first and smaller dopamine response in the brain is before the lever is pressed. That is, there is a rise in dopamine BEFORE the rat presses the lever. If stimulated dopamine, the animal would go press the lever. Then there is a larger reward dopamine signal when the drug hits.
Dopamine is the chicken and the egg: signal to USE and signal that has ARRIVED.

3. Changes that take place with drug use
There is a signal change over time that correlation with features of addiction.
The mice had an implanted brain electrode, tinier than human hair, 7 microns, biocompatability — don’t make the brain attack it as a foreign object so rat brain keeps working. The study involves tyrosine hydroxylase, a precursor of dopamine. A food pellet response of the tyrosine remains the same at 1, 2, 6 months so can monitor substance abuse brain changes. These are cocaine addicted rats. They get cocaine via a nose poke of a button when it lights up. Pellets, not iv (they learn that faster). There are 2 ports to nose poke: active and inactive. The signal that cocaine is available and the pellet is active: a light comes on for 20s and then drug arrives. Can take again after 20sec. The rats titrate cocaine use: not continuous. They pace cocaine use, wait for it to wear off. Over time, drug use 1 hour access daily… slow increase, relatively stable.
When the access is bumped up to 6 hours access daily… rats do increase use — first of 6 hours, escalation of drug use faster — in humans development of tolerance.
With 1 hour cocaine availability, the dopamine response to the cocaine in the rat brain is lower by the 2nd and 3rd week, slowly decreases, then with 6 hours of access the loss of dopamine is very robust, happens faster, dopamine signal gets smaller every time.
Rats long access: were there individual differences? Yes, metric, nonescalated vs escalated groups so like humans. 60 escalated 40 didn’t and stayed stable. So essentially I named these “Vulnerable addict rats” and “Maintenance rats”.
Which group most motivated to take cocaine? The study ups the price of cocaine for rats, how many times are you willing to receive the drug? The escalating animals made more responses, “worked harder” for the drug. The escalator brains, Vulnerable Addict Rats, had just about a complete loss of dopamine signal by three weeks.
The nonescalators had more stable dopamine responses, retained some dopamine brain function.
The greater the loss of dopamine, the more the animal escalates the drug use.
The Vulnerable Addict rats would use cocaine to the exclusion of food, water, sex and sleep and died early.
This is a feedback loop. The rats get a success signal when the drug is taken — but over time don’t get the success signal because dopamine receptors are gone — so take more. In the Vulnerable Addict escalators, the dopamine signal of anticipation goes down in response to the cue, the drug effect takes a little longer but the pharmacological response to drug actually remains.
They tried giving l-dopa, a parkinson’s drug and if treat, the rats get a restoration of the dopamine cue — pharmacological response didn’t change — how does this affect behavior? A daily shot of l-dopa and the animals on the l-dopa have less escalation. (wow!) The l-dopa didn’t affect the nonescalators/maintenance rats. When they remove the l-dopa in the vulnerable addict rats, the animals jump to higher use and so the brain changes are happening even when it is masked by the l-dopa but does not stop the brain changes.
They ask the question: can you reverse escalation? With the the l-dopa, they use less.
Dopamine signaling to take drugs (the anticipation cue when the light goes on) decreases in animals that escalate drug taking, but does not change in animals with stable drug taking.
Restoring dopamine signaling with l-dopa can prevent or reverse escalated drug taking.
This dopamine signaling….

4. Mechanisms — drug cue elicits dopamine.
So this is about triggers. This is a paired drug cue: the light signals that the drug is available. If a non-contingent drug given to animal, the light still elicits drug seeking. Using a naive animal: pair reward with cue, over time the cue will increase dopamine.
(hmm. Facebook. blogging. Instagram. “You have mail”. )
The initial addiction has a short access time. One hour out of 24. When this is changed to long access, some animals escalate vs non escalation — as take more and more drug, the response to the drug taking cue gets larger in the escalators/Vulnerable Addicts. Presentation of cue — by investigator vs animal:
If elicits drug seeking than the dopamine response gets larger to the cue over time.
If the cue is given but other choices of liquid, then the dopamine response gets smaller in some rats — so terminating drug seeking. The Vulnerable Addict Rats had a larger and larger dopamine craving cue spike, the longer they were off the drug. The the increase in the cue drives craving and decrease drives seeking — so both bad.
The conclusion in the rats is that craving for drug, related to cues, is dependent to length of time off drug. The longer the rats were off the drug, the larger the dopamine spike when the cue light comes on. The measure of cue behavior gets worse …. 60 day study in rats, this is not physiological withdrawal, is prolonged way beyond the withdrawal.
1. noncontingent
wait a day or wait a month
work harder to get drug, harder a month out
reaction to drug cue presentation, enhanced over time
at start of drug small signal to drug cue
long access then cue gets bigger
same a day after stop drug
but huge in a month after no drug — huge dopamine response

(my thought was then swearing. how do we treat this?)
In chronic drug use the cue signal shrinks which reinforces drug use AND stopping increases the cue response which ALSO reinforces.

5. Implications for treatment
treating rats
They discuss a virus with promotor that affects dopamine cells, light activated ion channel, cells release dopamine when light stimulated
only activates release of dopamine, to understand mechanisms.
For the self administered nose cue …. In the nonescalator maintenence rats, dopamine cue response stays fairly robust, stimulate those cells and no change.
In the escalator/vulnerable addict rats… if do a virus stimulation of dopamine in the brain, more dopamine to cue boosted, so they use less cocaine and look like the non-escalators.
5th cue less dopamine than 1st cue: if put dopamine back then maintains the drug seeking.

What underlies the decrease in dopamine release?
When the animals use cocaine, dynorphin goes up (kappa antagonist).
They injected a kappa receptor blocker — animal no longer escalate (not in humans at this time, don’t understand well enough) treating animals that are escalating, so the bad addict/vulnerable rats.
Most animals don’t escalate — but pretty serious amounts of drug cocaine so not abstinent.

For future
Dopamine diametric changes: dopamine may reduce consumption but might increase craving, so it is difficult to treat.
l-dopa — treatment — some studies, looking for abstinence, does NOT produce abstinence. Does not make abstinence worse. Says that promise seen relates to the status of the subject — helps with people who are still using (some) but doesn’t help increase or prolong abstinence. So could reduce harm but not abstinent….politically unpopular. Happier with turning alcoholic into a social alcohol user, but that idea is less popular/politically ok with cocaine/opioids (and especially meth).

They are studying mouse nosepokes for alcohol — reduced intake when the rats are on l-dopa.

There is a functional agonist for kappa receptors == buprenorphine, might have effects on drug consumption, speculation across different drugs.

Dynorphin is a stress related peptide, so does that signaling produce escalation of drug taking? So other stress drugs — like corisol, CRF, plan for more studies.

Question: Stress related hormones– babies in stress in utero and in stressful childhood have less dopamine receptors and need more dopamine for pleasure, susceptibility to drug addiction (ACE scores) so is still really early studying neurotransmitters.

Dr. Question: why do people do better with agonist therapy than abstinence in opioids vs other drugs? Answer: we don’t know….. yet.

further information:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920543/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC80880/
https://archives.drugabuse.gov/news-events/nida-notes/2017/03/impacts-drugs-neurotransmission
https://nida.nih.gov/