Abstract
Rationale
Rats emit 50-kHz ultrasonic vocalizations (USVs) in response to pleasurable stimuli, and these USVs are considered a tool for investigating reward and motivation.
Objectives
This study aimed to clarify how activity of adenosine A2A receptors, which modulate reward and motivation, influences 50-kHz USV emission in rats.
Methods
Rats received one of the following treatments in a test cage: (1) acute administration of the A2A receptor agonist CGS 21680 (0.05–0.2 mg/kg, i.p.) during social interactions; (2) long-term amphetamine (1 or 2 mg/kg, i.p.) or morphine (7.5 mg/kg, s.c.) administration on alternate days, alone or with CGS 21680, followed after 7 days of discontinuation by test cage re-exposure, to assess drug-conditioning effects, and thereafter drug challenge; (3) acute administration of the D1/D2 receptor agonist apomorphine (4 mg/kg, i.p.), alone or with CGS 21680; and (4) long-term administration of the non-selective A1/A2A receptor antagonist caffeine (15 mg/kg, i.p.), on alternate days. USVs and locomotor activity were evaluated throughout the treatments.
Results
CGS 21680 attenuated 50-kHz USV emission stimulated by social interactions, amphetamine, apomorphine, and morphine, and rats administered CGS 21680 with amphetamine or morphine emitted fewer conditioned 50-kHz USVs upon test cage re-exposure, compared with rats administered amphetamine or morphine alone. Moreover, CGS 21680 administration prevented long-term changes in locomotor activity in amphetamine- and morphine-treated rats. Finally, caffeine had no effect on 50-kHz USVs.
Conclusions
These results indicate that activation of A2A receptors attenuates 50-kHz USV emission in rats and further elucidate how these receptors modulate the motivational properties of natural and pharmacological stimuli.
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Acknowledgments
The authors are grateful to Ms. Flora Corrias and Mr. Riccardo Orrù for their help with the recordings of vocalizations and locomotor activity.
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All experiments were conducted in accordance with the guidelines for animal experimentation of the EU directives (2010/63/EU; L.276; 22 September 2010) and with the guidelines approved by the Ethical Committee of the University of Cagliari.
Funding
This work was supported by funds from Fondazione Banco di Sardegna (project number 2014.0395) and by funds from the Regione Autonoma della Sardegna (Legge Regionale 7 Agosto 2007, N.7, annualità 2010). Dr. Nicola Simola gratefully acknowledges the Sardinian Regional Government for financial support (P.O.R. Sardegna F.S.E. Operational Programme of the Autonomous Region of Sardinia, European Social Fund 2007–2013—Axis IV Human Resources, Objective l.3, Line of Activity l.3.1 “Avviso di chiamata per il finanziamento di Assegni di Ricerca”).
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Supplementary Table 1
Summary of the results of ANOVA followed by Tukey’s post hoc test obtained in day 1 of repeated treatment from rats administered amphetamine (1 or 2 mg/kg, i.p.) or morphine (7.5 mg/kg, s.c.). Each drug was administered alone or with the A2A receptor agonist CGS 21680 (0.05–0.2 mg/kg, i.p., 15 min before). Differences between the experimental groups are presented by comparing the group in each line with the group in each corresponding column. A = amphetamine, M = morphine, C = CGS 21680. ↑ = significantly higher compared with the group in the corresponding column; ↓ = significantly lower compared with the group in the corresponding column; n.s. = no significant difference compared with the group in the corresponding column; barred cells indicate that no statistical comparison between the two groups was performed. (DOC 89 kb)
Supplementary Table 2
Summary of the results of ANOVA followed by Tukey’s post hoc test obtained in day 5 of repeated treatment from rats administered amphetamine (1 or 2 mg/kg, i.p.) or morphine (7.5 mg/kg, s.c.). Each drug was administered alone or with the A2A receptor agonist CGS 21680 (0.05–0.2 mg/kg, i.p., 15 min before). Differences between the experimental groups are presented by comparing the group in each line with the group in each corresponding column. A = amphetamine, M = morphine, C = CGS 21680. ↑ = significantly higher compared with the group in the corresponding column; ↓ = significantly lower compared with the group in the corresponding column; n.s. = no significant difference compared with the group in the corresponding column; barred cells indicate that no statistical comparison between the two groups was performed. (DOC 91 kb)
Supplementary Table 3
Summary of the results of ANOVA followed by Tukey’s post hoc test obtained in day 9 of repeated treatment from rats administered amphetamine (1 or 2 mg/kg, i.p.) or morphine (7.5 mg/kg, s.c.). Each drug was administered alone or with the A2A receptor agonist CGS 21680 (0.05–0.2 mg/kg, i.p.). Differences between the experimental groups are presented by comparing the group in each line with the group in each corresponding column. A = amphetamine, M = morphine, C = CGS 21680. ↑ = significantly higher compared with the group in the corresponding column; ↓ = significantly lower compared with the group in the corresponding column; n.s. = no significant difference compared with the group in the corresponding column; barred cells indicate that no statistical comparison between the two groups was performed. (DOC 91 kb)
Supplementary Table 4
Summary of the results of ANOVA followed by Tukey’s post hoc test obtained after drug challenge (day 16) with amphetamine (1 or 2 mg/kg, i.p.) or morphine (7.5 mg/kg, s.c.) in rats repeatedly treated with either drug. Each drug was administered alone or with the A2A receptor agonist CGS 21680 (0.05–0.2 mg/kg, i.p.) during repeated treatment (days 1–9), whereas no CGS 21680 was administered in day 16. Differences between the experimental groups are presented by comparing the group in each line with the group in each corresponding column. A = amphetamine, M = morphine, C = CGS 21680. ↑ = significantly higher compared with the group in the corresponding column; ↓ = significantly lower compared with the group in the corresponding column; n.s. = no significant difference compared with the group in the corresponding column; barred cells indicate that no statistical comparison between the two groups was performed. (DOC 257 kb)
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Simola, N., Costa, G. & Morelli, M. Activation of adenosine A2A receptors suppresses the emission of pro-social and drug-stimulated 50-kHz ultrasonic vocalizations in rats: possible relevance to reward and motivation. Psychopharmacology 233, 507–519 (2016). https://doi.org/10.1007/s00213-015-4130-8
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DOI: https://doi.org/10.1007/s00213-015-4130-8