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Re: BuSpar thoughts » Paige

Posted by Cam W. on May 23, 2001, at 0:36:36

In reply to Re: thoughts » Cam W., posted by Paige on May 22, 2001, at 18:27:29

Paige - I am really not sure if they have totally figured out BuSpar™'s (buspirone) mechanism of action. Mood is regulated by a complex mix of serotonin, norepinephrine, and (to a lesser extent, but no less important) dopamine receptors; of which there are several varieties of each receptor. There are other neuroactive peptides and molecules that are also involved in the regulation of mood and emotion.

There are 15 to 17 (or more) different serotonin receptors, depending on who you talk to. Serotonin is chemically called 5-hydroxytrytamine, hence the abbreviation 5-HT. BuSpar is an "agonist" at the "serotonin-1A" receptor or "5-HT1A" receptor. An agonist acts at the receptor like serotonin would. The difference is that BuSpar is selective only for the 5-HT1A receptor and does not have significant activity at other serotonin receptors. Hence, taking BuSpar is like injecting serotonin at only the sites containing 5-HT1A receptors.

The 5-HT1A receptors are primarily located on the serotonin nerve cell body. This is the bulgy, round part of the nerve cell, as opposed to where SSRIs work, which is at the end of the axon (long, thinner part of the nerve cell, down which the action potential or electrical signal travels) at the axon terminal (which is located across the synaptic gap from the nerve cell to be receiving the electrical signal in the form of a neurotransmitter).

The 5-HT1A receptors are called "somatodendritic autoreceptors" because they are located on the little nerve spines (dendrites), which are located on the bulgy, round part (soma) of the nerve cell. They allow crosstalk between nerve cell bodies. It is called an "autoreceptor" because these dendrites release serotonin to talk to other nerve cells in the close vicinity of the releasing nerve cell and since the 5-HT1A receptor is located on the serotonin releasing dendrite, the serotonin that the dendrite releases stimulates it's own receptor.

Why would there be a receptor for serotonin on a serotonin releasing (serotonergic) dendrite? The 5-HT1A receptor acts as a brake, shutting off the flow of serotonin out of the dendrite when the serotonin in the synaptic gap reaches a certain concentration. Thus, a 5-HT1A agonist slows the flow of serotonin out of the dendrites and decreases the crosstalk between serotnin nerve cells, making them less excitable.

Simple, you say; I wish that it were that easy. The above is an oversimplified version of what really happens and is not entirely the true story of what goes on. First, 5-HT1A receptors are also found on norepinephrine nerve cells where their stimulation modulates norepinephrine release, which also acts on mood. Second, the body tries to compensate for the change in serotonin (and norepinephrine) release, possibly by making fewer (downregulating) 5-HT1A receptors and/or making the receptors less sensitive. Third, the body will also change the numbers and concentration of other neurotransmitters and their receptors in response to the change in serotonin levels. Fourth, BuSpar also acts on a couple of the dopamine receptors and I am not sure of the implications of this. Fifth, I am too tired to think of any more problems (there are many).

The reason that you are getting the same start-up side effects as with the SSRIs is that these antidepressants also stimulate 5-HT1A receptors. This stimulation happens within hours of taking your first dose of an SSRI. These start-up side effects (headache, anxiety, etc.) do go away in 1 to 3 weeks, depending on how fast your body can downregulate (desensitize) the 5-HT1A receptors.

So, you can expect your anxiety to get worse initially, but as your body adjusts to the BuSpar (or SSRI for that matter) the anxiety should decrease dramatically. On paper, BuSpar should be a much better anxiolytic (anti-anxiety agent) than it seems to be in clinical practice. There are many different psychological reasons for the seeming lack of effect of BuSpar, to go along with the physiological reasons given above. BuSpar's effects are subtle. There is no psychomotor slowing or "stoned" feeling with BuSpar, as is seen with benzodiazepines like Klonopin™ (clonazepam - Rivotril™ in Canada). On the upside, BuSpar has really no addictive potential and is safer in overdose than the benzodiazepines.

Benzodiazepines like Klonopin bind to a part of the GABA (gamma-amino butyric acid) receptor complex and facilitates the binding (allows easier binding) of GABA to this complex. GABA is an "inhibitory neurotransmitter" which means that it slows the action of other neurotransmitters (serotonin, norepinephrine, and dopamine are the main ones) by slowing their release from the nerve terminal. Benzodiazepines, while relieving anxiety in most people can actually cause more anxiety and aggression in some people. Also, benzodiazepines can cause memory problems in some people.

I hope that you can make sense of this. If you read it carefully, and perhaps rewrite it without the definitions, it might make more sense. Hey, you asked ;^)

- Cam




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