Neurobiology and Neurochemistry of Reward and Addictive Behaviours Flashcards
Addiction / substance dependence meaning
A persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences for the afflicted individual.
This disorder is Both physical and psychological.
Withdrawal symptoms meaning
Negative physiological and emotional features that occur when the drug is not taken.
Different for each drug of abuse, but generally opposite to positive experience induced by the drug.
Avoiding withdrawal symptoms is to the reason why people relapse into abusing drugs. if that was the case, keeping them away for a few days or weeks or months from drugs would help them get over those symptoms and get back to not abusing drugs anymore.
However, that is not the case. we are talking about a chronic, practically lifelong condition.
Tolerance
Describes the diminished response to the effect of a given amount of drug following repeated exposure to the drug.
This implies that increasingly, one needs larger doses of the drug to induce the same behavioural effect and this can lead to problems like an overdose because one is trying to reach the initial high that is very hard to replicate because one becomes tolerant to the repeated effect of the same amount of drug.
Where do drugs act in the brain?
Its the same system that signals natural rewards, things that make us feel good and we tend to try and look for them and repeat having them. like food, drink.
What the drugs do is hijack the natural reward system and that involves the MESOLIMBIC and MESOCORTICAL SYSTEM called the MESOCORTICALLIMBIC PATHWAY.
- That’s responsible both for rewards and reinforcements and it provides the salience of a particular stimulus in the environment that we find particularly pleasurable and positive so we try to look for it to have the same experience as before.*
- This is not the only system involved in reward and reinforcement. Addiction also involves the PREFRONTAL CORTEX which is the decision-making centre of the brain. also involved in impulsiveness and in self-monitoring. so the ability to not give in to impulsive and momentary decisions and also to monitor our desires for things and delay gratifying wishes or simply saying NO because we know that they will have negative consequences.*
- It’s part of the reason why addiction is a very human disease, there are no satisfactory models in animals of addiction.*
- The prefrontal cortex is very large in the human brain and its very evolved and well connected with the rest of the brain.*
- unfortunately, in addition, the prefrontal cortex is also hijacked and the thinking processes are distorted.*
- The AMYGDALA is also involved and we know that it is very involved in the emotional procession and memory. when people are no longer taking drugs and they see some paraphernalia associated with drug-taking like syringes and so on. that reminds them of the positive experience of taking drugs and makes them want to take drugs again even if they stayed away for a while.*
Anticipation of reward recruits NAcc
Here is an experiment, an imaging experiment with normal, healthy volunteers that shows that its the anticipation of the reward that recruits this important striatal nucleus, the NUCLEUS ACCUMBENS.
The nucleus accumbens is found in an area of the brain called the basal forebrain. There is a nucleus accumbens in each hemisphere; it is situated between the caudate and putamen. The nucleus accumbens is considered part of the basal ganglia and also is the main component of the ventral striatum.
The NUCLEUS ACCUMBENS is in the ventral striatum and in this experiment, people are in 4 different conditions.
They can get small, medium or large rewards, small, medium or large punishments when they respond to particular questions.
in any particular scenario during the task, they know whether they are going to have a reward or punishment or neither and we see the activation of the NUCLEUS ACCUMBENS selectively and exclusively when there is some kind of reward involved.
So in a) we are comparing large vs small reward and you can see that this activates the NUCLEUS ACCUMBENS a lot.
b) we are expecting a reward and we have subtracted the situation of neither reward or punishment, the neutral one and you see the very small activation of the nucleus accumbens.
while in cases c and d) when we are expecting either a large punishment or just a punishment vs no outcome, NUCLEUS ACCUMBENS is not activated at all.
So this is a signal in a very important part of the brain that makes us take notice and try and learn the reasons why a particular situation is going to lead to reward, it’s going to highlight the stimulus and the behaviour that leads to acquiring the stimulus in order to experience that particular reward.
extra note;
The anticipation of rewards rather than the reward itself that causes the recruitment of the Nucleus Accumbens
Experiment – click button appropriately then receive reward, get it wrong then either get punishment or no outcome
The anticipation of certain reward recruits NAcc more than when outcome not certain – may be punished or have no outcome. The anticipation of punishment results in no activation so determined by other pathway.
