Individual differences in the energizing effects of caffeine on effort-based decision-making tests in rats
Introduction
Caffeine is a naturally occurring methylxanthine that acts as a non-selective adenosine A1/A2A receptor antagonist (Fredholm et al., 1999). Caffeine is found in common beverages as well as a variety of medications (Barone and Roberts, 1996; Andrews et al., 2007), and is typically consumed in order to increase alertness, arousal and self-reported energy (Malinauskas et al., 2007; Smith, 2002). Consumption of caffeine has been related to very variable changes in performance (Smith, 2002), even among people with fatigue (Childs and de Wit, 2008). However, it enhances performance more in fatigued than well-rested subjects (Lorist et al., 1994).
The activational component of normal motivated behavior is very important, because in everyday life organisms must make cost/benefit analyses in which they weigh the value of a stimulus (e.g. taste of a food, caloric value, etc.) relative to the cost of obtaining it (e.g. effort required by the instrumental response to get access to the reinforcer) (Salamone and Correa, 2002, Salamone and Correa, 2012; Salamone et al., 2007). In effort-related decision-making tests, animals are given a choice between a more valued reinforcer that can only be obtained by engaging in a more demanding-higher effort activity vs. a low effort/low value option. Thus, in operant tasks animals are given a choice between lever pressing for the more preferred reward using fixed ratio (FR) or progressive ratio (PROG) schedules vs. approaching and consuming a less preferred reinforcer that is concurrently freely available in the chamber (Salamone et al., 1991; Randall et al., 2012; Pardo et al., 2015). When tested on concurrent FR/free reward choice tasks, rats typically spend most of the time pressing the lever for the preferred reward and much less time consuming freely available food or fluids (Salamone et al., 1991, Salamone et al., 2002; Pardo et al., 2015). These FR schedules (FR5 or FR7) typically generate high rates of responding uniformly across animals. Thus, they are not useful for assessing drugs or conditions that potentially can invigorate performance and bias animals even further towards the high-effort activity (i.e., lever pressing). For example, FR schedules are very sensitive to drugs that can impair performance, produce anergia, and make animals less active. In contrast, rats tested on the concurrent PROG/free chow choice task show more individual variability in the effort component, and some animals tend to disengage more readily from PROG lever pressing because of the increasing work requirement, shifting then to the less preferred source of food that is the less effort-demanding alternative (Randall et al., 2012, Randall et al., 2014a, Randall et al., 2014b).
This individual variability in willingness to keep lever pressing in spite of the increasing work demands has been reported to be associated with dopamine (DA) -related signal transduction activity in nucleus accumbens (Nacb) (Randall et al., 2012). Furthermore, treatment with drugs that increase DA transmission by blocking DA uptake, such as the antidepressant bupropion, increases selection of high-effort PROG lever pressing (Sommer et al., 2014; Randall et al., 2014b; Yohn et al., 2016b, Yohn et al., 2016c, Yohn et al., 2016d). Bupropion was shown to be more potent for improving performance of the “high workers” than the “low workers”, although at high doses it benefited both groups (Randall et al., 2014b). Nacb has also a high concentration of adenosine A1 and A2A receptors, (Ferré, 1997, Ferré, 2008; Ferré et al., 1997, Ferré et al., 2005; Fuxe et al., 2003). Microinjections of the adenosine A2A agonists into Nacb produced effects on the concurrent FR5/free chow procedure that resembled those produced by accumbens DA antagonism or depletion (Font et al., 2008), and selective A2A antagonists had no effect on the FR5/free chow procedure on its own (Salamone et al., 2009), but increased PROG lever pressing in rats tested on the PROG/chow feeding task (Randall et al., 2012).
