Differential actions of adenosine A1 and A2A antagonists on the effort-related effects of dopamine D2 antagonism

Abstract

Adenosine and dopamine receptors in striatal areas interact to regulate a number of different functions, including aspects of motor control and motivation. Recent studies indicate that adenosine A 2A receptor antagonists can reverse the effects of dopamine (DA) D 2 antagonists on instrumental tasks that provide measures of effort-related choice behavior. The present experiments compared the ability of the adenosine A 2A antagonist KW6002, the nonselective adenosine antagonist caffeine, and the adenosine A 1 receptor selective antagonist DPCPX, to reverse the behavioral effects of the DA D 2 antagonist haloperidol. For these studies, a concurrent choice procedure was used in which rats could select between lever pressing on a fixed ratio 5 schedule for a preferred food or approaching and consuming a less preferred lab chow that was concurrently available in the chamber. Under baseline or control conditions, rats show a strong preference for lever pressing, and eat little of the chow; IP injections of 0.1 mg/kg haloperidol significantly reduced lever pressing and substantially increased chow intake. The adenosine A 2A antagonist KW6002 (0.125-0.5 mg/kg IP) and the nonselective adenosine antagonist caffeine (5.0-20.0 mg/kg) significantly reversed the effects of haloperidol. However, the adenosine A 1 antagonist DPCPX (0.1875-0.75 mg/kg IP) failed to reverse the effects of the D 2 antagonist. The rank order of effect sizes in the reversal experiments was KW6002 > caffeine > DPCPX. None of these drugs had any effect on behavior when they were injected in the absence of haloperidol. These results indicate that the ability of an adenosine antagonist to reverse the effort-related effects of a D 2 antagonist depends upon the subtype of adenosine receptor being blocked. Together with other recent results, these experiments indicate that there is a specific interaction between DA D 2 and adenosine A 2A receptors, which could be related to the colocalization of these receptors on the same population of striatal neurons.

Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task

“…Though previous work has shown that MSX-3 had no effect of FR5/chow feeding choice performance when administered on its own (Farrar et al 2007), co-administration of MSX-3 significantly reversed the behavioral effects of IL-1β injections, restoring the baseline behavioral pattern by increasing lever pressing and decreasing chow intake in IL-1β-treated rats. These results are consistent with previous research demonstrating that adenosine A 2A receptor blockade or genetic deletion can reverse the effort-related effects of DA antagonism and depletion (Farrar et al 2007, 2010; Worden et al 2009; Mott et al 2009; Salamone et al 2009; Nunes et al 2010; Pardo et al 2012). Furthermore, the present findings are consistent with reports showing that the adenosine A 2A antagonists can produce effects that are consistent with the behavioral profile of an antidepressant in rodents tested on the swim test or tail suspension task (El Yacoubi et al 2001; Hodgson et al 2009; Hanff et al 2010).…”

“…Moreover, reductions in the presence of the DA metabolite homovanillic acid in cerebrospinal fluid were correlated with the degree of fatigue in patients treated with IFN-α (Felger and Miller 2012). These results suggest that cytokines may exert effects on DA that cause animals to reallocate their instrumental response selection based upon the response requirements of the task, and select lower cost alternatives to obtain food (Salamone et al 2007, 2009). Furthermore, as described above, the effects of IL-1β in rats responding on the FR5/chow feeding choice procedure resembled those produced by DA antagonism or depletion (Salamone et al 2007; Salamone and Correa 2012).…”

“…These experiments were conducted to characterize the behavioral effects of the pro-inflammatory cytokine interleukin 1 beta (IL-1β) using the concurrent FR5/chow feeding procedure (Salamone et al, 1991, 2009; Nunes et al, 2010). Administration of IL-1β shifted effort-related choice behavior as measured by the FR5/chow feeding choice task, decreasing lever pressing while producing a concomitant increase in the consumption of the concurrently available lab chow.…”

“…Rats trained on this procedure receive most of their food by responding on the lever for the more preferred sucrose pellet, and eat very little of the freely available chow. Previous research has shown that this task is sensitive to the effects of various pharmacological manipulations, including low doses of DA antagonists and accumbens DA depletions or antagonism (Salamone et al 1991, 2002, 2007, 2009; Farrar et al 2010), stimulation of accumbens core adenosine A 2A receptors (Font et al 2008), or stimulation of GABA A receptors in ventral pallidum (Farrar et al 2008), all of which shift choice behavior by decreasing lever pressing and increasing chow intake. This shift in choice behavior is not dependent upon changes in food consumption or preference, and is not mimicked by pre-feeding or appetite suppressant drugs, which fail to increase chow intake at doses that suppress lever pressing (Salamone et al 1991, 2002; Cousins et al 1994; Koch et al 2000; Sink et al 2008; Nunes et al 2013).…”

Caffeine, Mental Health, and Psychiatric Disorders

“…adults), wide dosage range, or flexible dose protocols are yet to be conducted. Interestingly, caffeine improves cognitive performance in an animal model of ADHD [121] and promotes effortrelated behavior in animals treated with dopamine antagonists [122]. Therefore, based on observational and experimental studies, caffeine is a candidate treatment for ADHD.…”