Dopamine as an “error” or “learning” signal
The neurotransmitter mediating the effect in the NUCLEUS ACCUMBENS is DOPAMINE but its not simply a case of getting dopamine high, it’s not the release of dopamine per say that is a reward.
As seen in the previous experiment, it was expecting the reward that made the NUCLEUS ACCUMBENS activate so the anticipation of reward can be a very powerful signal, sometimes more powerful than the reward itself.
In an experiment that looked at dopamine as an error signal or a learning signal rather than a reward in itself. in order to study that, we have a scenario of a non-human primate who is performing a particular task who have been trained to sit in a type of chair in a computer monitor and for example when a dot appears on the screen, you have to press a button or pull a lever and that gives them a drop of fruit juice or some type of reward and that motivates them to keep repeating that behaviour.
This repeating of behaviour in order to receive a reward is instrumental conditioning. which is different to Classical conditioning where the participant does not need to do anything g at all. , just by pairing to stimuli for example; the food and the bell in Pavlov’s dog make the association between the 2 very powerful and we know that the dogs respond immediately salivating just to the rining of the bell rather than the presentation of the food.
However, with instrumental conditioning, we actually need to train the participants to perform a particular behaviour. so what we have in the image is the animal performing a task while at the same time, we are very carefully monitoring the timing of the stimulus presentation, the timing of the response and we can also monitor the eye movements and we are recording with wires in the brain activity of single neurons which we can filter and amplify and store for of line analysis which you can see the bottom left, it spikes a neuronal activity from a particularly isolated neuron, multiple of them in A and B. you can see just one of them. sort of magnified. You can see that the time scale is different and you have a familiar form of an action potential.
Extra notes;
Dopamine is the primary activating neurotransmitter for the reward pathway
Monkey hooked up with electrodes within the brain, reading activity. Completes task of hitting button in response to stimulus on the screen, electrical activity measured at tip of electrode.
Set up to measure effect on a dopaminergic neuron in reward pathway
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Whereas in Pavlovian (classical) conditioning the organism does not need to do anything – that is, the process occurs by the simple pairing of two different types of stimuli (e.g. food and sound (bell ring) – instrumental conditioning begins with responses that are originally emitted without any apparent stimulus needed to produce them. The form and frequency of their subsequent occurrence are then altered depending upon the consequences of those responses. The term “instrumental” indicates that the behaviour is instrumental or necessary for the conditioning process to occur. Common examples of instrumental behaviours are those involved in driving a car, hitting a tennis ball, snorting cocaine, and writing a letter”.
From D. M. Grilly Drugs and human behaviour, 1989, Allyn and Bacon
Dopamine as an “error” or “learning” signal cont’d
Now we are going to be recording from the striatum in a macaque monkey who is performing a task. what we see at the top is a pain stimulus time histogram so an average of all the spikes that the neuron fires over time. time beginning on the left and going on towards the right.
Below that we have the rasterogram. so these are the individual spikes a neuron will fire overtime on a trial by trial basis. Every row is an individual trial and you can see there is some spontaneous firing so the neuron is sitting there, nothing much is happening. The pop pop pop are meant to spikes/action potential. and then unexpected regard arrives, perhaps the animal is looking up the screen not doing anything and suddenly a drop of juice is released in their mouth. so reward is that line in the middle indicated with R.
The neuron will fire many more action potentials indicating surprise for something positive so that was an unpredicted reward and the neuron has responded to it.
what the animal is gonna try and do is learn how to get more of that so perhaps they need to reach a particular button or pull a particular lever.
once they have learnt that and the conditioned stimulus appears across the screen, once this condition stimulus appears, you can see that the neurons now fire in anticipation of the reward. they know they have done the task correctly and there’s going to be a reward later so the anticipation of reward is telling the animal that you’ve done that right, you are going to have your reward and this anticipation is what is signalled by the neuron.
While at the time the reward is actually delivered, further down the timeline, we have a small triangle and the capital R (it’s rather truncated in this image), you don’t have the neuron firing to the presentation of the reward because that is exactly what was expected. the reward occurred , there is no surprise. All the firing, the release of dopamine has happened at the anticipation and the prediction of the reward.
