Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh The non-selective adenosine antagonist theophylline reverses the efects of dopamine antagonism on tremor, motor activity and efort-based decision- making Marta Pardo a,1,2 , Nicholas E. Paul b,2 , Lyndsey E. Collins-Praino b , John D. Salamone b , Mercè Correa a,b, ⁎ a Dept. Psychobiology, Universitat Jaume I, 12071 Castelló, Spain b Dept. Psychology, University of Connecticut, Storrs, CT 06269-1020, USA ARTICLEINFO Keywords: Adenosine antagonism Parkinsonism Muscarinic Depression Accumbens Decision-making Efort ABSTRACT Considerable evidence indicates that adenosine and dopamine systems interact in the regulation of basal ganglia function. Nonselective adenosine antagonists such as the methylxanthine cafeine as well as selective adenosine A 2A antagonists have been shown to produce antiparkinsonian and antidepressant efects in animal models. The present studies were conducted to assess if another methylxantine, theophylline, can reverse motor and moti- vational impairments induced by dopamine antagonism in rats. Results: Theophylline (3.75–30.0 mg/kg, IP) reversed tremulous jaw movements (TJMs), catalepsy, and loco- motor suppression induced by the dopamine D2 antagonist pimozide. It also reversed TJMs induced by the muscarinic receptor agonist pilocarpine, which is a well-known tremorogenic agent. Parallel studies assessed the ability of theophylline (5.0–20.0 mg/kg, IP) to reverse the changes in efort-related choice behavior induced by the dopamine D1 antagonist ecopipam (0.2 mg/kg, IP) and the D2 antagonist haloperidol (0.1 mg/kg, IP). Rats were tested on two diferent operant choice tasks which assess the tendency to work for a preferred reinforcer by lever pressing (for palatable pellets or a high 5% sucrose solution) vs. approaching and consuming a less pre- ferred reinforcer (freely available lab chow or a less concentrated 0.3% sucrose solution). Theophylline restored food and sucrose-reinforced lever pressing in animals treated with the D2 antagonist. However, it was unable to reverse the efects of the D1 antagonist. Overall, the efects of theophylline resembled those previously reported for adenosine A 2A antagonists, and suggest that theophylline could be clinically useful for the treatment of motor and motivational symptoms in humans. 1. Introduction Methylxanthines have the distinction of being the most commonly consumed psychoactive substances in the world (Fredholm et al., 1999; Fisone et al., 2004). Although cafeine is the predominant stimulant in most naturally occuring compounds such as cofee, tea or chocolate, other methylxanthines such as theophylline also are present. The motor and motivational activating properties of cafeine and theophylline are generally attributed to their pharmacological profle as adenosine an- tagonists (Howell et al., 1997; Fisone et al., 2004; Ferré, 2008; Randall et al., 2011; López-Cruz et al., 2014, 2018a; SanMiguel et al., 2018, 2019; Correa et al., 2018). It is thought that adenosine modulates motor activities largely through interactions between adenosine and dopa- mine (DA) receptors in the basal ganglia (Ferré et al., 2001, 2007, 2018; Ferré, 2008). In the brain, adenosine A 1 and A 2A receptors are the key subtypes involved in the neuromodulatory actions of adenosine. Whereas A 1 receptors are widely expressed, A 2A receptors are mainly concentrated in striatal areas (Schifmann et al., 2007). On striatal medium spiny neurons, A 1 receptors are co-localized with DA D 1 re- ceptors in substance P containing neurons, while A 2A receptors are co- localized and interact with D 2 receptors mainly present on enkephalin positive neurons (Ferré et al., 2007; Svenningsson et al., 1999; Schifmann et al., 2007). Adenosine and DA receptors are thought to form heteromeric complexes that infuence neurotransmitter binding, https://doi.org/10.1016/j.pbb.2020.173035 Received 31 May 2020; Received in revised form 18 August 2020; Accepted 2 September 2020 ⁎ Corresponding author at: Àrea de Psicobiologia, Campus de Riu Sec, Universitat Jaume I, 12071 Castelló, Spain. E-mail address: correa@uji.es (M. Correa). 1 Present address: Dept. Neurology, University of Miami, Miller School of Medicine, USA. 2 These authors contributed equally to this manuscript. Pharmacology, Biochemistry and Behavior 198 (2020) 173035 Available online 08 September 2020 0091-3057/ © 2020 Elsevier Inc. All rights reserved. T