Anxiolytic-like actions of buspirone in a runway model of intravenous cocaine self-administration

Abstract

In previous work from our laboratory, rats traversing a straight alley for a reward of IV cocaine have been observed to develop ambivalence about entering the goal box. Over trials, animals repeatedly run toward the goal box, stop at the entry point, and then retreat back toward the start box. This unique pattern of retreat behavior has been shown to reflect a form of "approach-avoidance conflict" that stems from the subjects' concurrent positive (cocaine reward) and negative (cocaine-induced anxiety) associations with the goal box. Buspirone, a partial 5-HT(1A) agonist, has been reported to produce anxiolytic-like actions in the clinic, but has had mixed results in experimental tests of anxiety using animal subjects. Since most animal tests of conflict/anxiety employ the administration of foot-shock - a relatively strong aversive stimulus - it was of interest to determine whether buspirone would alter the more subtle approach-avoidance conflict observed in well-trained animals running a straight alley for single daily injections of 1.0 mg/kg IV cocaine. Runway testing consisted of single daily trials that continued until consistent approach-avoidance retreats were exhibited. Each animal was then pretreated 30 min prior to runway testing with vehicle and one of three doses of buspirone (0.0, 1.0, 2.5 or 5.0 mg/kg IP). Testing continued in a counterbalanced manner until all rats had experienced each dose of buspirone with 3 days of cocaine-only trials between each test day. The number of retreats exhibited on each trial served as an index of the approach-avoidance conflict present on that trial. Results clearly demonstrated that buspirone (at the two higher doses) attenuated the retreat behavior of animals approaching a goal box for IV cocaine -- an action consistent with its anxiolytic-like actions in the clinic.

The dopamine antagonist cis-flupenthixol blocks the expression of the conditioned positive but not the negative effects of cocaine in rats

“…Cocaine is also a potent reuptake inhibitor at the serotonergic (5-hydroxytryptamine; 5-HT) transporter (Filip et al, 2005; Koe, 1976; Ritz et al, 1990) and while manipulations of 5-HT systems have at times produced contradictory and inconclusive results in behavioral tests of anxiety (e.g., Handley et al, 1993) there is a growing literature implicating 5-HT neurons emanating from the dorsal raphé nucleus in the behavioral response to a variety of stressors and anxiogenic drugs (e.g., Abrams et al, 2005; Chaouloff, 2000; Reuter and Jacobs, 1996; Rex et al, 2005; Sena et al, 2003). Indeed, we have previously reported that interfering with 5-HT function via lesion or pharmacological manipulations reduced the aversive response to cocaine while leaving the positive/rewarding effects intact (e.g., Ettenberg and Bernardi, 2006; 2007; Ettenberg et al, 2011). Such results nicely compliment those observed here and suggest a role for 5-HT signaling in the anxiogenic actions of cocaine.…”

“…Furthermore, DA signaling within the mesolimbic system has been shown to be integral for the demonstration of stress-induced reinstatement of cocaine seeking following a period of drug abstinence (Capriles et al, 2003; McFarland et al, 2004; Wang et al, 2005; Xi et al, 2004). It should be noted, however, that previous research has identified other catecholamine systems as potential substrates for the expression of cocaine’s negative/anxiogenic effects (Ettenberg et al, 2011; Ettenberg and Bernardi, 2006; Ettenberg and Bernardi, 2007; Schank et al, 2008; Smith and Aston-Jones, 2008; Wenzel et al, 2012). Thus the precise nature of the neuronal systems underlying these effects of cocaine remains unclear.…”

Anxiolytic effects of nicotine in a rodent test of approach–avoidance conflict

“…In addition to food+shock experiments, retreat behaviors have also been shown to occur in animals running for drug reinforcers known to have mixed positive+negative consequences (e.g., cocaine; Ettenberg and Geist 1991, 1993; Geist and Ettenberg 1997; Guzman and Ettenberg 2004). Additionally, pretreatment with anxiolytic drugs dose-dependently reduce retreat frequency in the runway – e.g., diazepam (Ettenberg and Geist 1991; Geist and Ettenberg 1997), alcohol (Knackstedt and Ettenberg 2005), heroin (Guzman and Ettenberg 2004), and buspirone, a partial 5-HT(1A) agonist (Ettenberg and Bernardi 2006). …”

Attenuation of the anxiogenic effects of cocaine by 5-HT1B autoreceptor stimulation in the bed nucleus of the stria terminalis of rats

“…The dose of 1 mg/kg i.v. cocaine was chosen based upon the results of previous runway work from our laboratory (Raven et al 2000; Ettenberg 2004; Ettenberg and Bernardi 2006; Wenzel et al 2011; 2014). …”

“…The rationale for examining the functional role of 5-HT with respect to cocaine’s anxiogenic effects stems from the fact that 5-HT has been implicated in the development and expression of anxiety-like behaviors (Watson and Mann 2000; Sena et al 2003; Abram et al 2005) and that cocaine has significant affinity for the 5-HT transporter (Cunningham et al 1992a, 1992b; Walsh and Cunningham 1997; Filip et al 2004). Additionally, in our own prior studies, inactivation of the 5-HT cell bodies within the dorsal raphé nucleus (Ettenberg et al 2011) or treatment with the anxiolytic 5-HT 1A partial agonist, buspirone, both reduced approach-avoidance “retreats” in the runway (Ettenberg and Bernardi 2006). Buspirone was also effective at selectively attenuating the delayed negative effects of cocaine without modifying the drug’s initial positive effects in a Conditioned Place Test (Ettenberg and Bernardi 2007).…”