Although blockade of the D2 receptor by eticlopride had little effect on SKF82958 response
patterns, it did cause a insurmountable dose-dependent decrease in SKF82958
self-administration (Figure 2). One explanation is that eticlopride is non-selectively
binding and antagonizing the D1 receptor. This
is unlikely since we do not observe a compensatory increase in response
rate that is indicative of competitive pharmacological
antagonism, as seen with SCH23390 (Figure 1).
Another possible explanation of the suppressive effects of eticlopride on response rate is
that blocking D2 receptors attenuates D1 reinforcement. Though
it has been suggested that D2
reinforcement may depend on D1 activation, the reciprocal scenario in which D1
reinforcement requires D2 activation has not been found to be true.7,8,10 Furthermore,
if D1 reinforcement did require D2 activation, then blockade of the D2 receptor by
eticlopride should dose-dependently decrease self-administration of all doses of SKF82958
to the same extent, since SKF82958 acts primarily at the D1 receptor. Figure
2, however, shows that attenuation of responses is dependent on the dose
of SKF82958, with higher doses of eticlopride required to decrease self-administration
of higher doses of
Previous studies have shown that eticlopride, like other DA antagonists, may decrease
behavior and motor activity.11,12 The decreases in response rates caused by
eticlopride may be attributed to its non-specific antagonism of motor activity and not to
pharmacological antagonism of D1 reinforcement.
As the dose of eticlopride increases, the duration of its effects increases
and may outlast the time between successive self-injections. At the SKF82958 dose with a
higher baseline number of responses (3 µg/kg/inj), the suppressive effects on motor
activity may outlast the baseline inter-response interval and impede the rat's ability
attempt for the next self-injection. As a result, the rat must wait longer between
successive responses and self-administers less drug during the 3 h session (Figure 2).
In contrast, at the SKF82958 dose with a lower baseline (30 µg/kg/inj), the
suppressive effects of eticlopride dissipate during the longer baseline inter-response
interval. As a result, the time between successive self-injections
is unaffected, and the total number of responses during the 3 h session
remains relatively constant
Furthermore, the dose-response curves for 3 and 10 µg/kg/inj SKF82958 overlap at the
higher eticlopride doses (1, 3, 10 µg/kg/inj), suggesting that the suppression of motor
activity may limit the number of self-injections attainable by the rat in the 3 h session,
independent of the dose of SKF82958 (Figure 2). Further evidence of this is seen
with the 10 µg/kg/inj eticlopride dose, at which response rates for all doses of SKF82958
are almost identical. These results strengthen the idea that the
effects of eticlopride on SKF82958 self-administration are non-specific,
that they are likely due to suppression of motor activity, not to
pharmacological attenuation of D1-mediated reinforcement.
In contrast to findings that D2-mediated reinforcement may depend on some threshold level of D1
activation, our results suggest that D1-mediated reinforcement does not depend on D2
activation, and that D1 reinforcement by SKF82958 can be pharmacologically antagonized by
the D1 antagonist SCH23390, not the D2 antagonist eticlopride.
would like to thank Dr. James Belluzzi for his counsel and assistance
in the preparation of this paper. I would also like
to thank my fellow lab workers, Susie Knoski, Joe Ma, and Ranji Varghese,
for their technical support, and the Committee on Undergraduate Scholarships
and the Undergraduate
Research Opportunities Program for their financial support.
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P., B. Giros, M. P. Martres, M. L. Bouthenet, and J. C. Schwartz. "Molecular
cloning and char-acterization of a novel dopamine receptor (D3)
as a target for neuroleptics." Nature 347 (1990): 146-51.
Tol, H. H. M., J. R. Bunzow, H. C. Guan, R. K. Sunahara, P. Seeman,
H. B. Niznik, and O. Civelli. "Cloning
of the gene for a human dopamine D4 receptor
with high affinity for the antipsychotic clozapine." Nature
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P. Than, C. Yam, S. Knoski, J. Ma, L. Stein, and J. D. Belluzzi.