The Cardiovascular Effects of Amperozide: Interactions with Cocaine

Abstract

Absrrwcr: Amperozide is a 5-HTZA receptor antagonist that significantly reduces the acquisition and expression, by rats, of a cocaine conditioned place preference. In order to rule out the possibility that amperozide affects a cocaine conditioned place preference due to effects on blood pressure or heart rate, the cardiovascular effects of amperozide were investigated. Alternating cumulative doses of amperozide (0.5, 1.0, 1.5 and 2.5 nig kg-l) or saline and phenylephrine (8 pg kg-I) were administered through the femoral vein of awake freely-moving Sprague-Dawley rats and blood pressure and heart rate were recorded from the femoral artery. A single dose of cocaine (5.0 mg kggl) was administered after all the amperozide or saline doses were given. Amperozide (0.5, 1.0, I .5 and 2.5 mg kg-I) did not have any significant effect on blood pressure compared to the saline control treatment to the same animals. However, 0.5 mg kg-I amperozide significantly decreased heart rate at 5 and 10 min. after administration, but higher doses did not further depress heart rate. Amperozide did not affect the increased blood pressure and decreased heart rate caused by phenylephrine, an al-adrenoceptor agonist. In addition, amperozide did not affect the cardiovascuhr response to an intravenous dose of 5.0 nig kg-I cocaine. These results suggest that amperozide does not cause direct cardiovascular effects. The mechanism by which the lowest dose of amperozide caused a decrease in heart rate is unknown. Amperozide affects neither a-adrenoceptor mediated vasoconstriction nor the increased sympathetic activity caused by the peripheral and central effects of cocaine. The significance of these results, in terms of locomotor activity and the cocaine conditioned place preference paradigm, is discussed.Amperozide is a novel putative antipsychotic drug characterized by high affinity for 5-hydro~ytryptamine~~ ( 5 -HTzA) receptors (Axelsson ef u/. 1991; Bjork et ul. 1992). Amperozide also has moderate affinity for a,-adrenergic receptors, a weak affinity for D2 dopamine receptors (Svartengren & Simonsson 1990; McMillen et nl. 1993) In a behavioural model used to study drug addiction, amperozide significantly reduced a cocaine-induced conditioned place preference (Jones & McMillen 1995). This report demonstrated that animals spent significantly more time in the cocaine associated chamber after repeated cocaine administration compared to the time spent in the cocaine-associated chamber before cocaine administration. Administration of amperozide prior to each dose of cocaine during the conditioning phase completely blocked a conditioned place preference. The mechanism by which amperozide reduced the cocaine-conditioned place preference is unknown. It is hypothesized that amperozide acts within the mesocorticolinibic system to inhibit the rewarding effects related to cocaine-associated conditioning cues, without a blockade of dopamine receptors (Jones & McMillen 1995). In the conditioned place preference paradigm, drugs are injected on training days...