Activation of postsynaptic receptors

Moreover, both compounds impacted positively dentritic remodeling in the hippocampus and PFC of ischemic mice. The present results suggest that activation of post-synaptic 5-HT 1A receptors is the molecular mechanism for serotonergic protective effects in BCCAO.

Moreover, post-synaptic biased agonists such as NLX might constitute promising therapeutics for treatment of functional and neurodegenerative outcomes of brain ischemia. Abstract Pharmacological interventions that selectively activate serotonin 5-hydroxytryptramine-1A 5-HT 1A heteroreceptors may prevent or attenuate the consequences of brain ischemic episodes. These drugs are called inverse agonists because they have the opposite effect that agonists have on the receptor.

Many drugs that were classified as antagonists are being relabeled as inverse agonists because we learn that they impede the resting activity of receptors—antihistamines that target H1 receptors are one such example, as H1 receptors are somewhat active even in the absence of a bound ligand. One final term you should familiarize yourself with is allosterism. An allosteric modulator is a drug or ligand that alters receptor activity by binding to a site other than the active site i.

Some noncompetitive antagonists are allosteric as mentioned above, but allosteric modulators can also increase agonist affinity or efficacy.

As we mentioned before, not all of the action has to occur on the postsynaptic receptors. Some drugs influence neurotransmission at different steps in the process. An indirect agonist is a drug that enhances receptor activity without binding directly to the receptor.

One way to accomplish this is to induce the release of a neurotransmitter, such as by binding to a heteroreceptor on the presynaptic neuron. This may cause the cell to produce more neurotransmitter or release it more easily. One very common method of indirect agonism is to increase the amount of neurotransmitter in the synaptic cleft by blocking the mechanisms meant to remove it. This increases the amount of neurotransmitter available to activate receptors see image below.

Reuptake inhibitors are a common type of drug and can be found in many therapeutic medications, such as in selective serotonin reuptake inhibitors SSRIs and selective norepinephrine reuptake inhibitors SNRIs. We will cover these in greater detail when we discuss antidepressants in Chapter If the neurotransmitter is broken down by enzymes within the synaptic cleft or after reuptake, an enzyme inhibitor can interfere with this process by inhibiting the enzymes responsible.

The result is similar to reuptake inhibitors; by preventing the breakdown of released neurotransmitter, the amount available to activate receptors increases.

An example are the monoamine oxidase inhibitors MAOIs used to treat some forms of depression by preventing monoamine oxidase MAO from breaking down monoamine neurotransmitters see diagram below. It is also possible to have indirect antagonistic effects. By inhibiting the production or release of neurotransmitters, a drug can indirectly reduce overall receptor activity by decreasing the amount of neurotransmitter available.

A presynaptic regulator binds to the autoreceptors on the presynaptic neuron and inhibits neurotransmitter release see diagram below.

Ultimately, drugs can target any step in the neurotransmission process; what is important to remember is that the effect of the drug is defined by the end effect it has on the target receptor. Of course, many ligands act at multiple receptors. Part of the difficulty in developing a new drug has to do with finding a more selective compound that acts at the desired site without activating other receptors and triggering adverse side-effects. The effects of a drug can also be influenced by the presence of other drugs or substances.

When two drugs with similar effects are used together, the result can be additive , meaning the total response is what you would expect if you added the independent effects of the drugs together. A synergistic interaction, meanwhile, is greater than you would expect—the two drugs interact in a way that multiplies their effect.

Finally, the drugs could reduce the effectiveness of each other, which would be considered antagonistic. Causes of drug interactions are numerous. We covered many possible causes in the previous chapter on pharmacokinetics. Competition for plasma protein binding sites is one such cause, as this can change the bioavailability of the drug; other drugs or substances alter drug metabolism to similar effect. Drugs can also interact in a pharmacodynamic manner by competing over certain receptors or pathways.

Usually this is unintended and can result in severe consequences, but there are cases where this is desirable. Naloxone, a competitive opioid antagonist, is administered in the case of an opioid overdose because it has an antagonistic interaction with other opioids. By blocking opioid receptors, the effects of opioid overdose most importantly, respiratory failure, which is life-threatening can be reversed.

Does it produce a strong response? How much drug is needed? As the amount of drug changes, how does the effect change? And most importantly, is the drug safe to use? To answer these questions, pharmacodynamics provides a set of tools to evaluate and compare the effects of drugs. In the second half of this chapter, we will learn about these tools and how to use them. In pharmacology, it is important to know how strong the response will be for a given dose.

If we administer 1. What about 5. In reality, what we are interested in is what the effect of a drug will be at any dose and how that effect changes. This will allow us to select the proper dosage for the drug and determine whether this drug is safe and useful. By taking measurements at a few key points and understanding the mechanism of action , it is possible to produce a graph showing the intensity of effects across a range of doses. This graph is called a dose-response curve or a dose-effect curve.

You can see an example below:. The dose of the drug goes on the x-axis. Because we want to see a wide range of doses, we actually plot them in log scale to compress the graph; note how the intervals do not go 1, 2, 3, 4, 5, but rather 0. The graph is called a semi-log graph because only one axis is in logarithmic scale. This tonic influence persisted if the receptor for the other ligand was blocked.

We conclude that endocannabinoids and dopamine can be co-released. Retrograde signaling through endocannabinoids and dopamine changes inhibition independently from each other.