Finally, When we have a case where we have a presentation of the conditioned stimulus, the animal does what they are supposed to do, they press the lever. so they are anticipating the reward, Dopamine is released, there is the prediction for reward, but actually, no reward is given. and now the neurons go silent. so that’s another way of signalling something that was not predicted. something that went wrong, so that is an error signal. The prediction was wrong because we didn’t get the reward we were expecting.
This is basically a demonstration of how dopamine is acting as an error signal or a learning signal and not as the reward signal itself. so the reinforcement system is activated by the unexpected, reinforcing stimuli and by the presence of reward relative to its prediction. and these are all parts of instrumental behaviours that the animals has been taught to do.
Dopmaine as an “error” or “learning” signal
lecturer’s notes.
If just given a reward with no stimulus i.e. an unexpected award that cannot be predicted then there is a spike in activity after the reward
However, if presented with stimulus prior to the reward then we note a spike in activity before the reward i.e. reward predicted and the response is in anticipation of the reward
Note that this spike is more intense than that of the one when he actually receives the reward i.e. the anticipation is more ‘pleasurable’ than the reward itself
If reward does not come (monkey makes an error on test) then still get the anticipation spike but see a fall in dopaminergic effect at time that reward would have come
If just given a reward with no stimulus i.e. an unexpected award that cannot be predicted then there is a spike in activity after the reward
However, if presented with stimulus prior to the reward then we note a spike in activity before the reward i.e. reward predicted and the response is in anticipation of the reward
Note that this spike is more intense than that of the one when he actually receives the reward i.e. the anticipation is more ‘pleasurable’ than the reward itself
If reward does not come (monkey makes an error on test) then still get the anticipation spike but see a fall in dopaminergic effect at time that reward would have come
This response relates to learning
The response from the previous slide relates to learning and being able to make prediction. In this experiment with human participants, we saw that being able to predict the reward vs being given the reward that was not predicted in the human brain. you can see that this also activates the NUCLEUS ACCUMBENS. so when you subtract the condition of predictable reward from the condition of unpredictable reward, you can see the NUCLEUS ACCUMBENS is activated in A. so that’s the same scenario as we saw in the previous experiment with single neurons in A) where the animal was given an unpredicted reward.
While in the opposite scenario, when we subtracted the unpredictable from the predictable, where have a completely different part of the brain activated. a different circuit.
so the NUCLEUS ACCUMBENS is selectively Involved in signalling and learning whatever it is that has brought us an unpredicted reward.
extra note;
When a reward is unexpected then we see activity in the Nucleus Accumbens – think of this as a response that ‘tells’ our brain that there is something we should be learning
However, once it is learnt, i.e. predictable, this response disappears from the NAcc and the response is seen in the temporal lobes – indicating that learning has taken place
Functions of the Reinforcement System in the brain
It’s extremely important for survival.
1• It Detects reinforcing stimulus
2• Recognise something good has just happened
3• Its Time to learn- its time to dedicate resources in understanding how we can change our behaviours in order to get more of that positive stimulus.
4• It involves Strengthening neural connections between the neurons that detect the stimuli and the neurons that produce the instrumental response and this involves long term potentiation.
5• Between neurons that detect the stimulus and the neurons that produce the instrumental response. The neurons that detect the stimulus and the reward prediction, are in the ventral (front) of the striatum in the nucleus accumbens while the neurons that produce the instrumental response that are involved in the formation of habits and behaviours and motor actions that would lead to learning how to get more of that stimulus are in the dorsal (back) of the striatum. so very very close to each other.
we have a schematic representation of the ventral tegmental area, the nucleus accumbens and the prefrontal cortex. and we have a complicated circuit involving GLUTAMATE, DOPAMINE and GABA. in terms of neurotransmitters, as well as feedback loops so you can see that the prefrontal cortex will decide if a particular stimulus is to be sought after if a particular behaviour is to be executed and if a particular decision needs to be made.
