Serotonin involvement in the discriminative stimulus effects of κ opioids in pigeons

Abstract

The purpose of the present study was to examine the role of serotonin (5HT) in the discriminative stimulus effects of kappa opioids. Pigeons were trained to discriminate 5.6 mg/kg of the kappa opioid, U50,488, from water. During substitution tests, both U50,488 and another kappa opioid, spiradoline, produced > 80% responding on the U50,488-appropriate key. In contrast, the non-opioid compound, phencyclidine and several serotonergic compounds failed to substitute for the U50,488 discriminative stimulus across a wide range of doses. During combination tests, the selective 5HT1A agonist, 8-OH-DPAT (0.001-3.2 mg/kg), dose-dependently attenuated the discriminative stimulus effects of 5.6 mg/kg U50,488 and 3.2 mg/kg spiradoline. This effect was reversed by the 5HT1A antagonist, NAN-190 (0.01-1 mg/kg), in a dose-dependent manner. Buspirone (0.01-10 mg/kg), a 5HT1A partial agonist, also attenuated the discriminative stimulus effects of the training dose of U50,488 but ipsapirone, another 5HT1A partial agonist, did not. Ketanserin, a 5HT2 antagonist, and MDL72222, a 5HT3 antagonist, attenuated the effects of U50,488, whereas the 5HT1B,1C agonist, mCPP, and the 5HT2 agonist, DOI, did not. Depletion of 5HT with p-CPA also attenuated U50,488's discriminative stimulus effects. Taken together, the results suggest that serotonin release is an important component in the discriminative stimulus effects produced by kappa opioids; however, the effects of DOI and mCPP alone suggest that activation of post-synaptic 5HT receptors is not sufficient to produce the full spectrum of kappa opioid discriminative stimulus effects.

Discriminative Stimulus Effects of Hallucinogenic Drugs: a Possible Relation to Reinforcing and Aversive Effects

“…Previous studies have indicated that the activation of 5-HT 2 receptors plays a role in the discriminative stimulus effects of U50,488H, PCP, MDMA, and LSD in animals (7,34). Even though these hallucinogenic drugs in some cases induce similar behavioral phenotypes, each type of drug exerts different discriminative stimulus effects by regulating different receptors and signals (Fig.…”

Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys: kappa opioid and serotonergic mechanisms

“…However, several lines of evidence indicate that kappa opioid agonists also can alter the 5-HT system. For example, kappa opioid agonists have been found to enhance 5-HT release (Ho and Takemori 1989; 1990; Berger et al 2006) and induce behavioral effects that can be reversed by 5-HT depletion or with 5-HT antagonists (Von Voigtlander et al 1984; Ho and Takemori 1989; Bronson et al 1993; Powell et al 1994). In nonhuman primates, 5-HT appears to play a general inhibitory role in modulating the reinforcing and discriminative stimulus effects of cocaine (Spealman 1993; Howell and Byrd 1999; Czoty et al 2002).…”

“…The capacity of 8-OH-DPAT to antagonize both kappa opioid agonist- and 5-HT transport inhibitor-induced behavioral effects has been observed previously. For example, 8-OH-DPAT dose-dependently attenuated the discriminative stimulus and rate-decreasing effects of U50,488H in pigeons trained to discriminate the kappa opioid agonist from vehicle (Bronson et al 1993) and blocked conditioned nausea induced by fluoxetine in rats (Limebeer et al 2009). Collectively, these results support the idea that modulation of 5-HT can be an important mechanism underlying the capacity of kappa opioid agonists to attenuate the abuse-related effects of cocaine.…”

“…10 min prior to the infusion of spiradoline (0.3 mg/kg) or fluoxetine (5.6 mg/kg) combined with the maximally effective dose of cocaine (1.0 mg/kg). The dose and pretreatment interval for 8-OH-DPAT was based on an earlier study by Bronson et al (1993). We also determined the capacity of 8-OH-DPAT (0.003 – 0.1 mg/kg) to reinstate cocaine-seeking behavior in the absence of cocaine priming and to alter the effects of cocaine priming in the absence of either spiradoline or fluoxetine.…”

“…Moreover, kappa opioid agonist-induced analgesia was attenuated by 5-HT depletion with p -chlorophenylalanine as well as by several 5-HT antagonists (Von Voigtlander et al 1984; Ho and Takemori 1989). In drug discrimination studies in pigeons and rats, the discriminative stimulus effects of U50,488H were attenuated following 5-HT depletion as well as after pretreatment with several 5-HT ligands including the 5-HT 1A receptor agonist 8-OH-DPAT, the 5-HT 2 receptor antagonist ketanserin, and the 5-HT 3 receptor antagonist MDL72222 – all of which inhibit serotonergic activity (Bronson et al 1993; Powell et al 1994). Lastly, the kappa opioid agonist U69593 attenuated drug seeking induced by priming injections of cocaine and RTI-55 (a cocaine analog with greater affinity for the 5-HT transporter compared to the DA transporter), but not drug seeking induced by the DA uptake inhibitor GBR 12909 or by WIN 35,428 (a cocaine analog with greater affinity for the DA transporter compared to the 5-HT transporter) (Schenk et al 2000).…”