I wrote this piece because understanding diseases by framing them as high or low levels of dopamine, acetylcholine, glutamate, or GABA has significantly improved my grasp of their pathophysiology and treatment strategies. Too often, medicine is taught as isolated pieces of information, disconnected from a bigger, cohesive picture. This fragmentation makes the material less relevant and harder to apply in clinical practice.
Picture acetylcholine (Ach) and dopamine as two partners in a volatile relationship, constantly struggling for dominance. Neither is ever fully at peace, as one is always trying to overpower the other, disrupting the delicate balance necessary for normal function. When this balance tips too far in one direction, pathological conditions arise. Treatment, therefore, often aims to restore this equilibrium.
In vitro studies reveal that acetylcholine stimulates the release of dopamine, while dopamine, via D2 receptors, inhibits the release of acetylcholine. This dynamic emphasizes a central theme in neurophysiology: balance is everything.
1. Psychosis: ‘The Dopamine Hypothesis‘ (relatively HIGH DOPAMINE state)
The “dopamine hypothesis of schizophrenia/psychosis” suggests that the positive symptoms of schizophrenia—such as delusions and hallucinations—can be attributed, at least in part, to the overactivation of D2 receptors. Have you noticed that nearly all antipsychotic medications are primarily antidopaminergic in their mechanisms of action? This antidopaminergic approach to treating psychosis is one of the key reasons the dopamine hypothesis was initially developed.
A closely related concept is “substance-induced psychosis” (e.g., psychosis caused by cocaine, crack, or other stimulants), which is believed to result from chronically elevated dopamine levels in the synaptic space due to the effects of these substances. After all, the euphoric feeling, or “getting high,” is largely a “dopamine hit,” isn’t it?
Interestingly, there’s also a controversial hypothesis suggesting that people with schizophrenia may self-medicate with nicotine, specifically through smoking. The idea is that nicotine could have a therapeutic effect by restoring the balance between acetylcholine (Ach) and dopamine via nicotinic cholinergic signaling. Too much dopamine? Increase acetylcholine to restore equilibrium!
2. Parkinsonian Diseases (relatively LOW DOPAMINE state)
Whether due to Parkinson’s disease—a condition characterized by a deficit in dopamine production from the substantia nigra—or as a result of antidopaminergic drugs causing Parkinsonian extrapyramidal symptoms, the end result of relatively low dopamine levels is well known. This dopamine deficiency manifests as the classic symptoms of cogwheel rigidity, tremors, and other Parkinsonian signs you’re likely familiar with.
To restore balance, treatment approaches include either:
a) Replenishing dopamine directly (e.g., with levodopa or carbidopa), or
b) Restoring the dopamine-acetylcholine balance by reducing acetylcholine’s effects through anticholinergics (e.g., benztropine).
Even if both dopamine and acetylcholine are low, achieving this balance between the two can alleviate the symptoms.
3. Psychosis in Parkinson’s (relatively HIGH DOPAMINE state)
Now, let’s bring it all together. One of the most characteristic non-motor manifestations of Parkinson’s disease is psychosis, which is classically visual and often accompanied by paranoid delusions. This condition affects up to 40% of Parkinson’s patients. The leading cause of this psychosis is thought to be the dopamine agonists used in Parkinson’s treatment.
Since stopping all antiparkinsonian drugs is rarely an option, managing the psychosis usually involves either reducing the dopamine replacement dose or adding—no surprise here—an antidopaminergic antipsychotic. Additionally, there is some (though inconsistent) evidence that adding an anticholinesterase inhibitor, thereby increasing cholinergic tone, may help manage this psychosis.
Once again, the takeaway is clear: it’s not the absolute levels of dopamine or acetylcholine that matter, but rather the balance between the two. Too much dopamine? Lower it, or increase acetylcholine!
4. Metoclopramide (relatively LOW DOPAMINERGIC state)
Another example to consider is metoclopramide, or other anti-dopaminergic anti-emetics like domperidone. Due to its dopamine antagonism, metoclopramide can induce Parkinsonian extrapyramidal symptoms (EPS). These effects can be mitigated with benzodiazepines, or more intriguingly, through the anticholinergic actions of medications like diphenhydramine (Benadryl) or benztropine.
Okay, so we’ve extensively discussed the importance of balancing dopamine and acetylcholine. Now, let’s delve a bit deeper into acetylcholine itself. There are various clinical scenarios where either an excess or a deficiency in cholinergic effect can lead to disease states:
5. Myasthenia Gravis (relatively LOW CHOLINERGIC state)
Myasthenia gravis (MG) is an autoimmune disease where, despite having sufficient acetylcholine (Ach), the body generates autoantibodies against postsynaptic Ach receptors. This leads to a deficiency in cholinergic signaling, causing the hallmark motor weakness that typically worsens with use throughout the day.
