SKF82958 3 and 10 g/kg/inj, the decline in responses for SKF82958 30 g/kg/inj was not statistically significant.

Self-administration of SKF82958 30 g/kg/inj alone produced highly regular response patterns and evenly spaced inter-response intervals (Figures 3 and 4). Low doses of SCH23390 (0.1 and 0.3 g/kg/inj) decreased the inter-response intervals for SKF82958 30 g/kg/inj self-administration, while maintaining the regular overall response patterns (Figure 3).  However, when combined with higher doses of antagonist (1, 3, 10 g/kg/inj), responses became erratic and the regular self-administration pattern was lost.  With the exception of the 3 g/kg/inj dose, eticlopride did not significantly affect the regularity of response patterns for 30 g/kg/inj SKF82958 (Figure 4).

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Figure 3
Response pattern of a representative rat self-administration SKF82958 30 mg/kg/inj alone and in combination with SCH23390 (0.1, 0.3, 1, 3, 10 mg/kg/inj).  Each vertical tick mark represents one self-injection.  Total self-injections per 3 h session are shown at the end of each line.  (SK=SKF82958, SC=SCH23390)

Discussion

Our study examined the effects of SCH23390 and eticlopride on SKF82958 self-administration.  The effects of SCH23390 on response rate and pattern of SKF82958 self-administration suggest that the two drugs are competing for the same binding site (D1 receptor), and that blocking the D1 receptor attenuates reinforcement mediated by SKF82958.  As shown in Figure 1, low doses of SCH23390 reduced self-administration of the low dose of SKF82958 (3 g/kg/inj), but caused an increase in response rate for the higher SKF82958 doses (10 and 30 g/kg/inj). Rats increased self-administration in the latter case in an effort to compensate for the effects of the antagonist, an important indication that the two drugs are competing for the same site, and that the antagonism could be overcome by increasing agonist intake.  This point is further demonstrated in the effect of SKF82958 on the

SCH23390 dose-response curve (Figure 1).  Increasing the agonist dose caused a rightward shift in the antagonist dose-response curve, another indication of competitive pharmacological antagonism that could be surmounted by increasing the agonist dose.

Figure 3 presents further evidence of competitive and surmountable antagonism by SCH23390.   Although low doses of SCH23390 (0.1 and 0.3 g/kg/inj) caused compensatory increases in SKF82958 30 g/kg/inj self-administration, they did not completely block reinforcement since rats maintained highly regular response patterns.  Higher doses of antagonist, however, produced erratic patterns of response indicative of attenuated reinforcement that could not be overcome by increasing self-administration.  As seen in Figure 3 for SCH23390 3 g/kg/inj, the rat was unable to surmount the antagonist's effect despite rapid successive self-injections, resulting in diminished reinforcement and extinction of self-administration.

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Figure 4
Response pattern of a representative rat self-administration SKF82958 30 ug/kg/inj alone and in combination with eticlopride (0.3, 1, 3, 10 ug/kg/inj).  Each vertical tick mark represents one self-injection.  Total self-injections per 3 h session are shown at the end of each line.  (SK=SKF82958, ET=Eticlopride)


In contrast to SCH23390, the effects of eticlopride on the rate and pattern of SKF82958 self-administration suggest that the two drugs are not competing for the same binding site, and that blockade of the D
2 receptor by eticlopride does not attenuate reinforcement mediated by SKF82958 at the D1 receptor.  As shown in Figure 4, with the exception of the 3 g/kg/inj antagonist dose, eticlopride had little or no effect on the pattern of SKF82958 30 g/kg/inj self-administration.   This suggests that, unlike SCH23390 (Figure 3, lines 1 and 6), eticlopride did not block D1 reinforcement mediated by SKF82958, indicated by the fact that the highest dose of eticlopride yielded a pattern of self-administration similar to the one produced by self-administration of SKF82958 30 g/kg/inj alone (Figure 4, lines 1 and 5).

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Mohammad Helmy - Effects of the D1-Antagonist SCH23390... [1] [2] [3] [4] [5] [6]