In the present studies rats were tested in the PROG/free reinforcer choice procedure in order to determine if caffeine, across a broad range of doses, can increase the willingness to work in a highly demanding effort-based decision-making task. Because sweet taste stimulation can act as a powerful natural reward (Levine et al., 2003; Yamamoto, 2003), sweet food or sweet fluids were used as the more preferred reinforcer. In two independent experiments, different reinforcers with different values were employed: experiment 1, palatable high carbohydrate pellets versus chow, and in experiment 2, a solution containing a high sucrose concentration versus a low concentration (5% versus 0.3% w/v). In the first experiment reinforcers were different in palatability and gustatory stimulation, but in addition, because animals were food restricted, conditions were set so that motivation also had a homeostatic component. In the second experiment animals were not water deprived, thus the operant reinforcer did not have a strong homeostatic value, and sucrose solutions were used to evaluate the willingness to work for a purely gustatory stimulus. These different conditions can create differences in motivation. For example, the free reinforcer could have a stronger influence on effort-based decision-making in animals that are deprived shifting behavior towards the less preferred-less effort option in a clearer way than in animals that are not deprived. The impact of caffeine on effort-based decision-making was studied taking into account those two homeostatic conditions. In addition, the presence of a freely available less valued reinforcer could be a factor influencing also baseline performance in different animals, and caffeine could affect those individual differences. Finally, other groups of animals received caffeine at the highest dose and were evaluated with a concurrent FR7/free fluid sucrose task, on free sucrose preference and consumption tests, and on locomotor activity.
Section snippets
Subjects
Adult male, Sprague-Dawley rats (Harlan Sprague-Dawley, Indianapolis, IN) were housed in pairs in a colony maintained at 23 °C with 12-h light/dark cycles (lights on at 8:00 h). Rats in experiment 1 (N = 12) were food restricted to 85% of their free-feeding body weight for training and they were fed supplemental laboratory chow (Laboratory Diet, 5P00 Prolab RHM 3000, Purina Mills, St. Louis, MO, USA) during weekends to maintain weight throughout the study with water available ad libitum in the
Experiment 1. Effect of caffeine on PROG/free chow feeding choice performance: analysis of high and low performers
The effect of caffeine (0, 2.5, 5.0, 10.0 and 20.0 mg/kg) on PROG/chow feeding choice performance is shown in Fig. 1A–C. Repeated measures ANOVA revealed a significant effect of caffeine on total lever presses (F(4,44) = 2.47; p < 0.05). Planned comparisons showed that total lever presses were significantly increased at 5.0 mg/kg compared to vehicle (p < 0.05). Repeated measures ANOVA did not reveal any significant effect of caffeine on pellets consumed (in grams) (F(4,44) = 2.10; n.s.), or on
Discussion
The present results show how caffeine can act as a drug that helps to activate high levels of performance to achieve access to valued reinforcers. However, this property of caffeine is dependent on individual differences in baseline levels of performance. Moreover, these differences can also explain the ability of caffeine to impair performance under the same conditions in different groups of animals. Thus, when homeostatic demands are high (experiment 1), even the higher dose of caffeine did
Acknowledgements
This work was supported by a grant to M. Correa from Ministerio de Economía y Competitividad (PSI2015-68497-R), Spain, and to J.D. Salamone by NIH/NIMH (R03MH094966-01A1). N. SanMiguel was supported by a fellowship awarded by UJI (PREDOC/2012/28), L. López-Cruz was supported by a fellowship (FPU AP2010-3793) awarded by Ministerio de Educación, and C. Carratalá-Ros was supported by a fellowship (FPI BES-2016-077177) awarded by Ministerio de Economía y Competitividad.
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2020, Pharmacology Biochemistry and BehaviorCitation Excerpt :Adenosine and DA receptors are thought to form heteromeric complexes that influence neurotransmitter binding, and they also converge onto the same cAMP/protein kinase A-related signal transduction pathways (Svenningsson et al., 1999; Ferré et al., 2007; Ferré, 2008). Adenosine A2A antagonists have been shown to act as psychomotor stimulants (Garrett and Holtzman 1994; Daly and Fredholm, 1998; Karcz-Kubicha et al., 2003; Antoniou et al., 2005; Ferré, 2008; Randall et al., 2011; Pardo et al., 2013; SanMiguel et al., 2018). A2A receptor deletion or antagonism attenuates several of the behavioral effects of DA depletion and D2 antagonists and cholinomimetics on motor and motivated behaviors (see Salamone et al., 2008a, 2008b, 2013, 2018; Salamone et al., 2012; Salamone and Correa, 2009).
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2019, Physiology and BehaviorCitation Excerpt :It is also noteworthy that the effects of caffeine under these conditions can be modified by a host of factors. For example, the effects of caffeine mitigated fatigue-like responding in animals exhibiting low baseline motivational levels but exacerbated behavior in animals with higher baseline values [40]. Pharmacological validation of these models has been described.
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Present address: Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK.