3.2.1. Attention

#### Attention and Behavioral Flexibility

Pandolfo et al. [51] examined the impact of chronic caffeine treatment during adolescence on SHR and Wistar Kyoto (WKY) rats' performance in an attention set-shifting task, placing emphasis on response to conflict. The task was divided into different phases: familiarization, response discrimination, and visual cue discrimination. During the response discrimination phase, statistical analysis showed that vehicle-treated SHR needed a superior amount of trials to reach the benchmark of 10 consecutive correct choices, compared with WKY rats. Importantly, treatment with caffeine (2 mg/kg, i.p.) improved SHR discriminative learning in a selective manner, as indicated by a reduction in the number of trials needed to reach the benchmark, while treatment with caffeine had no effect on WKY rats. During the visual cue discrimination phase, SHR required more trials to master the task, compared with WKY rats. Once more, caffeine treatment (2 mg/kg, i.p.) diminished the number of trials needed to reach the benchmark. Finally, statistical analysis showed that vehicle-treated SHR made significantly more regressive and never-reinforced errors than vehicle-treated WKY rats. Remarkably, while treatment with caffeine (2 mg/kg, i.p.) diminished the number of these errors in SHR, it had no effect on WKY rats.


**Table 1.**

Summary of included studies.


**Table 1.** *Cont.*


**Table 1.** *Cont.*




Kyoto rat, SHR:

Cancer Research mice, SI: social isolation, PND: postnatal day, BDNF: brain-derived

spontaneously

 hypertensive

 rat, MPD:

methylphenidate,

 6-OHDA:

6-hydroxy-dopamine,

 neurotrophic

 factor, SNAP-25:

 A2AR: Adenosine A2A

receptors, ICR mice: Institute of

synaptosomal-associated

 protein 25.

#### Spatial Attention

Ouchi et al. [52] tested the effect of SI on latent learning using the water-finding test, measuring entering latency and drinking latency. The authors eventually discussed the utility of SI as an ADHD epigenetic model. They socially isolated male or female Institute of Cancer Research (ICR) mice for one week or more. Subsequently, the animals displayed spatial attention deficit during the water-finding task. Five weeks of resocialization following one week of SI failed to improve this deficit. Drinking latency depended on how much attention the animal paid to environmental factors, including the location of a tap water nozzle, which they were exposed to in the training trial. Therefore, a decrease in drinking latency correlated with the animal remembering the position/location of the nozzle. Caffeine (0.3–1 mg/kg, i.p.) induced changes in drinking latency on the water-finding test, in this sense, significantly ameliorating SI-induced latent learning deficits in a dose-dependent manner, independently of gender or age.

Caballero et al. [53] examined caffeine's therapeutic use in neonatal 6-OHDA lesioned rats, which constitute another existing ADHD animal model. At postnatal day (PND) 7, the rats were lesioned at the left striatum with 6-OHDA. At PND 25, spatial attention was measured with an eight arm radial maze, the Olton maze. The animals were then placed in the maze. The total number of arms the animals walked before completing six out of eight, or until they repeated one of them, was measured. After 14 days of treatment with caffeine, administered ad libitum into the drinking water, the authors assessed caffeine's effects on the attention deficit of the animals, using the same task. Interestingly, the 6-OHDA lesioned rats significantly improved their attention deficit after caffeine treatment. Consequently, the authors highlighted the properties through which caffeine managed the attentional deficits occurring during the prepubertal period of ADHD.

#### Discrimination

Ruiz-Oliveira et al. [54] evaluated the effect of caffeine on zebrafish performance in a task requiring focus and attention, the discrimination task. The task took place in three phases: tank acclimation, training, and test. The authors used visual cues during the training trials and the test trials. Distractors, objects resembling the target, were used to confuse the fish and impair conditioning. The fish were exposed to different caffeine concentrations for 14 days: 0 mg/L (control), 10 mg/L (low), and 50 mg/L (high). Notably, low caffeine doses improved the fishes' ability to discriminate the cues and reach the target; the fish spent most of the time close to the target where the reward was offered, and showing the shortest latency to reaching the target. The higher dose impaired the fishes' ability to find the target; the fish demonstrated increased anxiety, a possible side effect of the substance.
