Examples of Neurotransmitters that are usually excitatory

There’s literally hundreds of neurotransmitters they’ve discovered and we’re only going to mention a few of them here.  The following are usually excitatory (usually, meaning, there are exceptions!):

Acetylcholine (ACh) certainly excites the nervous system. If you inject someone with ACh, when it reaches their brain it will open up sodium ion channels and depolarize them but it wont last long because there’s acetylcholinesterase. That’s why they would use a mimetic (a synthetic drug that’s similar but slightly different than our normal neurotransmitter that would take hours for our enzyme to break down rather than minutes).

Glutamic acid: A large number of neurotransmitters are amino acids or modified amino acids. Certainly in a biology class, we have learned that amino acids are the building blocks for making proteins, but now I’m telling you another role of amino acids. Many neurons either simply release amino acids as neurotransmitters or the neurotransmitter is a modified amino acid.  Glutamic acid is a name of one of the amino acids. It excites and increase electrical activity but its effects don’t last long because there’s enzymes that break it down.

Nitric Oxide: They discovered this 30 years ago and they couldn’t believe it at the time. Nitric oxide is a gas released by some neurons from their synaptic knobs which goes into blood vessels and the main action is vasodilation.

• First off, if you want to know about nitric oxide sooner rather than later, look up Viagra. Viagra dilates the blood vessels in the penis and it does that by triggering the release of NO in the vessels of the penis.
• Some of you have heard that when somebody needs their coronary arteries to be dilated (like people with angina pectoris), they give a coronary vasodilator called nitroglycerine which mimics the action of nitric oxide. Nitroglycerine, in other words, is a mimetic or agonist.

Catecholamines

1. norepinephrine (noradrenalin)
2. epinephrine (adrenalin)
3. dopamine

The three neurotransmitters above are made from the amino acid tyrosine and are collectively called catecholamines.  Tyrosine is one of the essential amino acids and it absorbs something called L-DOPA (dihydroxy-phenylalanine) and some of the enzymes convert it into dopamine.

• Other neurons turn the dopamine enzymatically into norepinephrine (which has a OH group).
• Other neurons, after they form norepinephrine, convert it one more step into epinephrine (which has a CH3 group).

If you inject someone with epinephrine, it’s going to increase their electrical activity in their body and last for 5 minutes because the enzymes break it down really quickly. The enzyme that breaks down all three catecholamine’s is called Monoamine Oxidase (MAO). Just like how acetylcholinesterase breaks down acetylcholine, MAO’s break down catecholamine’s.

Why do MAO and MAO inhibitors work with catecholamines?

At the end of dopamine is NH2.   That’s an amine.  The end of norepinephrine and epinephrine have NH2 as well. So they all have one amine group (monoamine) and monoamine oxidase can break that off.

If you want the effects of epinephrine going on, you have to give an IV drip, but one of the things you could do to make the epinephrine last longer is stop the enzyme from working. This is how monoamine oxidase inhibitors (MAOI) work, which are commonly anti-depressants, although they are not prescribed as often now.

The chemical structures of amphetamine and epinephrine look very alike. Structurally they are very similar. The main difference between epinephrine and amphetamine are the missing OH’s.  Due to this, amphetamine will activate the same receptor sites as norepinephrine but not break down as quickly.

There’s a little more to the story for catecholamine’s.

When we went over proteins in the cell membrane, we went over a diagram.  When a ligand attaches to a receptor site, it activates a g-protein and normally most neurotransmitters (ligands) cause an ion channel to open. We gave the example of acetylcholine activating the receptor site causing the sodium channels to open (exactly what happens at the neuromuscular junction). Epinephrine does not directly open up an ion channel. It activates an enzyme. So it works a little bit different than most NT’s.  All catecholamine’s activate an enzyme called adenyl cyclase. (They’ve changed the spelling of the name to adenylyl cyclase).

Adenylyl cyclase converts a small number of ATP’s (adenosine TRIphosphate) into cyclic-AMP and PPi.

• PPi = two phosphate groups
• AMP = one phosphate group

Adenylyl cyclase converts A-P-P-P(ATP) into A-P (AMP) because cyclase enzyme breaks it off before the second phosphate. Now what the hell is AMP? AMP is commonly called the intracellular messenger (the second messenger) and it causes the opening up of sodium ion channels.  In other words, cyclic AMP is what increases the permeability of the sodium ion channels.

Aren’t I still saying that the catecholamine’s open up the sodium ion channels? Yes, but we’ve added an intermediate step for catecholamine’s that c-AMP has to be formed that is actually what is opening up the sodium ion channels.

Just like how there is an enzyme for everything, you have to break down c-AMP because it’s what’s actually making the sodium channel open.  The enzyme that breaks down c-AMP is phosphodiesterase is what breaks down c-AMP into the “metabolite” 5’AMP.   The metabolite is the inactivated form.

So, the catecholamines activate adenylyl cyclase enzyme that creates c-AMP.  And phosphodiestease is what breaks down c-AMP to be inactive.

What if we had a drug that inhibited phosphodiesterase?

That means c-AMP won’t be broken down and it will accumulate.  Cyclic AMP excites our neurons because of the indirectly-adrenalin-made c-AMP.  The phosphodiesterase inhibitor that all of us have tried is caffeine.

So you could take a mimetic like methamphetamine or take a MAOI or a phosphodiesterase inhibitor and they would all do the same thing.

People talk about herbal and regular tea. Herbal teas are like chamomile, mint, etc and they don’t have caffeine in them. Real tea has “caffeine” in it but it’s actually not caffeine but it’s similar to it. Theophylline is the caffeine-like chemical that’s in tea that’s also a phosphodiesteraste inhibitor and is used in medicine under the brand name Theodur or Monodur.

The context that they use these are for people with really bad asthma. So they won’t usually give them adrenalin but something that mimics adrenalin called albuterol (proventil) that actives these receptor sites but specifically on the airways and helps dilates airways. When it’s really bad asthma, they add theophylline (side effect is that it speeds up the heart rate) to the albuterol to really help jack up the c-AMP levels.

Now let’s go over examples of neurotransmitters that are USUALLY inhibitory…