Effects of a 5-HT1B Receptor Agonist on Locomotion and Reinstatement of Cocaine-Conditioned Place Preference after Abstinence from Repeated Injections in Mice

Abstract

5-HT1B receptors (5-HT1BRs) modulate behavioral effects of cocaine. Here we examined the effects of the 5-HT1BR agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine (CP94253) on spontaneous and cocaine-induced locomotion and on cocaine-primed reinstatement of conditioned place preference (CPP) in male mice given daily repeated injections of either saline or cocaine (15 mg/kg, IP) for 20 days. In the locomotor activity experiment, testing occurred both 1 and 20 days after the final injection. In the CPP experiment, mice underwent conditioning procedures while receiving the last of their daily injections, which were given either during or ≥2 h after CPP procedures. The CPP procedural timeline consisted of baseline preference testing (days 12–13 of the chronic regimen), conditioning (days 14–19, 2 daily 30-min sessions separated by 5 h), CPP test (day 21), extinction (days 22–34; no injections), CPP extinction test (day 35), and reinstatement test (day 36). Mice that had not extinguished received additional extinction sessions prior to reinstatement testing on day 42. On test days, mice were pretreated with either saline or CP94253 (10 mg/kg, IP). Testing began 30 min later, immediately after mice were primed with either saline or cocaine (5 mg/kg for locomotion; 15 mg/kg for reinstatement). We found that CP94253 increased spontaneous locomotion in mice receiving repeated injections of either saline or cocaine when tested 1 day after the last injection, but had no effect on spontaneous locomotion after 20 days abstinence from repeated injections. Surprisingly, cocaine-induced locomotion was sensitized regardless of whether the mice had received repeated saline or cocaine. CP94253 attenuated expression of the sensitized locomotion after 20 days abstinence. A control experiment in noninjected, drug-naïve mice showed that CP94253 had no effect on spontaneous or cocaine-induced locomotion. Mice reinstated cocaine-CPP when given a cocaine prime, and CP94253 pretreatment attenuated cocaine reinstatement.The findings suggest that stress from repeated saline injections and/or co-housing with cocaine-injected mice may cross-sensitize with cocaine effects on locomotion and that CP94253 attenuates these effects, as well as reinstatement of cocaine-CPP. This study supports the idea that 5-HT1BR agonists may be useful anti-cocaine medications.

Neural Circuits Associated with 5-HT1B Receptor Agonist Inhibition of Methamphetamine Seeking in the Conditioned Place Preference Model

“…Experiment 1: Unconditioned Effects of Acute CP94253 and Methamphetamine on FOS. The dose of CP94253 (10 mg/kg, IP) selected for this experiment blocks cocaine-primed reinstatement of cocaine-CPP in mice, 31 and the dose of methamphetamine was selected based on an unpublished pilot study from our lab demonstrating CPP at this dose. FOS immunolabeled cell density was analyzed in unconditioned mice in response to CP94253 (10 mg/kg, IP) and/or methamphetamine (Meth; 3 mg/kg, IP) by separate ANOVAs for each brain region with pretreatment (vehicle or CP94253) and treatment (saline or Meth) as between subjects factors.…”

“…In the CPP model, a low dose of the 5-HT 1B R agonist, CP94253, enhances acquisition of cocaine CPP in rats. 30 However, in mice receiving chronic administration of cocaine for 21 days, the 5-HT 1B R agonist, CP94253, blocks cocaine-primed reinstatement of extinguished cocaine CPP, 31 again suggesting a decrease in the incentive motivation effects of the priming injection. Expression of drug CPP is thought to reflect drug-seeking behavior motivated by exposure to environmental cues previously present during the drug experience.…”

Education and training in substance use disorders and addictions: The University of New Mexico integrated training model.

“…Seven of the nine research active faculty (77.8%) in the CBB area are engaged in basic science and neuroscience research examining addiction and related disorders, as well as behavioral vulnerabilities for addiction (e.g., reward processing; Der-Ghazarian et al, 2017). CBB faculty conduct basic science research on fetal alcohol spectrum disorders and effects of alcohol exposure on later development (Hamilton, 2014).…”

5-HT1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats

“…After a period of abstinence from cocaine, the 5-HT 1B R agonist CP94253 given during a relapse challenge test produces the opposite effects of those observed during maintenance of SA, evident as a decrease in breakpoints on a progressive ratio schedule of cocaine reinforcement and a downward shift in the cocaine SA doseresponse function (Pentkowski et al, 2014). Additionally, CP94253 given after extinction training decreases reinstatement of cocaine conditioned place preference in male mice (Der-Ghazarian et al, 2017). Furthermore, following extinction training, both viral-mediated overexpression of 5-HT 1B Rs and systemic treatment with 5-HT 1B R agonists dose-dependently decrease cocaine-seeking behavior during cue-induced and cocaine-primed reinstatement tests (Acosta et al, 2005;Nair et al, 2013;Pentkowski et al, 2009Pentkowski et al, , 2012.…”