Effects of buspirone on the immediate positive and delayed negative properties of intravenous cocaine as measured in the conditioned place preference test

Abstract

In prior work, we have demonstrated that the behavioral effects of cocaine adhere to the predictions of the opponent-process theory of drug action. Animals develop conditioned place preferences for distinct locations paired with the immediate effects of IV cocaine, but learn to avoid places paired with the effects present 15-min post-injection. It was of interest to assess the putative role of 5-HT in producing the negative properties of cocaine since cocaine acts to inhibit the reuptake of serotonin (5-HT) and since such actions have been associated with anxiogenic consequences. Male rats were administered a reinforcing dose of cocaine (1.0 mg/kg IV) and then placed - either immediately or after a 15-min delay - into one side of a two-compartment (black-white) conditioned place preference (CPP) box for 5-min. On alternate days, the animals received IV saline injections and were placed in the opposite side of the CPP box. This continued for eight days after which animals had experienced 4 pairings of cocaine with one side (black or white) of the CPP apparatus, and 4 saline pairings with the opposite side. Other groups of rats were treated identically except that 30-min prior to placement into the apparatus, these animals received an IP injection of saline or buspirone (a partial 5-HT1A agonist) at a dose that we have shown to be anxiolytic (2.5 mg/kg IP). Control animals experienced either buspirone or saline pretreatments without cocaine. Our results confirm that animals increase the time spent on the side paired with the immediate effects of cocaine (compared to baseline), but tend to avoid the side paired with effects present 15-min post-injection. Buspirone had no effect on the immediate rewarding properties of cocaine, but completely reversed the negative properties present 15-min post-cocaine. These results are consistent with the view that attenuation of 5-HT neurotransmission (via the autoreceptor agonist properties of buspirone) can reverse the negative impact of IV cocaine.

Figure 1

Mean (+SEM) time spent (sec) in the drug-paired side of the place preference apparatus for each group during a pre-treatment baseline trial and an identical test trial conducted after drug-place conditioning. Panel A shows the effects of pairing an environment with the immediate effects of cocaine (SAL/COC 0’ Delay) or with the effects present 15-min post-injection (SAL/COC 15’ Delay). Panel B depicts these same two conditions in animals pretreated with buspirone. Panel C depicts the behavior of control animals that received no place-cocaine conditioning (a BUS/SAL 0’ Delay group and a SAL/SAL 0’ Delay group).

Figure 2

Mean (± SEM) Difference Scores (Test Trial– Baseline Trial) of each of six groups of rats. Bars above the zero-line represent conditioned shifts in preference toward the drug-paired side of the apparatus, while the single bar below the line represents a conditioned avoidance of the drug-paired environment. As shown in Panel A, animals exhibited conditioned place preferences (CPP) for the side of the apparatus paired with the immediate effects of IV cocaine (SAL/COC 0’ Delay), but tended to avoid the side paired with the effects of the drug present 15-min post-injection (SAL/COC 15’ Delay). In Panel B, busprione pretreatment produced no evidence of an enhancement of cocaine’s rewarding effects (BUS/SAL 0’ Delay vs SAL/COC 0’delay), but did reverse the delayed negative properties of cocaine (BUS/COC 15’ Delay vs SAL/COC 0’ Delay). Control groups (Panel C) produced no reliable shifts in preference or aversion from baseline to test.