bookwhoreder asked: Hi, Is there any chance you would be able to explain how alcohol alters the release of dopamine in the VTA and nucleus accumbens? And its relation to the reward/pleasure system?
Sure! Thanks for the question.
For people who don’t know, all addictions are thought to act on the mesolimbic dopamine system (the reward system), which includes the ventral tegmental area (VTA) which releases dopamine, Nucleus Accumbens (on which the dopamine acts), and prefrontal cortex. Drugs of addiction, including alcohol, act on this system to increase dopamine, a neurotransmitter which can produce that good feeling that drives addiction (as a simple explanation). Alcohol isn’t as obvious as, say, cocaine which increases dopamine by blocking the dopamine transporter. Unlike other drugs, alcohol doesn’t seem to act on a specific receptor in the brain (at least that we have found thus far). Instead, it appears that alcohol may act on other effectors of the dopaminergic system, such as GABA, glutamate, and serotonin. These systems seem to cause neuroadaptive changes that upon withdrawal of alcohol can cause dopaminergic decrease and withdrawal symptoms. For instance, alcohol seems to inhibit glutamate receptors, as shown in the image above. Chronic use will cause chronic inhibition of these receptors, which will modulate postsynaptic responses and protein composition (i.e. it could change the number of receptors) to glutamate. These neurons are located throughout the mesolimbic system. Thus, since their response is changed, the way the mesolimbic system works will also change. It’s been found in rats that chronic ethanol (alcohol) will increase sensitivity to glutamate and withdrawal from ethanol can cause hyperexcitability of the brain which leads to things like seizures. Anyway, to be clear, the whole effect of alcohol on the mesolimbic dopamine system is very complex, and it seems like alccohol may mediate the activity in this system through other neurotransmitters (aside from dopamine), but still have an effect on the dopaminergic system. Hope this helps!
[Image Source- NIAAA publication]
themodernsound asked: Could you talk about the Post-Synaptic Density a bit? I've just learned a little about it but I don't quite understand how it functions.
First of all, thanks so much for the question! The post-synaptic density (pictured above) is so named for the dense concentration of proteins and molecules in the synapse that was first seen with electron microscopy. The synapse is just the space between two communicating neurons. As you can see, it’s a pretty small space. In this space, there are proteins that hold the neurons in place and keep them connected as well as anchor receptors and things important for signaling in place (i.e. scaffolding proteins). There are also a lot of receptors to accept the signal from the pre-synaptic neuron. These signals can include the neurotransmitters I most recently spoke about (glutamate, GABA, norepinephrine, dopamine, serotonin, etc). I hope this helps!
Sorry for the silence as of late! I had to move a couple times and then get started with my post-doctoral fellowship! Things are finally settling down a bit, so in the next month or so, I should be able to get back to regular postings.
Since the last thing I spoke about was dopamine, I’ll give you a fun dopamine figure! Here, you can see the basic pathway for dopamine synthesis. Dopamine is made from the precursor L-DOPA, which is a small molecule that can pass through the blood brain barrier (thus why it can be used to treat Parkinson’s- it can be given, will get into the brain, and can then be made into dopamine and used by the remaining dopaminergic neurons). L-DOPA can also be made from tyrosine, which is an amino acid that can be made in the body or ingested- it is found in many protein sources, including poultry, milk, etc.
This image also shows some other things which are interesting- including MAOs (monoamine oxidases- breaks down dopamine- and other monoamine class neurotransmitters) and MAO inhibitors.
[Image Source - Moussa et al., 2006]
Alright, moving along to dopamine (DA), which is probably my favorite neurotransmitter (and likely yours too- even though you don’t realize it!). Dopamine is the neurotransmitter involved in addiction (shown above for cocaine- since cocaine blocks the dopamine transporter, it causes dopamine to stay in the synapse longer), and basically anything rewarding. When you get a surprise or win some money, dopamine is what causes that feel-good rush! It’s the transmitter involved in reward, but it also has other functions as well- it helps with prefrontal concentration, accurate movements, control of thoughts (too much can cause hallucinations), etc. It’s really an incredible molecule!
Dopamine is produced in the Ventral Tegmental Area (VTA) and Substantia Nigra (SN) in the midbrain and has widespread effects throughout the brain- in the basal ganglia circuitry and throughout cortex. I’ll be talking more about this one in coming posts since it’s quite fascinating to me!
Another neurotransmitter is serotonin (5HT is the abbreviation- derived from the chemical name, 5-hydroxytryptamine). 5HT is largely found in the gastrointestinal tract where it regulates the muscles there. However, I think its functions in the brain are even more interesting. Serotonin is largely produced by the Raphe Nuclei in the brain and have functions throughout cortex. The context you have most likely heard about 5HT in the past is because most anti-depressants target serotonin. Selective Serotonin Reuptake Inhibitors (SSRIs) block the reuptake of serotonin and thus keep serotonin in the synapse for longer allowing for greater/prolonged activation of serotonin receptors. Other anti-psychotics also target the serotonin system.
