Adenosinergic system and nucleoside transporters in attention deficit hyperactivity disorder: Current findings.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heterogeneity that can affect individuals of any age. It is characterized by three main symptoms: inattention, hyperactivity, and impulsivity. These neurobehavioral alterations and neurochemical and pharmacological findings are mainly attributed to unbalanced catecholaminergic signaling, especially involving dopaminergic pathways within prefrontal and striatal areas. Dopamine receptors and transporters are not solely implicated in this imbalance, as evidence indicates that the dopaminergic signaling is modulated by adenosine activity. To this extent, alterations in adenosinergic signaling are probably involved in ADHD. Here, we review the current knowledge about adenosine's role in the modulation of chemical, behavioral and cognitive parameters of ADHD, especially regarding dopaminergic signaling. Current literature usually links adenosine receptors signaling to the dopaminergic imbalance found in ADHD, but there is evidence that equilibrative nucleoside transporters (ENTs) could also be implicated as players in dopaminergic signaling alterations seen in ADHD, since their involvement in other neurobehavioral impairments.

The association of caffeine and nandrolone decanoate modulates aversive memory and nociception in rats.

Caffeine and anabolic-androgenic steroids (AAS) are commonly used to improve muscle mass and athletic performance. Nandrolone Decanoate (ND) is one of the most abused AAS worldwide, leading to behavioral changes in both humans and rodents. Caffeine, the most widely consumed psychostimulant globally, is present in various thermogenic and gym supplements. Low and moderate doses of caffeine antagonize adenosine receptors and have been linked to improved memory and pain relief. We have previously demonstrated that consuming caffeine prevents the risk-taking behavior triggered by nandrolone. In this study, we aimed to investigate the long-term effects of ND and caffeine, either alone or in combination, on passive avoidance memory and nociception. We used the step-down and hot-plate tasks in male and female Lister Hooded rats. Our results confirmed the antinociceptive effect of caffeine and indicated that chronic administration of the ND-caffeine association promotes the evocation of aversive memory in female rats.

Effects of Gestational Exercise on Nociception, BDNF, and Irisin Levels in an Animal Model of ADHD.

Abnormal cognitive and sensorial properties have been reported in patients with psychiatric and neurodevelopmental conditions, such as attention deficit hyperactivity disorder (ADHD). ADHD patients exhibit impaired dopaminergic signaling and plasticity in brain areas related to cognitive and sensory processing. The spontaneous hypertensive rat (SHR), in comparison to the Wistar Kyoto rat (WKY), is the most used genetic animal model to study ADHD. Brain neurotrophic factor (BDNF), critical for midbrain and hippocampal dopaminergic neuron survival and differentiation, is reduced in both ADHD subjects and SHR. Physical exercise (e.g. swimming) promotes neuroplasticity and improves cognition by increasing BDNF and irisin. Here we investigate the effects of gestational swimming on sensorial and behavioral phenotypes, striatal dopaminergic parameters, and hippocampal FNDC5/irisin and BDNF levels observed in WKY and SHR. Gestational swimming improved nociception in SHR rats (p = 0.006) and increased hippocampal BDNF levels (p = 0.02) in a sex-dependent manner in adolescent offspring. Sex differences were observed in hippocampal FNDC5/irisin levels (p = 0.002), with females presenting lower levels than males. Our results contribute to the notion that swimming during pregnancy is a promising alternative to improve ADHD phenotypes in the offspring.

Adenosine receptors participate in anabolic-androgenic steroid-induced changes on risk assessment/anxiety-like behaviors in male and female rats.

Anabolic-androgenic steroids (AAS) and caffeine can induce several behavioral alterations in humans and rodents. Administration of nandrolone decanoate is known to affect defensive responses to aversive stimuli, generally decreasing inhibitory control and increasing aggressivity but whether caffeine intake influences behavioral changes induced by AAS is unknown. The present study aimed to investigate behavioral effects of caffeine (a non-selective antagonist of adenosine receptors) alone or combined with nandrolone decanoate (one of the most commonly AAS abused) in female and male Lister Hooded rats. Our results indicated that chronic administration of nandrolone decanoate (10 mg/kg, i.m., once a week for 8 weeks) decreased risk assessment/anxiety-like behaviors (in the elevated plus maze test), regardless of sex. These effects were prevented by combined caffeine intake (0.1 g/L, p.o., ad libitum). Overall, the present study heralds a key role for caffeine intake in the modulation of nandrolone decanoate-induced behavioral changes in rats, suggesting adenosine receptors as candidate targets to manage impact of AAS on brain function and behavior.

Trace amine-associated receptor 1 modulates motor hyperactivity, cognition, and anxiety-like behavior in an animal model of ADHD.

Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that has recently been implicated in several psychiatric conditions related to monoaminergic dysfunction, such as schizophrenia, substance use disorders, and mood disorders. Although attention-deficit/hyperactivity disorder (ADHD) is also related to changes in monoaminergic neurotransmission, studies that assess whether TAAR1 participates in the neurobiology of ADHD are lacking. We hypothesized that TAAR1 plays an important role in ADHD and might represent a potential therapeutic target. Here, we investigate if TAAR1 modulates behavioral phenotypes in Spontaneously Hypertensive Rats (SHR), the most validated animal model of ADHD, and Wistar Kyoto rats (WKY, used as a control strain). Our results showed that TAAR1 is downregulated in ADHD-related brain regions in SHR compared with WKY. While intracerebroventricular (i.c.v.) administration of the selective TAAR1 antagonist EPPTB impaired cognitive performance in SHR, i.c.v. administration of highly selective TAAR1 full agonist RO5256390 decreased motor hyperactivity, novelty-induced locomotion, and induced an anxiolytic-like behavior. Overall, our findings show that changes in TAAR1 levels/activity underlie behavior in SHR, suggesting that TAAR1 plays a role in the neurobiology of ADHD. Although additional confirmatory studies are required, TAAR1 might be a potential pharmacological target for individuals with this disorder.

Differential expression of glutamatergic receptor subunits in the hippocampus in carioca high- and low-conditioned freezing rats.

Anxiety is an emotional state that affects the quality of human life. Several neurotransmitters are involved in the regulation of anxiety, including glutamate. The major actions of glutamate are mediated by N-methyl-d-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The present study performed a behavioral and neurochemical analysis of Carioca High-conditioned Freezing (CHF) and Carioca Low-conditioned Freezing (CLF) rats compared with control rats. We evaluated thermal nociception, anxiety-like behavior, depressive-like behavior, spatial memory, habituation memory, and the content and localization of different glutamatergic receptor subunits and postsynaptic density-95 (PSD-95), a postsynaptic protein. The CHF group exhibited an anxious-like phenotype, impairments in habituation and spatial memory, and a depressive-like phenotype compared with the control group. In the ventral hippocampus, an increase in the PSD-95, GluN1 and GluA1 subunits and a decrease in the GluN2A subunit of glutamatergic receptors. The CLF group exhibited a less anxious-like phenotype, hyperlocomotion and habituation impairments. Also, CLF animals, presented, in the ventral hippocampus, an increase in the PSD-95, GluN1 and GluA2 subunits and a decrease in the GluN2B subunit. These results suggest that the differential composition of NMDAR and AMPAR subunits may be related to the modulation of different phenotypes in CHF and CLF rats, which may help identify new targets for therapeutic interventions for anxiety disorders and other comorbidities.

A single episode of stress during adolescence impairs short-term memory and increases risk behaviour in an animal model of attention-deficit/hyperactivity disorder.

Adolescence is a period of increased sensitivity to stress and vulnerability to the manifestation of psychiatric disorders, such as attention-deficit/hyperactivity disorder (ADHD). Nevertheless, the relationship between stress during adolescence and ADHD is still unclear. Knowing that stress can have long-term consequences, the aim of this study was to evaluate the impact of a single episode of restraint stress during adolescence on locomotion, risk behaviour and short-term memory in adult spontaneously hypertensive rats (SHR), a validated animal model of ADHD. A single episode of stress during adolescence increased risk behaviour and impaired short-term recognition memory, but did not alter locomotion in adult SHR. These findings show that stress during adolescence, even acute, may lead to long-term behavioural consequences in an animal model of ADHD.

Role of Neuropeptide S on Behavioural and Neurochemical Changes of an Animal Model of Attention-Deficit/Hyperactivity Disorder.