Treatment options generally fall into two categories:
- Immune modulation—using therapies like prednisone, thymectomy, IVIg, plasmapheresis, cyclophosphamide, cyclosporine, or newer biologic agents to address the autoimmune aspect.
- Alternatively (and more commonly), clinicians aim to saturate the remaining functional postsynaptic receptors with Ach. This is achieved through acetylcholinesterase inhibitors, which slow down the degradation of Ach, thereby increasing overall cholinergic activity.
The most commonly used drug for this purpose is pyridostigmine (Mestinon). As a quaternary ammonium compound, it doesn’t cross the blood-brain barrier (BBB), making it ideal for treating a peripheral disease like MG. If it did cross the BBB, central cholinergic side effects could occur—think excess salivation or lethargy. In contrast, smaller molecules like tertiary compounds (e.g., physostigmine) do cross the BBB.
So far, so good, right?
6. Sidequest: RSI with the MG Patient
Let’s dive a little deeper since we’ve come this far already. Let’s imagine the worst-case scenario of a myasthenic crisis with respiratory involvement requiring intubation. The classic case is the MG patient who got sick from say a viral illness, which maybe caused some vomiting, which in turn worsened their MG symptoms – all of this is further aggravated by their inability to tolerate their oral meds.
Their respiratory effort is weak and getting weaker by the minute, it seems. When the nurse asks you what you want to do, you fumble around and mumble something about MIPs and MEPS but the patient is clearly deteriorating in front of you. You’ve already tried BiPAP and high-flow, but nothing’s working – it’s time to boogie.
If you HAVE to intubate:
- Avoid paralytics if at all possible
- If you have to, choose a nondepolarizing agent and go low.
- Why NON-depolarizing? Depolarizing agents such as succinylcholine require up to 2.5x higher doses to overwhelm the relatively low number of receptors into depolarizing and thus a paralytic effect. Usually patients are already on an acetylcholinerase inhibitor like pyridostigmine, and with this high dose, the succinylcholine will remain effective for an unpredictably long duration of time.
- Even when using a nondepolarizing agent like rocuronium, you will have to decrease the dose significantly, since it won’t take much to just occupy the few receptors that are left without fully depolarizing. Starting at 0.1 to 0.2mg/kg can often provide sufficient neuromuscular blockade.
7. Anticholinergic Toxicity (relatively LOW CHOLINERGIC state)
As one of the more common toxidromes, the anticholinergic patient presents with delirium, hyperthermia, flushed dry skin, inability to urinate/defecate, and vision problems / mydriasis. As some of the common culprits are antihistamines and sleeping aids like diphenhydramine (Benadryl), dimenhydrinate (Gravol), doxylamine and any allergy medications, somnolence/drowsiness/coma is also a frequent presentation. The same can be said of TCAs and their 7 mechanisms of action – anything from coma to seizure to combative delirium is possible.
The treatment for these toxidromes is almost always supportive. Benzodiazepines for seizures, cooling for hyperthermia, activated charcoal for decontamination, fluids to replace losses and watchful waiting. Rarely, sodium bicarbonate may need to be used for wide complex tachydysrhythmias. How about a cholinergic-boosting medication?
Enter physostigmine. Yes, a “stigmine”, and thus an acetylcholinesterase inhibitor that increases the cholinergic signal. Why not pyridostigmine like in MG, or neostigmine, like in Ogilvie syndrome? Physostigmine is a tertiary ammonium compound, and therefore it crosses the BBB, which we want in the case of anticholinergic poisoning. It is the only drug that can rapidly resolve the central antimuscarinic effects causing delirium, and is the only agent that is both diagnostic and therapeutic. One retrospective series involving 52 patients found that physostigmine was 96% effective for treatment of agitation and 87% effective for delirium reversal, compared to benzodiazepines, which were only 24% effective for agitation and wholly ineffective at delirium reversal.
Sounds like a miracle drug – why not use it for every suspected case of Benadryl or Gravol overdose? Well, it can be lethally dangerous for a number of reasons:
- It is a salicylate-based carbamate, and therefore in the event of an aspirin co-ingestion or allergy, it can be lethal.
- It can also be deadly in sodium channel blockade (e.g. co-ingestion of TCA or any other sodium-channel blocking agent – i.e. a LOT of drugs). The physostigmine will successfully remove the anticholinergic signal causing the tachycardia and hypertension, but then you will be left with unopposed sodium channel blockade, i.e. hypotension, malignant bradyarrhythmia – death.
If you ARE going to use it, give 1mg and give it slow – anywhere from 1 minute to 1 hour. Some toxicologists have told me that it should be stopped at the first sign of a single tear or drop of sweat (cholinergic signal restoration).
