Drugs of Abuse: More on Bupropion, Smoking, Melatonin and DHEA
phis at sprynet.com
Fri Dec 20 18:10:38 EST 1996
Drugs of abuse: More on Bupropion, Smoking, Melatonin and DHEA
This is a response to Andrew Ray's post, "Melatonin et al.," of December 18.
Mr. Ray posed a number of questions regarding my post, "Bupropion,
Smoking, Melatonin and DHEA," of December 15. Since Mr. Ray posed a
number of questions and made comments regarding my post without
reproducing any of my post, I feel I should explain a few things about it so
my answers have more relevance to anyone who reads this. My post
consisted of three parts: (1) An introduction relating information from a
newspaper article about the use of the antidepressant, bupropion
(wellbutrin), as an aid to help people stop smoking. In this section, I stated
"I intend to show you that the effect of bupropion in inhibiting smoking is
simply that it stimulates our natural hormone, melatonin." (2) The second
section consisted of a copy of a "letter to the editor" that I published in my
local newspaper. The reason for including this letter is two fold; it explains,
in a simple manner, why I think melatonin and DHEA are involved in
smoking, and the letter connects my theory of smoking to a published, dated
source. That letter was constrained by length and audience; I wanted to
reach the average person of my area. I invited the reader of my post to read
my theory of sleep in detail at http://www.naples.net/~nfn03605 on the web.
For sake of brevity I omitted the opening paragraph of this letter. Mr Ray
makes some points about "pleasure centers" in his critique. The following is
the omitted paragraph, which shows why I used "pleasure center."
"According to The News (Sept. 22, 4B), the brain's nicotine 'pleasure switch'
has been found. Researchers say this 'switch' is part of the brain's 'reward
system' that causes smokers to light up again and again. They hope this will
help identify the natural mechanism that nicotine mimics. My work may
explain nicotine's effects, as well as the mechanism it mimics."
(3) This part of my post presented the evidence supporting my contention
that bupropion exerts its effects by stimulating melatonin production.
The following are Mr. Ray's questions and comments and my responses to
them. None of his questions deal specifically with my idea regarding
nicotine and melatonin, nor bupropion and melatonin, however, I will
respond to the material he considered important.
Andrew Ray says: "If your theory is true, explain the fact that taking DHEA
in the early evening or at night will not wake you up, nor will it keep you
awake. Rather, it seems to enhance REM sleep in large enough doses.
According to your theory, if DHEA is 'used up', replacing it will stimulate you
enough to wake you up."
James Howard responds: The basic principle of my work is that I think
DHEA is directly involved in transcription and replication of DHEA. In
transcription, I suggest that DHEA acts along with specific proteins which
select specific areas where DHEA is used. If these proteins are not
available, DHEA will exert reduced actions. As DHEA is used up during the
day, so are the proteins that direct DHEA. It is a cycle of stimulation and
use; both DHEA and these proteins decline during the day. Simply giving
DHEA will not have the same effect that DHEA and these proteins produce.
In the fourth diagram, in my article on sleep, at my website, one can see the
rise and fall of DHEA and melatonin. According to my theory, melatonin
causes the beginning of a cascade of proteins that stimulate/direct DHEA.
When these proteins are produced in proper amounts, along with DHEA,
consciousness occurs. One study using very large amounts of DHEA during
sleep found that DHEA caused REM sleep (American Journal of Physiology
1995; 268: E107). It is my theory that REM sleep is caused by small
increases in DHEA that cycle along with some specific proteins, while we
sleep. Apparently, given enough DHEA this can be caused to occur. So,
specifically, a specific set of proteins must be stimulated for consciousness
Andrew Ray says: "Also, you don't go directly into slow wave sleep. You
move through several stages of sleep (I and II) before SWS. In addition,
melatonin does not immediately surge - it increases gradually into the
evening and night. There's no sudden large release, it's a bell curve more or
James Howard responds: Please look at the fourth diagram in my article on
sleep at my website. You will see that I consider this in detail and why it
Andrew Ray says: "How are cocaine and caffeine related structurally?