This involves GLUTAMATE-ERGIC activation of the VTA (ventral tegmental area), but crucially, the VTA sends dopamine signals back to the prefrontal cortex that allows it to continue this GLUTAMATE-ERGIC activation.
Also the glutamate from the prefrontal cortex activates GABA interneurons in the VTA that keep in check the dopaminergic neurons that can activate dopaminergic neurons in the nucleus accumbens.
so if we don’t have enough GLUTAMATE coming from the prefrontal cortex, if the prefrontal cortex is hypoactive. its under-functioning. that means that these GABA neurons will not be inhibiting enough the dopaminergic neurons in the VTA. and they will be more active than they should be, activating the nucleus accumbens more.
Also, this out of control overactivation of the VTA dopaminergic neurons leading to increased activation of the nucleus accumbens is closely related to positive symptoms of schizophrenia including delusions and hallucination
The mesocorticolimbic dopamine system
In an animal model, eg a rodent. This is how the mesocorticolimbic dopamine system looks like. it projects from the ventral tegmental area to the nucleus accumbens and from there to the cortex and you can see all the important connection involved in that .
The ventral tegmental area, or VTA, is in the midbrain, situated adjacent to the substantia nigra. Although it contains several different types of neurons, it is primarily characterized by its dopaminergic neurons, which project from the VTA throughout the brain
Mesocorticolimbic dopamine system
This system is involved in both reward and reinforcement. so you have natural reinforcers for eg food or sex and they will lead to extracellular dopaminergic release in the nucleus accumbens. but that system can also be hijacked by addictive drugs, making these natural reinforcers lose their appeal and the whole system becomes extremely focussed on getting the rewards offered by addictive drugs rather than natural reinforcers.
Mesocorticolimbic dopamine system
There are several areas in the brain where dopamine is concentrated. (substantial nigra, Ventral segmented area in the midbrain, hypothalamus, olfactory bulb and retina.)
There are several major dopamine pathways that carry dopamine from these areas of concentration to other parts of the brain.
- NIGROSTRIATAL PATHWAY -stretches form the substantial nigra to the stratum (basal ganglia nucleus)
- Mesolimbic pathway- stretches from the ventral tegemented area (VTA) to the nucleus accumbens and other limbic structures.
- MESOCORTICAL PATHWAY- STRETCHES from the VTA throughout the cerebral cortex.
Mesolimbic pathway—transports dopamine from the VTA to the nucleus accumbens and amygdala. The nucleus accumbens is found in the ventral medial portion of the striatum and is believed to play a role in reward, desire, and the placebo effect.
The behaviours that activate this Mesocorticolimbic dopamine system are reinforced and are more likely to be repeated.
Addictive drugs cause more powerful and reliable activation compared to natural rewards and that is why we talk about the hijacking system and making natural rewards much less effective at giving the normal feelings of reward and pleasure.
we also know that if we block dopamine in this part of the brain, that attenuates the most measurable reinforcing and rewarding effects of addictive drugs.
so if we were to take cocaine or heroin, but we had blocked the release of dopamine in the mesocorticolimbic dopamine system, we wouldn’t really be experiencing their various rewarding effects, and we wouldn’t become addicted to them.
Common drug effects on Dopaminergic system
The cartoon summarises the common drug effect on the dopaminergic system because all the drugs have an effect on the dopaminergic system, although though slightly different mechanism.
The table summarises the different actions for the different types of drugs.
on the left is a cartoon of the communication between a VTA neuron and the nucleus accumbens neuron.
In the baseline state, you can see the VTA neuron releases dopamine in the synaptic cleft and the nucleus accumbens neuron has a number of dendrites, receives and responds to these signals of dopamine.
now, following acute drug exposure, you can see that the VTA neuron releases a lot more dopamine in the synaptic cleft . This will have a much stronger effect on the nucleus accumbens cells.
you can see that a number of different drugs have both direct effect on increasing the release of dopamine on the VTA neuron but also a number of indirect effect, for example, NICOTINE has a direct effect on the dopaminergic neuron but may also have an indirect effect through the cholinergic increase of stimulation of the dopaminergic neuron or even glutaminergic increase of activity of the dopaminergic neuron.
this is the scenario of the acute drug exposure but following repeated drug exposure, we start having structural, morphological and functional differences in the communication between the VTA and the nucleus accumbens.
you can see that the VTA neurons has practically shrunk, its much smaller and the opposite effect is what you can see in the nucleus accumbens, its become larger in the sense that there are many more dendrites. so its become much more sensitive to the release of dopamine from the VTA neuron so that means effectively that the same amount of dopamine can have a much higher effect on the nucleus accumbens neuron.
