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 D
2 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 SKF82958.

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 D
1 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 g/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 g/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 (Figure 4).

Furthermore, the dose-response curves for 3 and 10 g/kg/inj SKF82958 overlap at the higher eticlopride doses (1, 3, 10 g/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 g/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, and

 

that they are likely due to suppression of motor activity, not to pharmacological attenuation of D1-mediated reinforcement.

In contrast to findings that D
2-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.


Acknowledgements

I 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.


Works Cited

1Heikkila, R. E., H. Orlansky, and G. Cohen. "Studies on the distinction between uptake inhibition and release of [3H]dopamine in rat brain tissue slices." Biochemical Pharmacology 24 (175): 847-52.

2Kebabian, J. W., and D. B. Calne. "Multiple receptors for dopamine." Nature 277 (1979): 93-6.

3Sokoloff, 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.

4Van 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 350 (1990): 610-4.

5Sunahara, R. K., H. C. Guan, B. F. O'Dowd, P. Seeman, L. G. Laurier, G. Ng, S. R. George, J. Torchia, H. H. M. Van Tol, and H. B. Niznik. "Cloning of the gene for human dopamine D receptor with higher affinity for dopamine than D1." Nature 350 (1990): 614-9.

6Belluzzi, J. D., S. R. Kossuth, D. Lam, F. Derakhshanfar, A. Shin, and L. Stein. "Cocaine self-administration patterns: duplication by combination of dopamine D1 and D2 agonists." Society for Neuroscience Abstracts 19 (1993): 1862.

7Del Rio, J. A., M. Helmy, K. Golshani, P. Than, C. Yam, S. Knoski, J. Ma, L. Stein, and J. D. Belluzzi.

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