Mode of benzodiazepine action

Bill Skaggs bill at darwin.bns.pitt.edu
Tue Dec 15 17:42:50 EST 1998


rawheatley at canadalane.demon.co.uk (Dr. Alan Wheatley) writes:

> 
> This month's "Chemistry in Britain", the magazine of the Royal Society of
> Chemistry, carries an article by one of their in-house writers on drug
> addiction entitled "Drugs against drugs".  While the article is
> interesting, it seems to be at conflict with my previous understanding of
> the mode of action of benzodiazepines.  The article suggests that
> addiction results from an increase in dopamine activity:  "It is thought
> that all habit-forming drugs affect the dopamine (DA) system in the brain
> either directly as DA agonists, or by enhancing DA release, or by acting
> on other neurons responding to different neurotransmitters, which synapse
> upon this DA system to activate it."  The benzodiazepines are explicitly
> included in this explanation:  "Depressant drugs such as alcohol,
> benzodiazepines, barbiturates and opiates virtually all act on the
> gamma-aminobutyric acid (GABA) inhibitory neurotransmitter system.  These
> substances indirectly affect the DA system by lowering the threshold of
> its activation."  There is an accompanying diagram, showing a GABAergic
> neuron synapsing directly onto a dopaminergic neuron.  When I last had
> reason to consider this matter, several years ago, the prevailing view was
> that the principal action of benzodiazepines was the production of
> inhibitory GABA-like effects that led to a reduced turnover of monoamines
> in the brain.  Does that view still hold?  If so, are the quotes from the
> article simply wrong, or do the benzodiazepines come within the category
> "acting on other neurons responding to different neurotransmitters, which
> synapse upon this DA system to activate it"?  I should welcome any light
> that can be thrown on this apparent discrepancy, please.
> 
> Dr. Alan Wheatley at www.canadalane.demon.co.uk

Assuming you've summarized it correctly, the article is obviously
wrong.  It doesn't even make sense:  the action of benzodiazepines is
to *increase* GABA effects, so the circuit you describe would actually
suppress dopamine rather than activate it.

I think the article is also wrong on a more basic level.  DA is an
essential part of the brain's pleasure system, and so drugs that
activate dopamine tend to be habit-forming, but the brain also
contains a separate "pain-punishment" system (whose neural basis is
less well understood), and drugs that suppress the "pain-punishment"
system also tend to be habit forming.  They also tend to indirectly
activate the DA system (perhaps as a consequence of suppressing the
other system), but it seems likely to me that this is only part of the
explanation of their properties.  All of the depressant drugs listed
above fall into this class.  The functional distinction is that when
they are taken away, the result is a clear withdrawal syndrome
consisting of malaise and physical distress, whereas when pure
DA-activating drugs like cocaine or amphetamine are taken away, there
is a much less pronounced withdrawal syndrome.

	-- Bill



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