But repeated opiate exposure may actually have the opposite effect that means that the nucleus accumbens neuron loses quite a few of its dendrites and becomes less sensitive to the release of dopamine.
overall, quite a few different effects have been reported following repeated exposure of psychostimulants. for eg, they have decreased baseline levels of dopamine in the nucleus accumbens and enhanced dopamine release involved in drug experiences.
so overall, we have an increased signal, particularly when there is exposure to addictive drugs. but overall, the baseline state, including rewards for natural reinforcers, food, sex, other pleasurable activities becomes less.
so the person does not have the same experience of reward when not involved in drug-taking activities. so we can see here the intracellular effects and actions of the different dopamine receptors.
Dopamine receptors differentially regulate cAMP intracellular signaling and
cellular activity.
The intracellular effect and actions of the different dopamine receptors.
The D1 receptors is associated with stimulatory G proteins and that will lead to a familiar cascade of events.
Increase of conversion fo ATP to cAMP increase phosphorylation and activation of PKA (Protein kinase A) that will have a direct effect of depolarising other ion channels sensitizing the postsynaptic membrane but also leading to long term effects by activating gene expression that can have long-lasting effects and real structural changes for the synapse.
The opposite effect is obvious when we have activation of D2 receptor because that is associated with a different set of G proteins. the inhibitory ones, so we have an opposite cascade of event. we have inhibition of the conversion of ATP to cAMP and inhibition of gene expression and protein transcription and so on.
This dopaminergic response is a normal reaction
The dopaminergic response that we see in normal pleasurable activities like celebrating good exam results, celebrating a good sports outcome, or just enjoying our favourite food. This is central to motivation bit once this has been hijacked by drugs of addiction, we can not experience these natural rewards with the same intensity, we are far less motivated, not motivated to engage in them. the things that motivate us are related to the activity of repeated drug taking.
How is the drug-taking reinforced? how do we get addicted?
We have a different model that focuses on different types of changes that we have already talked about.
1. On one hand, we have the homeostatic changes and the neuronal adaptation that leads to tolerance. so we have a diminishing effect of the drug after repeated administration. therefore, we need more of the same drug to get the same effect. always chasing the first high.
We also have the dependence, both physical and emotional and this is homeostatic response to repeated drug administration that can be unmasked by the withdrawal symptoms , which are always unpleasant and we always try to avoid those withdrawal symptoms by repeating the drug taking behaviours.
- and other other hand, we have the associative learning processes and the synaptic plasticity processes. we have also seen in detail that these lead to sensitisation. so repeated administration can elicit escalating effects . Those nucleus accumbens dendritic outgrowth. This is an effect we see on psycho stimulants when using animal models.
In addiction which involves compulsive taking that involves compromise of decision making and the ability to resist behaviours that have adverse consequences in our life.
and also the overall craving and relapse, that may happen after several years of abstinence from drugs because these kinds of effects are chronic and possibly last a lifetime.
Cocaine and amphetamine – Dopamine agonists
Amphetamine is a powerful stimulator of the central nervous system. It is used to treat some medical conditions, but it is also highly addictive, with a history of abuse.
Cocaine, also known as coke, is a strong stimulant most frequently used as a recreational drug. It is commonly snorted, inhaled as smoke, or dissolved and injected into a vein. Mental effects may include an intense feeling of happiness, sexual arousal, loss of contact with reality, or agitation
They are both dopamine agonists, they potentiate the monoaminergic transmission by inhibiting the monoamine reuptake transporters.
cocaine specifically blocks and inhibits the transporter. Therefore, prolonging the pool of available extracellular dopamine in the synaptic cleft.