Nicotine acts as an acetylcholinergic agonist, meaning it increases the activity of the ACh receptors. Ach acts on muscles- and is found in the brain. For people who don’t know, nicotine is the addictive chemical in cigarettes. In some parts of the brain, the activity on these receptors can increase release of dopamine (which is what is thought to be responsible for the addictive properties). Nicotinic promotion of these receptors also increases activity in the sympathetic nervous system, which regulates the fight or flight type response (increased heart rate, decreased digestion, etc.).
Acetylcholine (ACh) is another neurotransmitter, best known for being the neurotransmitter that bridges the gaps between neurons and muscles. Unlike neurotransmitters acting upon other neurons, ACh has a 1:1 action on muscles. One action potential causes a muscle contraction, no need for build up (like with EPSPs and IPSPs). The amount of ACh released and the pattern in which it is released will determine how much the muscle contracts and for how long.
I found this great infographic online to show the process of ACh on muscle contraction from here. Nicotine, the addictive substance in cigarettes, acts upon ACh receptors. ACh also has its own actions in the brain, which I will talk about another time.
Image showing GABAergic neurons in the mouse brain (left). GABA is widespread through the human brain as well, and plays an important role in inhibition especially. See the previous post for more information.
The next neurotransmitter I will talk about is GABA (gamma-aminobutyric acid). GABA is the primary inhibitory neurotransmitter in the brain, but depending on the receptor type, it can be inhibitory or excitatory. We mainly talk about it’s actions as an inhibitory neurotransmitter, but it’s important to note that it can act as an excitatory one as well, depending on the receptor that it acts upon.
There are two main receptor subtypes for GABA, which are known as GABA-A and GABA-B receptors. GABA-A receptors are ligand-gated chloride channels. Hopefully, without further explanation, from my past entries, this makes sense. If you need a refresher, this means that when GABA interacts with these GABA-A receptors, they undergo a conformational change that opens their “pore” to allow chloride (Cl-) ions to flow through. Since Cl- is negative, it can hyperpolarize the cell (make it more negative) and make it less likely to fire, in the simplest explanation.
GABA-B receptors are more complex, as they are those G-protein coupled receptors. Downstream effects can be to open Cl- channels or K+ channels (since there is more potassium inside the cell, K+ might flow out or even if it does not move, shunt an excitatory signal if it arrives while the channels are open), amongst other things.
Inhibitory actions can be very complex on their own and really help to fine-tune the rest of the brain’s activity. The image above shows a presynaptic cell below and a postsynaptic neuron above it, as GABA is involved in the hypothalamus/feeding behavior- found in this paper (Richards & Berthoud, 2006).
This is to give a pictoral representation of the process of LTP (long-term potentiation), which seems to be related to the glutamatergic signaling I spoke about previously. (A) would be before LTP and (b) would be after. You can see that Ca2+ entering through NMDA receptors acts through various downstream molecules to insert more AMPA receptors into the membrane (“AMPAfication”).
[See here for image source and more in depth information]
Alright, we can start talking about neurotransmitters! The first one up is the most abundant in the brain (chemical structure pictured above). It’s largely excitatory and generally acts on ion channels. Have you guessed it yet? It’s glutamate!
Glutamate is implicated in synaptic plasticity and long-term potentiation. Two of the main receptors it acts upon are the AMPA and NMDA receptors. AMPA receptors let Na+ into the neuron, depolarizing it and potentially causing an action potential. NMDA receptors, which are voltage-dependent (they have a Magnesium block that only moves when the inside of the cell is depolarized enough) AND ligand-gated (they also need glutamate to open), let in both Na+ AND Ca2+ (calcium)- they are less ion specific. This calcium seems to have effects for long-term potentiation (LTP- which is the core of learning and memory, whereby the same activation will make a cell more likely to fire after LTP… so we increase the EPSP after LTP, thus, making it closer to the threshold for an action potential - see here).
The calcium that enters essentially (through downstream effectors) causes more AMPA receptors to be inserted into the postsynaptic membrane. A process sometimes called “AMPAfication” (amplification- ampafication- get it?). This means that when glutamate is released the next time by the presynaptic neuron, more AMPA receptors will open and more sodium will enter the postsynaptic neuron, meaning there will be more depolarization!
I mentioned in a previous post that neurotransmitters can act by opening a ligand-gated ion channel, which can let a specific ion into the cell/neuron. Neurotransmitters can have more complicated actions by acting on G-protein coupled receptors (shown in the image above).