Bupropion and cocaine inhibit dopamine reuptake - caffeine binds to the
Adenosine receptor. Methamphetamine is structurally very different from
James Howard responds: Take some paper and draw the structures of
cocaine, methamphetamine, nicotine, caffeine and bupropion. Leaving
caffeine for last, take a red pen and circle the five membered heterocycle,
with a methyl group attached, on the cocaine. Then circle the very similar
structure on nicotine; then look at the -NCH3 on methamphetamine. I
suggest these exert similar actions at the same receptor. Next, circle the
phenyl ring of cocaine; then the same structure in methamphetamine, and
the very similar heterocycle of nicotine. Now consider their actions, as
stimulants. Methamphetamine is the longest lasting; I suggest it binds to the
receptor and stays the longest. Cocaine is powerful, but not long lasting.
Cocaine can flex to reach the same positions as methamphetamine, but this
flexing, I suggest, causes it to last a short time. Nicotine is similar to
these; it exerts a much milder effect. Caffeine is much less powerful, but it
approximates these same structures. The same can be said for bupropion.
A review of some basic organic chemistry may possibly explain the
differences in effects of the -NCH3 alone, compared to -N(CH3)3 and within
a ring. The same can be said of small differences in the ring structures.
I think these similarities cause similar phenomena. Some of the following
are not "iron clad," but the similarities are consistent enough to be
remarkable. They follow the same general pattern. In my post of
December 15 th., I included citations demonstrating that bupropion increases
melatonin production. Cocaine increases melatonin in pineal glands in
organ culture (Psychiatry Res. 1990; 34: 185). Caffeine increases
melatonin (Journal of Neurochemistry 1995; 65: 1332). My work suggests
there is a melatonin-DHEA cycle; the first part of which is stimulation of
melatonin. Now, while I could not find that nicotine stimulates melatonin, it
does stimulate DHEA (J. Steroid Biochem Mol Biol 1993; 46: 245 and J. Clin
Endocrinol Metab 1994; 79: 1310).
Andrew Ray says: "There are no 'pleasure centers' in the brain. Areas
which are involved in reinforcement of behavior (which might be considered
pleasure centers, although not acurately) are excited, not inhibited, during
behaviors which would be reinforced. Nicotine does not 'relax' the pleasure
center. It may, however, reduce dopamine release in the nucleus
accumbens, but there's no good evidence for this. Of course pleasure and
stimulation are simultaneous, increased dopaminergic activity occurs during
reinforcement - since icreased dopamine transmission is a hallmark of
antidepressant activity, this would make sense. As would the fact that many
stimulants (e.g. cocaine) increase dopamine activity."
James Howard responds: My general idea about how these drugs work is
that they first cause a "down regulation" of function to which the nervous
system reponds. That is, these drugs shut us down to produce an effect. Of
course, I think the universal response is to start the melatonin-DHEA cycle to
counteract the "poisoning," if you will, that these drugs cause. I also suggest
these drugs act in different areas of the brain, due to their ability to
different areas. My idea is that the specific part of the brain that is shut
down, eventually increases receptors for DHEA. The increased DHEA that
is absorbed by the specific part of the brain actually causes the stimulation.
The shut down is the "pleasure." Now, as drug use continues over time, the
response of DHEA increases, because of increased receptors. This DHEA
stimulates this part of the brain, and increased DHEA receptors increase
DHEA absorption and, therefore, stimulation. The stimulation is the drive
that needs to be satisfied, that is, needs to be reduced. This becomes the
"drug craving." As time goes by, it is more and more difficult to "relax" this
stimulation. The drugs themselves then become agents to block receptors,
from DHEA. The drugs are increased to merely block the craving; no
pleasure comes at this point because the drive cannot be reduced.
In one citation I found some support for this. "...systemic nicotine injections
inhibit the action potentials of normally inactive NAS [nucleus accumbens]
neurons, evoked by fimbria stimulation..." and "in contrast to the fimbria-
driven NAS responses, spontaneously active NAS neurons wer not affected
by nicotine injections yet were subsequently inhibed with systemic
morphine." (Synapse 1993; 15: 191). In the case of cocaine, I found this:
"To examine potential neural mechanisms involved in cocaine self-
administration, the activity of single neurons in the nucleus accumbens of
rats was recorded during intravenous cocaine self-administration. On a time
base comparable to the interinfusion interval, half the neurons exhibited
phasic firing patterns time locked to the cocaine reinforced lever press. For
almost all neurons, this pattern consisted of a change in firing rate postpress,
typically a decrease, followed by a reversal of tha change." (Journal of
Neuroscience 1996; 16: 3459). In the case of methamphetamine, consider
this: "Methamphetamine reduced the firing rates of the dopamine cells in a
dose-dependent manner in the SNC and the VTA." (Jpn J Pharmacol 1985;
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