Amphetaminegoes a step further by reversing the transporter and increasing further the extracellular dopamine levels.
it’s their action on the dopamine transporter (DAT) that directly relates to reinforcing effects of those drugs.
initially, they have the feeling of euphoria through the mesolimbic activation. but the actions of the transporters might also be located in other parts of the brain.
cocaine and amphetamines basically both increase the amount of extracellular dopamine in the nucleus accumbens.
cocaine pharmacology
In the image is a cartoon that shows how cocaine underside/blocks dopamine reuptake transporter.
cocaine represented as a yellow rectangle, not allowing an extra amount of dopamine available in the synaptic cleft to be recycled and broken down in the presynaptic nerve terminal.
cocaine pharmacology 2
Another cartoon that shows how cocaine and amphetamine have slightly different actions on the transporter.
On the top, you see cocaine blocking the transporter, to allowing the excess dopamine to go back in the presynaptic cell.
In the lower cartoon, we see that amphetamines make the transporter run backwards, making any dopamine available in the presynaptic terminal to be released, not by the normal vesicle fusion but by the transporter that normally runs in the opposite direction.
Binding sites of cocaine following acute administration
Here is the first experiment, imaging experiment that shows how cocaine binds directly in the striatum, the nucleus accumbens.
By having radioactive injections, in this case of cocaine, we can see in real-time, the timecourse in minutes showing us the binding of the radioactive tracer, cocaine in this case, already starting after 3-4 minutes after the injection and highlighting the binding concentration specifically in the striatum.
This was very exciting because it showed directly how cocaine affected the brain and also it revealed the similarity of the timecourse between the dopamine transporter occupancy by cocaine and also the time course of the psychological effects of cocaine.
you can see after about 20-30minutes cocaine is no longer binding to nucleus accumbens which coincides with the psychological effects wearing off by that time after injection.
This is also useful evidence that agrees on the fact that high doses of cocaine can cause paranoia and psychosis, these are symptoms associated with schizophrenia.
its direct evidence about the involvement of dopaminergic pathways in schizoprenia and a to of the medication that we have available for the symptoms of psychosis are directly targeting the dopaminergic limbic pathway.
Increased excitatory strength
24 hours after injection
In this animal experiment, it shows that by injecting either saline or a drug or an addictive drug to a rodent, then sacrificing it and having a histological examination of the number of available receptors in these animals, we can see that all drugs of abuse effectively increase the ratio of the AMPA to the NMDA receptors so that’s overall an increase in the baseline excitation, in the baseline synaptic strength between VTA and the nucleus accumbens.
one injection can lead to changes that persist for up to five days, while if we have consistent injections over 2 weeks, changes can persist in the VTAs for a lot longer.
This is a reminder of the long term effects of drug exposure that lead to shrinkage of the VTA neuron but a dendritic outgrowth of the nucleus accumbens and sensitisation to small amounts of the drug.
Fewer D2 receptors in addiction
This is another pet experiment that shows the difference in the brain of a non-drug use, and a cocaine abuser in the striatum. we are looking at the dopamine D2 receptor availability.
In addiction, there are fewer D2 receptors, D2 receptors cause inhibition and suppress different behaviours. so they would suppress bad decision making effectively and drug-taking behaviours but because these receptors are a lot less in the case of drug addiction, it seems to be responsible or to contribute to compulsive taking of drugs to being sensitive to cues associated with drugs taking and also to the fact that we have overall withdrawal and apathy when someone is not engaged in drug-taking behaviour and this reduced sensitivity to natural rewards that develop in addiction.
In this digram, we are showing the emotional dependence that develops with drug abuse of psychomotor stimulants for example, and these symotomps include dysphoria, anhedonia, the inability to experience pleasure, the anxiety or withdrawal.
Overall, we have an increased activity of D1 receptors. These are the stimulatory coupled ones in the nucleus accumbens and we also have an involvement of K opioid receptors. These inhibit the VTA neuron firing and the nucleus accumbens dopamine release.
So overall there is less dopamine release in the nucleus accumbens and that is what happens in the absence of drug-taking, so it explains why there is not enough dopamine released in response natural rewarding stimuli leading to overall unpleasant feelings.