When a neutrotransmitter binds to a G-protein coupled receptor, ions do not pass through- instead, the receptor undergoes a conformational (shape) change that “activates” the G-protein. Depending on the type of G-protein that is associated with that receptor, it can have different downstream effects. Essentially, once that G-protein has been activated, it can activate or shut down different molecules inside the cell, which will then have their own actions on other molecules, through a whole cascade of events.
Compared to a ligand-gated ion channel, the actions through a G-protein coupled receptor are slow, but they can be much further reaching. For instance, through that cascade, different molecules can be activated that may activate certain genes that change the way the cell/neuron will act in the future. Note that of course, like many other things I talk about, this is all a simplified explanation of what is going on, but will help you understand the basic principles.
To make it a bit more complicated, for example… One major effector of G-protein coupled signaling is the cAMP (cyclic adenosine monophosphate- often said as cyclic A-M-P), which can have big effects with calcium pathways and protein kinase A (PKA). For an example of a faster effect, one thing that this pathway does is open HCN and KCNQ channels, which cause a current leak in a dendrite, by letting out potassium. This can then “shunt” a signal coming in with sodium, such that the neuron would be less likely to build to a action potential. I’ll mention here that at Yale, Amy Arnsten’s lab has done some fabulous work to look at how this process may act in prefrontal cortex (http://www.ncbi.nlm.nih.gov/pubmed/17448997).
The process I mentioned before with action potentials is much more complicated than I described. For instance, though I described sodium coming in through ligand-gated ion channels, it is not so simple. It is not always a 1:1 presynaptic neuron has one action potential causing one action potential in the postsynaptic neuron. It can take many action potentials in the presynaptic neuron to cause an action potential in the postsynaptic neuron (or sometimes just one). There are also other ion channels (such as chloride Cl-) which can cause hyperpolarization or negative current in the neuron. It really depends on which neurons are involved and which neurons are giving them input.
I am going to try to put it in simple terms, but when we record from the postsynaptic neuron, we can see “post-synaptic potentials” (PSPs), which are just changes in the membrane potential, akin to perhaps mini-action potentials in the dendrites of the neuron (but not carrying a message on to the next cell). Simply, these PSPs are voltage changes in the postsynaptic cell/neuron. These post-synaptic potentials can be excitatory (EPSPs) or inhibitory (IPSPs). You can see examples of these in the image above.
An EPSP could be caused by ligand-gated sodium ion channels opening in the postsynaptic neuron and causing a positive influx. It can take a few EPSPs (so a few action potentials from a presynaptic neuron) to build up to a “threshold” at which point the action potential will fire. This threshold is determined by the voltage at which the voltage-gated sodium channels will open, as I described before.
An IPSP could be caused by a different neurotransmitter opening ligand-gated chloride channels for instance, which could cause Cl- to enter the neuron and decrease the membrane’s voltage. You could imagine that if this happens at the same time as an EPSP, this could prevent the postsynaptic neuron from reaching that threshold for an action potential, and thus, inhibit the signal.
The height of the EPSP can be determined by the number of ion channels in the postsynaptic membrane, where more ion channels will let in more sodium and depolarize the membrane more (make it more positive). You may wish to note that IPSPs are not always negative- they really just make the cell less likely to fire. This can get really complicated though, so I will not say much more than that at this time.
So, now that we know what an action potential looks like, how does it begin?
The action potential begins with ligand-gated Na+ channels. These “ligands” are small molecules, often called neurotransmitters. Neurotransmitters are packaged into little containers called synaptic vesicles. Note that pre-synaptic means the neuron before the synapse (space between two neurons) and post-synaptic means the neuron after the synapse. The pre-synaptic neuron is communicating the message to the post-synaptic neuron, through the release of neurotransmitter.
The synaptic vesicles will fuse with the pre-synaptic membrane and pour out their contents into the synapse, the space between two neurons that they use to communicate. How do they know when to do this? Well, the action potential comes down the axon from the pre-synaptic neuron and causes voltage-gated Ca2+ (calcium) channels to open. Ca2+ causes the vesicles to fuse to the pre-synaptic membrane and the neurotransmitters to be released into the synapse. These neurotransmitters can then cause the ligand-gated Na+ channels to open on the next neuron and begin an action potential there.
This all leads us into talking about the observed action potential. If you put in some electrodes to measure voltage across the membrane, this is what you would see. In phase 1, “leak” channels are open and the Na-K pump is maintaining the negative potential.
Phase 2 is when the ligand-gated Na+ channels have opened causing the voltage-gated Na+ channels to open and sodium to rush into the cell. The ball closes the pore and phase 3 is then caused by the slow to open voltage-gated K+ channels opening and K+ leaving the neuron.
Phase 4 is caused by the slow K+ VG channels being slow to close. Too much K+ has left! Resting state (labeled phase 1 here) is restored when those channels have closed and the Na-K pump sets to work!