Neuropeptide S (NPS) is a recently discovered peptide signalling through its receptor NPSR, which is expressed throughout the brain. Since NPSR activation increases dopaminergic transmission, we now tested if NPSR modulates behavioural and neurochemical alterations displayed by an animal model of attention-deficit/hyperactivity disorder (ADHD), Spontaneous Hypertensive Rats (SHR), compared to its control strain, Wistar Kyoto rats (WKY). NPS (0.1 and 1 nmol, intracerebroventricularly (icv)) did not modify the performance in the open field test in both strains; however, NPSR antagonism with [tBu-d-Gly5]NPS (3 nmol, icv) increased, per se, the total distance travelled by WKY. In the elevated plus-maze, NPS (1 nmol, icv) increased the percentage of entries in the open arms (%EO) only in WKY, an effect prevented by pretreatment with [tBu-d-Gly5]NPS (3 nmol, icv), which decreased per se the %EO in WKY and increased their number of entries in the closed arms. Immunoblotting of frontal cortical extracts showed no differences of NPSR density, although SHR had a lower NPS content than WKY. SHR showed higher activity of dopamine uptake than WKY, and NPS (1 nmol, icv) did not change this profile. Overall, the present work shows that the pattern of functioning of the NPS system is distinct in WKY and SHR, suggesting that this system may contribute to the pathophysiology of ADHD.

TRPA1 mediates damage of the retina induced by ischemia and reperfusion in mice.

Oxidative stress is implicated in retinal cell injury associated with glaucoma and other retinal diseases. However, the mechanism by which oxidative stress leads to retinal damage is not completely understood. Transient receptor potential ankyrin 1 (TRPA1) is a redox-sensitive channel that, by amplifying the oxidative stress signal, promotes inflammation and tissue injury. Here, we investigated the role of TRPA1 in retinal damage evoked by ischemia (1 hour) and reperfusion (I/R) in mice. In wild-type mice, retinal cell numbers and thickness were reduced at both day-2 and day-7 after I/R. By contrast, mice with genetic deletion of TRPA1 were protected from the damage seen in their wild-type littermates. Daily instillation of eye drops containing two different TRPA1 antagonists, an oxidative stress scavenger, or a NADPH oxidase-1 inhibitor also protected the retinas of C57BL/6J mice exposed to I/R. Mice with genetic deletion of the proinflammatory TRP channels, vanilloid 1 (TRPV1) or vanilloid 4 (TRPV4), were not protected from I/R damage. Surprisingly, genetic deletion or pharmacological blockade of TRPA1 also attenuated the increase in the number of infiltrating macrophages and in the levels of the oxidative stress biomarker, 4-hydroxynonenal, and of the apoptosis biomarker, active caspase-3, evoked by I/R. These findings suggest that TRPA1 mediates the oxidative stress burden and inflammation that result in murine retinal cell death. We also found that TRPA1 (both mRNA and protein) is expressed by human retinal cells. Thus, it is possible that inhibition of a TRPA1-dependent pathway could also attenuate glaucoma-related retinal damage.

Single Cocaine Exposure Inhibits GABA Uptake via Dopamine D1-Like Receptors in Adolescent Mice Frontal Cortex.

Cocaine (COC) is a psychostimulant that acts by increasing catecholaminergic neurotransmission mainly due to its effects on the dopamine transporter (DAT). However, other neurotransmitter systems may also be regulated by COC, including the GABAergic system. Since the effect of COC in modulating gamma-aminobutyric acid (GABA) reuptake is not defined, we investigated the molecular mechanisms related to the increase in GABA uptake induced by acute COC exposure and its effects on locomotor activity in adolescent mice. Behavioral experiments showed that COC increased locomotor activity and decreased immobilization time in mice. A single COC exposure reduced both GABA uptake and GAT-1 protein levels. On the other hand, cyclic adenosine monophosphate (cAMP) levels increased after a COC challenge. The major changes induced by acute COC on behavioral and neurochemical assays were avoided by previous treatment with the selective D1 receptor antagonist SCH-23390 (0.5 mg/kg). Our findings suggest that GABA uptake naturally decreases during mice development from preadolescence until adulthood and that dopamine (DA) D1-like receptors are key players in the regulation of GABA uptake levels following a single COC exposure in adolescent mice.

Psycho-Neuroendocrine-Immune Interactions in COVID-19: Potential Impacts on Mental Health.

Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The impacts of the disease may be beyond the respiratory system, also affecting mental health. Several factors may be involved in the association between COVID-19 and psychiatric outcomes, such as fear inherent in the pandemic, adverse effects of treatments, as well as financial stress, and social isolation. Herein we discuss the growing evidence suggesting that the relationship between SARS-CoV-2 and host may also trigger changes in brain and behavior. Based on the similarity of SARS-CoV-2 with other coronaviruses, it is conceivable that changes in endocrine and immune response in the periphery or in the central nervous system may be involved in the association between SARS-CoV-2 infection and impaired mental health. This is likely to be further enhanced, since millions of people worldwide are isolated in quarantine to minimize the transmission of SARS-CoV-2 and social isolation can also lead to neuroendocrine-immune changes. Accordingly, we highlight here the hypothesis that neuroendocrine-immune interactions may be involved in negative impacts of SARS-CoV-2 infection and social isolation on psychiatric issues.

Caffeine and cannabinoid receptors modulate impulsive behavior in an animal model of attentional deficit and hyperactivity disorder.

Attention deficit and hyperactivity disorder (ADHD) is characterized by impaired levels of hyperactivity, impulsivity, and inattention. Adenosine and endocannabinoid systems tightly interact in the modulation of dopamine signaling, involved in the neurobiology of ADHD. In this study, we evaluated the modulating effects of the cannabinoid and adenosine systems in a tolerance to delay of reward task using the most widely used animal model of ADHD. Spontaneous Hypertensive Rats (SHR) and Wistar-Kyoto rats were treated chronically or acutely with caffeine, a non-selective adenosine receptor antagonist, or acutely with a cannabinoid agonist (WIN55212-2, WIN) or antagonist (AM251). Subsequently, animals were tested in the tolerance to delay of reward task, in which they had to choose between a small, but immediate, or a large, but delayed, reward. Treatment with WIN decreased, whereas treatment with AM251 increased the choices of the large reward, selectively in SHR rats, indicating a CB1 receptor-mediated increase in impulsive behavior. An acute pre-treatment with caffeine blocked WIN effects. Conversely, a chronic treatment with caffeine increased the impulsive phenotype and potentiated the WIN effects. The results indicate that both cannabinoid and adenosine receptors modulate impulsive behavior in SHR: the antagonism of cannabinoid receptors might be effective in reducing impulsive symptoms present in ADHD; in addition, caffeine showed the opposite effects on impulsive behavior depending on the length of treatment. These observations are of particular importance to consider when therapeutic manipulation of CB1 receptors is applied to ADHD patients who consume coffee.

Neonatal handling impairs intradimensional shift and alters plasticity markers in the medial prefrontal cortex of adult rats.

Stress response can be modulated by neonatal/childhood events. Neonatal handling (NH) is an animal model in which the animals are subjected to brief separations from the dam during the first days of life, and it leads to lower emotionality and behavioral changes in adulthood. The aim of this study was to observe if early events, such as (NH), may program associative learning and behavioral flexibility in adult male rats and if these changes could be related to altered neurochemistry in the medial prefrontal cortex (mPFC). We evaluated proteins related to synaptic plasticity (brain-derived neurotrophic factor [BDNF] and synaptophysin [SYP]) as well as Na+/K+-ATPase activity. Additionally, we evaluated proteins related to the dopaminergic system (tyrosine hydroxylase [TH] and phosphorylated TH [pTH]), since this system appears to be affected in some neonatal interventions. Neonatally handled animals exhibited impairment in simple discrimination and intradimensional shift but not in reversal or compound discrimination; in addition, no alteration in switching from an egocentric spatial to a cued strategy was observed. These effects were accompanied by a decrease in SYP levels and Na+/K+-ATPase activity, suggesting reduced synaptic function. These results indicate that NH increases attention to irrelevant stimuli and/or impairs associative learning, and this is accompanied by neurochemical alterations in the (mPFC).

Adenosine A2A Receptors in the Rat Prelimbic Medial Prefrontal Cortex Control Delay-Based Cost-Benefit Decision Making.