8. Cholinergic Toxicity (relatively HIGH CHOLINERGIC state)
The typical agents involved in cholinergic toxidromes are organophosphates and carbamates, such as pesticides. In recent years, some neonicotinoid pesticides have been introduced as safer alternatives to older organophosphates like Malathion. Although these newer agents are considered less toxic, they also lack proven antidotes.
Cholinergic toxicity manifests differently based on the acetylcholine receptor stimulated:
- Nicotinic: SLUDGE (Salivation, Lacrimation, Urination, Defecation, GI cramping, Emesis)
- Muscarinic: MTWTF (Muscle cramps, Tachycardia, Weakness, Twitching, Fasciculations) and the Killer B’s (see below)
- Central: Agitation, Confusion, Lethargy, Coma, Seizure, Death
There are clinically relevant ways to categorize the toxidrome. The Killer B’s—Bronchorrhea, Bronchospasm, and Bradycardia—represent the fatal pathways through which cholinergic toxidromes typically cause death. The Serious C’s involve central neurologic toxicity, including Confusion, Convulsions (seizures), and Coma. Additionally, the DUMBELLS acronym (Diarrhea/Diaphoresis, Urination, Miosis, Bradycardia or Tachycardia, Emesis, Lacrimation, Lethargy, Salivation) can help recognize the cholinergic toxidrome. It’s worth noting that both bradycardia (muscarinic) and tachycardia (nicotinic) can occur, and depending on receptor activation, bronchospasm (muscarinic) or bronchodilation (nicotinic) may also be present.
One cornerstone of treating cholinergic toxicity is atropine, an anticholinergic agent. It is important to understand that atropine only affects muscarinic receptors, helping alleviate SLUDGE symptoms and, more critically, preventing death caused by the Killer B’s.
Interestingly, tachycardia is not a contraindication to the use of atropine. While we often associate atropine with treating bradycardia, in the context of organophosphate poisoning, tachycardia can result from hypoxia due to bronchospasm or bronchorrhea. Furthermore, atropine does not address nicotinic symptoms, such as muscle weakness. The therapeutic goal of atropine administration is to control secretions.
Other anticholinergics, such as glycopyrrolate, have been studied, but dosing is not well defined, and there is no proven benefit over atropine. Ipratropium bromide (Atrovent) has shown some benefit in treating pulmonary toxicity, but since neither of these agents cross the blood-brain barrier (BBB), they are ineffective in managing central symptoms (the Serious C’s). Atropine, however, does cross the BBB and can prevent or abort seizures caused by cholinergic overstimulation.
9. Bonus Round: GABA and Glutamate: Sedation vs Seizure
Glutamate is the brain’s primary excitatory neurotransmitter (think seizures), while GABA is the main inhibitory neurotransmitter (think sedation). Normally, these two are well balanced. Interestingly, glutamate is a metabolic precursor to GABA, though we won’t dive into that for now. When there’s too much glutamate (acting on NMDA receptors) or not enough GABA (acting on GABA receptors), seizures occur. On the other hand, increased GABA signaling or decreased NMDA signaling leads to sedation or even coma.
Here are some practical examples to illustrate these dynamics:
- Benzodiazepines and Propofol: Both increase GABA activity (GABA ↑↑↑), resulting in sedation and anti-seizure effects—this is why propofol is the preferred RSI induction agent in status epilepticus.
- Alcohol Withdrawal: Involves a decrease in GABA (GABA ↓↓↓). Since alcohol enhances GABAergic activity, its absence leads to a relative GABA deficiency due to upregulated receptors, resulting in withdrawal seizures.
- Amanita muscaria: This mushroom’s ibotenic acid leads to an increase in NMDA activity (NMDA ↑↑↑), which can cause seizures.
- Magnesium: Reduces NMDA activity (NMDA ↓↓↓), which is why it’s used for treating insomnia or anxiety.
- Ketamine, PCP, Nitrous Oxide: These drugs decrease NMDA activity (NMDA ↓↓↓), producing sedative effects and making them drugs of abuse.
- Tricyclic Antidepressants (TCAs): These have a complex profile with seven different effects. They can cause sedation through GABA antagonism and antihistaminergic effects. However, their anticholinergic action can also cause hyperactive, even combative, delirium. As a result, TCA presentations vary widely, ranging from coma and sedation to balanced states, or from “mad as a hatter” delirium to seizures.
In summary, while this content simplifies some of the intricate relationships between neurotransmitters, the aim is to provide a conceptual framework. With this understanding, you can better discuss the clinical effects caused by relative increases or decreases in glutamate, GABA, NMDA, and acetylcholine. Hopefully, this was helpful!