Associative Learning - what makes drugs addictive?
Associative learning is a mechanism presumably responsible for making drugs addictive in the long term and making addiction a chronic, possibly lifelong problem.
long term potentiation and the summary of cells that fire together wire together. so we have this coincident firing between sensory pathways and the mesocorticolimbic pathway that will induce LTP and strengthen these synaptic connections.
and unfortunately, these can create long term memories that are very very difficult to forget.
The problem with that is you have this kind of changes in connections between widespread networks and very important part of the brain including the nucleus accumbens, the VTA, the frontal cortex, the hippocampus and the amygdala.
so all the sensory information, the context including the people, the places, the noises, the emotions that were present at the time when we had the drug-induced dopamine release. They become associated with taking the drug which is why you have this dopamine release in anticipation of drug-taking rather than following as a reward to the drug-taking.
This is clinically relevant because if a particular place like a nightclub is associated with cocaine use, then the highest risk of relapse is returning to those particular places. where people who will
experience increased craving and they will more likely to give in to their compulsive behaviour.
Dopamine enhances Long Term Potentiation
The enhancement of LTP through the activation of D1 receptors, activation of adenylate cyclase, conversion of ATP to cAMP, activation of protein kinase A. how this glutamatergic transmission allowing induction of LTP.
and then in the late phases of LTP, we have the CREB mediated gene transcription, new protein synthesis and effectively a remodelling of the synapse. we have an increased number and increased size pf spine and dendritic branches, we have the formation of the mushroom synapses and these are long term molecular and cellular changes that remain for months. possibly years after someone has stopped engaging with drug taking behaviour, but these are the memories stored in these pathways that may trigger a relapse many years later.
Opiates (e.g. morphine and heroin)
Opiate interact with the endogenous opiate receptors and their overall result is inhibitory because they decrease the adenylate cyclase activity leading to opening potassium channels and closing calcium channels.
There are different opioid receptor subtypes and you find them in different distributions across different cells in different brain regions.
The 3 subtypes we know are the MU, KAPA, and DELTa. most of the morphine’s analgesic and rewarding properties are though actions at the MU receptors.
so mu receptors are more important for the study of morphine’s action in the brain and spinal cord. The effect of reward and reinforcement is mediated both by disinhibition of dopaminergic neurons in the VTA and by the action of opiate receptors in the nucleus accumbens. so 2 different parts of the dopaminergic system and that is independent of the dopamine release from the VTA.
Alcohol (EtOH)
Alcohol is a GABA(A) agonist , when it binds its makes the inhibitory signal even stronger. so it has an inhibitory effect and its an NMDA, a GLUTAMATE receptor antagonist so it blocks excitation. in very large doses, it inhibits the functioning of most voltage-gated channels. so it has a very wide banket effect.
Alcohol leads to increased dopamine release in the nucleus accumbens. The NMDA antagonist of cortical inputs from the prefrontal cortex to VTA disinhibits the Dopaminergic neurons there, and that fire more and increases dopamine release in the nucleus accumbens.
The ethanol rewarding effect is blocked by dopamine receptor antagonist in the nucleus accumbens. The opiate system is also involved. there is Naltrexone, an opiate antagonist that reduces ethanol self-administration in animals because it doesn’t involve the rewards associated with taking it and it can be used as a treatment to reduce alcohol consumption, relapse and craving of alcohol with heavy chronic drinking problems.
Normal system
Cortical control of VTA firing
The circuits for controlling firing in VTA and in the nucleus accumbens. we have the excitatory GLUTAMATERGIC input from the prefrontal cortex at the top left going to the VTA GABERGIC neuron which needs to fire in order to inhibit the dopaminergic neurons that activate the nucleus accumbens.
In the case of the opioid addiction, there is a disinhibition of the dopaminergic neurons in VTA because Morphine acts om the MU opioids receptors which are inhibitory. so they inhibit the GABAergic neurons, they do not fire, they do not inhibit the dopaminergic neurons and VTA. The dopaminergic neuron in VTA fire a lot more and activate the nucleus accumbens a lot more. In the case of alcohol addiction, we have suppression of cortical input from the prefrontal cortex, we dont have the glutamatergic input on the gabaergic VTA neurons and that means that dopaminergic neurons in VAT become uninhibited. They increase their firing and they activate the nucleus accumbens a lot more.