Adenosine A2A receptors (A2ARs) were recently described to control synaptic plasticity and network activity in the prefrontal cortex (PFC). We now probed the role of these PFC A2AR by evaluating the behavioral performance (locomotor activity, anxiety-related behavior, cost-benefit decision making and working memory) of rats upon downregulation of A2AR selectively in the prelimbic medial PFC (PLmPFC) via viral small hairpin RNA targeting the A2AR (shA2AR). The most evident alteration observed in shA2AR-treated rats, when compared to sh-control (shCTRL)-treated rats, was a decrease in the choice of the large reward upon an imposed delay of 15 s assessed in a T-maze-based cost-benefit decision-making paradigm, suggestive of impulsive decision making. Spontaneous locomotion in the open field was not altered, suggesting no changes in exploratory behavior. Furthermore, rats treated with shA2AR in the PLmPFC also displayed a tendency for higher anxiety levels in the elevated plus maze (less entries in the open arms), but not in the open field test (time spent in the center was not affected). Finally, working memory performance was not significantly altered, as revealed by the spontaneous alternation in the Y-maze test and the latency to reach the platform in the repeated trial Morris water maze. These findings constitute the first direct demonstration of a role of PFC A2AR in the control of behavior in physiological conditions, showing their major contribution for the control of delay-based cost-benefit decisions.

Leishmania amazonensis infection induces behavioral alterations and modulates cytokine and neurotrophin production in the murine cerebral cortex.

Neurological symptoms have been associated with Leishmania infection, however little is known about how the nervous system is affected in leishmaniasis. This work aimed to analyze parasitic load, production of cytokines/neurotrophins in the prefrontal cortex and behavioral changes in BALB/c mice infected with Leishmania amazonensis. At 2 and 4months post-infection, infected mice showed a decrease in IFN-γ, IL-1, IL-6, IL-4, IL-10 cytokines and BDNF and NGF neurotrophins in prefrontal cortex associated with increased anxiety behavior. Parasite DNA was found in brain of all animals at 4months post-infection, when the levels of IBA-1 (activated macrophage/microglia marker) and TNF-α was increased in the prefrontal cortex. However TNF-α returned to normal levels at 6months post-infection suggesting a neuroprotective mechanism.

Methylglyoxal can mediate behavioral and neurochemical alterations in rat brain.

Diabetes is associated with loss of cognitive function and increased risk for Alzheimer's disease (AD). Advanced glycation end products (AGEs) are elevated in diabetes and AD and have been suggested to act as mediators of the cognitive decline observed in these pathologies. Methylglyoxal (MG) is an extremely reactive carbonyl compound that propagates glycation reactions and is, therefore, able to generate AGEs. Herein, we evaluated persistent behavioral and biochemical parameters to explore the hypothesis that elevated exogenous MG concentrations, induced by intracerebroventricular (ICV) infusion, lead to cognitive decline in Wistar rats. A high and sustained administration of MG (3µmol/µL; subdivided into 6days) was found to decrease the recognition index of rats, as evaluated by the object-recognition test. However, MG was unable to impair learning-memory processes, as shown by the habituation in the open field (OF) and Y-maze tasks. Moreover, a single high dose of MG induced persistent alterations in anxiety-related behavior, diminishing the anxiety-like parameters evaluated in the OF test. Importantly, MG did not alter locomotion behavior in the different tasks performed. Our biochemical findings support the hypothesis that MG induces persistent alterations in the hippocampus, but not in the cortex, related to glyoxalase 1 activity, AGEs content and glutamate uptake. Glial fibrillary acidic protein and S100B content, as well as S100B secretion (astroglial-related parameters of brain injury), were not altered by ICV MG administration. Taken together, our data suggest that MG interferes directly in brain function and that the time and the levels of exogenous MG determine the different features that can be seen in diabetic patients.

Neonatal handling causes impulsive behavior and decreased pharmacological response to methylphenidate in male adult wistar rats.

Neonatal handling has an impact on adult behavior of experimental animals and is associated with rapid and increased palatable food ingestion, impaired behavioral flexibility, and fearless behavior to novel environments. These symptoms are characteristic features of impulsive trait, being controlled by the medial prefrontal cortex (mPFC). Impulsive behavior is a key component of many psychiatric disorders such as attention deficit hyperactivity disorder (ADHD), manic behavior, and schizophrenia. Others have reported a methylphenidate (MPH)-induced enhancement of mPFC functioning and improvements in behavioral core symptoms of ADHD patients. The aims of the present study were: (i) to find in vivo evidence for an association between neonatal handling and the development of impulsive behavior in adult Wistar rats and (ii) to test whether neonatal handling could have an impact on monoamine levels in the mPFC and the pharmacological response to MPH in vivo. Therefore, experimental animals (litters) were classified as: "non-handled" and "handled" (10[Formula: see text]min/day, postnatal days 1-10). After puberty, they were exposed to either a larger and delayed or smaller and immediate reward (tolerance to delay of reward task). Acute MPH (3[Formula: see text]mg/Kg. i.p.) was used to suppress and/or regulate impulsive behavior. Our results show that only neonatally handled male adult Wistar rats exhibit impulsive behavior with no significant differences in monoamine levels in the medial prefrontal cortex, together with a decreased response to MPH. On this basis, we postulate that early life interventions may have long-term effects on inhibitory control mechanisms and affect the later response to pharmacological agents during adulthood.

