dopamine receptor agonists and operant behavior

MGLinWS mglinws at aol.com
Thu Sep 14 16:38:29 EST 1995


bill at nsma.arizona.edu (Bill Skaggs) wrote:

:I don't have a collection of references, but the story as I understand
:it is that rewarding effects require activation of both D1 and D2
:receptors in the nucleus accumbens.  Thus, specific D2 agonists are
:only minimally rewarding at best.  (Cocaine and amphetamine work by
:increasing the amount of dopamine at the synapses, thereby activating
:both D1 and D2 receptors equally.)  In large doses, D2 agonists
:actually make you throw up, by activating dopaminergic cells in the
:brain's poison-detection system.  On the other hand, specific D2
:antagonists, such as neuroleptics, are highly effective in reducing
:reward -- which is probably a major reason why schizophrenics hate
:them so much.

:The requirement for both D1 and D2 activation makes a lot of sense
:when you think about it.  Short-circuiting of the brain's reward
:system is a functional disaster, because it leads to drug-seeking
:behavior instead of adaptive behavior.  The requirement that two types
:of receptor be simultaneously activated dramatically reduces the
:possibilities for short-circuiting the system -- essentially the only
:way to do it is either to use a cocktail of D1 and D2 agonists or else
:to increase the level of dopamine itself.

Thanks for your reply !

The basis for my question was the fact that dopamine antagonists or
depletions increase reaction-times and obliterate the speeding of
reactions that occur after long preparatory intervals (see Amalric and
Koob, J. Neurosci., 1987; Brown and Robbins, Brain, 1991).  In the absence
of striatal dopamine, subjects are less ready to respond to trigger
stimuli.  Previous studies have used rather dirty drugs (amphetamine,
haldol, etc.) to study how dopaminergic function relates to reaction-time
performance.  As raclopride produces effects that are similar to haldol,
it may be that the D2 receptors are somehow critical for the mediation of
motor readiness.  I am using more specific D2/D3 ligands, raclopride and
quinpirole, to gain insight into how the dopamine D2/D3 receptors are
involved in reaction-time performance.  Specifically, I want to know how
these drugs will affect neurons with activity related to movement
preparation and execution when reaction-times are slowed with raclopride
or when anticipatory responding occurs more with quinpirole.

A pilot study using within session cumulative dosing found that quinpirole
is a very potent drug with biphasic effects.  30 micrograms per kg
produced a cessation of spontaneous activity (and a lack of reaction-time
performance).  100 micrograms per kp produced stereotypy after about 45
trials (with 30 anticipatory responses).  Is this sort of result typical
of quinpirole?  If what is important is the animal's reaction-time
performance, then what should I do?  Try lower doses and smaller
increments?

There's alot available regarding raclopride in the extant literature. 
Still, I am interested in any information that anyone may have regarding
the effects of quinpirole (or any other selective D2-like agonist) on
operant performance (e.g., rate-dependent effects) and whether
pretreatment with raclopride interferes with the action of quinpirole.

Does anyone know of any work related to this issue?

Thanks again in advance for any information.

Mark Laubach



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