Nicotine
- Acts at nicotinic acetylcholine receptors (nAChRs)
- Ach receptors are ligand-gated ion channels that can be located both on the pre and postsynaptic ends. you can find them throughout the brain.
- Their action can be either excitatory or modulatory.
- when they’re on the presynaptic cells, they increase the intracellular calcium concentration leading to increased transmitter release. Using nicotine increases dopamine release in the nucleus accumbens and this release of dopamine is possibly due to activations of receptors on the cell body in the VTA. so we have increased cell firing of the dopaminergic neurons in the VTA and facilitation of dopamine release by presynaptic receptors in the nucleus accumbens so acting both pre and postsynaptically on the VTA and on the nucleus accumbens.
we have opiate system involvement when we use opiates and dopamine antagonists, we can block nicotine-induced behaviours and self-administration.
Naltrexone is a drug that can help to stop smoking behaviour and associated weight gain that comes with stopping smoking.
there are several clinical trail with encouraging g preliminary results but the picture right now is rather less clear.
Physical dependence to opiates
The opiate receptors are found on the mesocorticolimbic circuit but also in other systems, in pain pathways, on the spinal cord.
The Locus Coerulus (LC) contains the noradrenergic nuclei that control attention, arousal and vigilance.
what happens with chronic activation of opiate receptors is a homeostatic mechanism that compensates for the functional changes that lead to tolerance and to physical dependence.
with acute opiate administration, we have inhibition of firing of the Locus Coerulus (LC) neurons. if we have chronic use of opiates, these LC neurons get used to this inhibition, they increase their ability to activate inhibitory actions and they return to their normal firing rates which becomes a huge problem when there is no morphine present during withdrawal when you try and stop taking morphine because suddenly there is a dramatic increase in LC firing and this correlates with the physical withdrawal symptoms. you can trigger overactivation of the autonomic nervous system, and this can be blocked by an A2 adrenergic receptor agonist (CLONIDINE).
There is an intracellular mechanism in the LC neurons that lead to compensation and the same thing happens in terms of analgesic effects so you need to take more and more morphine to have the same type of analgesic effect because of tolerance.
List of drugs and the neurotransmitter that they mimick and what drug receptors they occupy.
Physical dependence to opiates contd
The little diagrams help to explain the change of balance we just described.
The LC neurons area activated by multiple pathways both ionotropic and metabotropic.
So metabotropic means cascade of 2nd messengers leading eventually to gene expression, protein synthesis, change in plasticity, morphological structural changes of the synapse that lead to functional changes. when we have acute morphine administration, we have inhibition of firing of the LC through the Gi pathway. you can see the Gi pathway on the seesaw where it becomes absolutely dominant but the LC neurons adapt to that over time. when we have chronic treatment, the LC neurons have now balanced again a different balance of the stimulatory and inhibitory pathways but they are both overgrown and when we have withdrawal, a dramatic increase in the LC firing is what happens, cause this stimulation is no longer balanced by the inhibition.
In the absence of the Gi inhibition, the Gs systems become hypersensitive. A very similar mechanism happens with the physical dependence to alcohol.
Physical dependence to alcohol
A very similar mechanism happens with physical dependence to alcohol. so we’ve seen that the acute effects of alcohol are on agonism of the GABA A receptor, an inhibitory receptor and antagonism of the NMDA receptor which is the glutamate receptor.
so the cells are overall inhibited from firing. with chronic alcohol use, we have an overall downregulation of GABA (A) receptors.so we have overall fewer GABA (A) receptors, overall less inhibition and we have an upregulation of an NMDA receptor. so upregulation of overall excitation. when alcohol is present, this is a precarious balance that sort of works. the firing rates are sort of normal that when there is no alcohol in the system, what is revealed is this balance shift towards excitation.
very little inhibition present, a lot of excitation present and the physical symptoms that arise from that have to do with agitation, tremors, hypertension and in extreme cases, seizures as well.
