Stimulant effects of adenosine antagonists on operant behavior: differential actions of selective A2A and A1 antagonists

Abstract

Rationale Adenosine A2A antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone. Objective The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists. Methods Six drugs were tested: two nonselective adenosine antagonists (caffeine and theophylline), two adenosine A1 antagonists (DPCPX and CPT), and two adenosine A2A antagonists (istradefylline (KW6002) and MSX-3). Two schedules of reinforcement were employed; a fixed interval 240-s (FI-240 sec) schedule was used to generate low baseline rates of responding and a fixed ratio 20 (FR20) schedule generated high rates. Results Caffeine and theophylline produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec schedule but decreasing responding on the FR20 schedule. The A2A antagonists MSX-3 and istradefylline increased FI-240 sec lever pressing but did not suppress FR20 lever pressing in the dose range tested. In fact, there was a tendency for istradefylline to increase FR20 responding at a moderate dose. A1 antagonists failed to increase lever pressing rate, but DPCPX decreased FR20 responding at higher doses. Conclusions These results suggest that adenosine A2A antagonists enhance operant response rates, but A1 antagonists do not. The involvement of adenosine A2A receptors in regulating aspects of instrumental response output and behavioral activation may have implications for the treatment of effort-related psychiatric dysfunctions, such as psychomotor slowing and anergia in depression.

Effects of caffeine and its metabolite paraxanthine on intracranial self-stimulation in male rats.

“…Caffeine also increased both reinforced responding and non-reinforced responding, and this agrees with evidence for caffeine-induced stimulation of low response rates under other circumstances, such as the early segments of intervals from fixed-interval schedules of food-maintained responding (McMillan, 1979; Michaelis, Holloway, Bird, & Huerta, 1987; Randall et al, 2011; Spealman, 1988; Valdes, et al, 1982). However, in contrast to the effects of amphetamine, the response increasing effects of caffeine on both reinforced and non-reinforced responding were characterized by an inverted-U shaped dose-effect curve, and peak increases in reinforced and non-reinforced responding were smaller than those produced by amphetamine or cocaine.…”

Mechanisms of the psychostimulant effects of caffeine: implications for substance use disorders

“…With the availability of selective A 2A receptor ligands, a large number of experiments demonstrated that A 2A receptor agonists and antagonists induce the same qualitative psychomotor depressant and activating effects that D 2 receptor antagonists and agonists, respectively; (Ferré et al 1991c; Kanda et al 1994; Rimondini et al 1997; Shiozaki et al 1999; Randall et al 2011; Nunes et al 2013); that A 2A receptor agonists and antagonists selectively counteract and potentiate the psychomotor activating effects of D 2 receptor agonists, respectively (Popoli et al 1996; Rimondini et al 1998; Stromberg et al 2000; Ferré et al 2001); but also, that selective A 2A , but not A 1 , receptor antagonists counteract the psychomotor depressant effects of reserpine and D 2 receptor antagonists (Kanda et al 1994; Shiozaki et al 1999; Pardo et al 2012; Nunes et al 2013; Minor and Hanff 2015). Initial studies dealt mostly with locomotor activity recording, but more recent studies about the psychomotor activating effects of caffeine also dealt with measures of specific reward-oriented behavior, with caffeine and A 2A receptor antagonists increasing the responsiveness to specific rewarding stimuli, such as those associated with regular food (Randall et al 2011; Nunes et al 2013), sucrose solutions (Brianna Sheppard et al 2012) and those eliciting maternal behavior (Pereira et al 2011) and intracranial self-stimulation (Lazenka et al 2015).…”

“…Initial studies dealt mostly with locomotor activity recording, but more recent studies about the psychomotor activating effects of caffeine also dealt with measures of specific reward-oriented behavior, with caffeine and A 2A receptor antagonists increasing the responsiveness to specific rewarding stimuli, such as those associated with regular food (Randall et al 2011; Nunes et al 2013), sucrose solutions (Brianna Sheppard et al 2012) and those eliciting maternal behavior (Pereira et al 2011) and intracranial self-stimulation (Lazenka et al 2015). Lastly, A 2A but not A 1 receptor antagonists induce sensitization to their psychomotor-activating effects and cross-sensitization to caffeine (Hsu et al 2009, 2010).…”

Past, present and future of A2A adenosine receptor antagonists in the therapy of Parkinson's disease

“…In contrast to the 8-unsubstituted xanthine derivatives ( 1-4 ), which exhibit acceptable to good water-solubility, the 8-styrylxanthines ( 5-7 ) are relatively insoluble in water. Therefore, water soluble prodrugs of MSX-2 have been developed, such as the phosphate prodrug MSX-3 ( 7a : Hockemeyer et al, 2004) and the L -valine ester prodrug MSX-4 ( 7b : Vollmann et al, 2008), which represent very valuable pharmacological tools, particularly for in vivo studies ( e.g ., Randall et al, 2011; Collins et al, 2010; Mott et al, 2009; Bilkei-Gorzo et al, 2008; Schindler et al, 2005; Blum et al, 2003; Hauber et al, 1998). These drugs are very water-soluble but readily cleaved by enzymatic hydrolysis.…”