Cellular prion protein (PrP(C)) modulates ethanol-induced behavioral adaptive changes in mice.

Chronic consumption of drugs with addictive potential induces profound synaptic changes in the dopaminergic mesocorticolimbic pathway that underlie the long-term behavioral alterations seen in addicted subjects. Thus, exploring modulation systems of dopaminergic function may reveal novel targets to interfere with drug addiction. We recently showed that cellular prion protein (PrP(C)) affects the homeostasis of the dopaminergic system by interfering with dopamine synthesis, content, receptor density and signaling pathways in different brain areas. Here we report that the genetic deletion of PrP(C) modulates ethanol (EtOH)-induced behavioral alterations including the maintenance of drug seeking, voluntary consumption and the development of EtOH tolerance, all pivotal steps in drug addiction. Notably, these behavioral changes were accompanied by a significant depletion of dopamine levels in the prefrontal cortex and reduced dopamine D1 receptors in PrP(C) knockout mice. Furthermore, the pharmacological blockade of dopamine D1 receptors, but not D2 receptors, attenuated the abnormal EtOH consumption in PrP(C) knockout mice. Altogether, these findings provide new evidence that the PrP(C)/dopamine interaction plays a pivotal role in EtOH addictive properties in mice.

Biochemical, histopathological and behavioral alterations caused by intrastriatal administration of quinolic acid to young rats.

Quinolinic acid (QUIN) is a neuroactive metabolite of the kinurenine pathway, and is considered to be involved in aging and some neurodegenerative disorders, including Huntington's disease. QUIN was injected intrastriatally into adolescent rats, and biochemical and histopathological analyses in the striatum, cortex, and hippocampus, as well as behavioral tests, were carried out in the rats over a period of 21 days after drug injection. Decreased [(3)H]glutamate uptake and increased (45)Ca(2+) uptake were detected shortly after injection in the striatum and cerebral cortex. In the hippocampus, increased (45)Ca(2+) uptake preceded the decreased [(3)H]glutamate uptake, without histopathological alterations. Also, corticostriatal astrogliosis was observed 7 days later, progressing to neuronal death at day 14. QUIN-treated rats also showed cognitive deficits 24 h after injection, concurrently with striatal astrogliosis. Motor deficits appeared later, after corticostriatal neurodegeneration. We assume that glutamate excitotoxicity could represent, at least in part, a molecular mechanism associated with the cognitive and motor impairments, corticostriatal astrogliosis and neuronal death observed in the QUIN-treated rats. We propose that our findings could be relevant for understanding the pathophysiology of human neurodegenerative diseases affecting young people, such as the juvenile form of Huntington's disease, and for the design of potential therapeutic strategies to slow down the progression of the disease.

Caffeine regulates frontocorticostriatal dopamine transporter density and improves attention and cognitive deficits in an animal model of attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) likely involves dopaminergic dysfunction in the frontal cortex and striatum, resulting in cognitive and motor abnormalities. Since both adenosine and dopamine modulation systems are tightly intertwined, we tested if caffeine (a non-selective adenosine receptor antagonist) attenuated the behavioral and neurochemical changes in adolescent spontaneously hypertensive rats (SHR, a validated ADHD animal model) compared to their control strain (Wistar Kyoto rats, WKY). SHR were hyperactive and had poorer performance in the attentional set-shifting and Y-maze paradigms and also displayed increased dopamine transporter (DAT) density and increased dopamine uptake in frontocortical and striatal terminals compared with WKY rats. Chronic caffeine treatment was devoid of effects in WKY rats while it improved memory and attention deficits and also normalized dopaminergic function in SHR. Additionally, we provide the first direct demonstration for the presence of adenosine A2A receptors (A2AR) in frontocortical nerve terminals, whose density was increased in SHR. These findings underscore the potential for caffeine treatment to normalize frontocortical dopaminergic function and to abrogate attention and cognitive changes characteristic of ADHD.