Adenosine A2A receptor antagonist treatment of Parkinson’s disease

Adenosine A2A receptors have a unique cellular and regional distribution in the basal ganglia (BG), being particularly concentrated in areas richly innervated by dopamine (DA) such as the caudateputamen, otherwise called striatum, and the globus pallidus. Adenosine A2A and DA D2 receptors are capable of forming functional heteromeric complexes and are colocalised in striatopallidal neurons. Based on the peculiar cellular and regional distribution of this receptor and in line with data showing that A2A receptor antagonists improve motor symptoms of Parkinson’s disease (PD) in animal models and in clinical trials, A2A receptor antagonists have emerged as an attractive nondopaminergic target to improve the motor deficits that characterise PD. Experimental data have also shown that A2A receptor antagonists are capable of exerting a neuroprotective effect and do not induce neuroplasticity phenomena that complicate long-term dopaminergic treatments. The present review will provide an updated summary of results reported in the literature concerning the biochemical characteristics and BG distribution of A2A receptors. We subsequently aim to examine the effects of adenosine A2A antagonists in rodent and primate models of PD and L-DOPA-induced dyskinesia. Finally, conclusive remarks will be made on the neuroprotective effects of A2A antagonists and on the translation of adenosine A2A receptor antagonists in the treatment of PD.peer-reviewe

Adenosine A2A receptor antagonist treatment of Parkinson’s disease

Adenosine A2A receptors have a unique cellular and regional distribution in the basal ganglia (BG), being particularly concentrated in areas richly innervated by dopamine (DA) such as the caudateputamen, otherwise called striatum, and the globus pallidus. Adenosine A2A and DA D2 receptors are capable of forming functional heteromeric complexes and are colocalised in striatopallidal neurons. Based on the peculiar cellular and regional distribution of this receptor and in line with data showing that A2A receptor antagonists improve motor symptoms of Parkinson’s disease (PD) in animal models and in clinical trials, A2A receptor antagonists have emerged as an attractive nondopaminergic target to improve the motor deficits that characterise PD. Experimental data have also shown that A2A receptor antagonists are capable of exerting a neuroprotective effect and do not induce neuroplasticity phenomena that complicate long-term dopaminergic treatments. The present review will provide an updated summary of results reported in the literature concerning the biochemical characteristics and BG distribution of A2A receptors. We subsequently aim to examine the effects of adenosine A2A antagonists in rodent and primate models of PD and L-DOPA-induced dyskinesia. Finally, conclusive remarks will be made on the neuroprotective effects of A2A antagonists and on the translation of adenosine A2A receptor antagonists in the treatment of PD.peer-reviewe

Sensibilizzazione alla caffeina e sensibilizzazione all'amfetamina: influenza della suscettibilità individuale agli effetti della caffeina

The present study evaluated the ability of a subchronic interrnittent administration of caffeine to induce a sensitized motor response and correlated the individual susceptibility of rats to acute caffeine to the development of sensitization. Moreover, individual susceptibility to caffeine and development of motor behaviour sensitization were correlated to the behavioural response obtained after a challenge with amphetamine. To this end, rats were subdivided in "low" and "high" responders according to their individual susceptibility to acute caffeine established on the basis of the motor activity observed after the first caffeine administration. "Low" and "high" responder rats were then repeatedly and intermittently treated with caffeine (15 mg/kg i.p.), or vehicle, every other day for fourteen days. Three days after treatment discontinuation, behavioural activation induced by acute amphetamine (0.5 mg/kg, s.c.) was measured in vehicle- and caffeine- ¬pretreated rats. Subchronic caffeine resulted in motor sensitization of a variatile degree among rats and no difference were observed between "low" and "high" responders. Moreover, caffeine pretreatment potentiated the behavioural effects of amphetamine according to the degree of caffeine sensitization but not to individual susceptibility to acute caffeine. These results demonstrate that individual susceptibility to acute caffeine does not influence the modifications in caffeine motor effects produced by its subchronic administration and does not affect the enhancement of acute behavioural effects of amphetamine in caffeine-pretreated rats, rather sensitization to subchronic caffeine administration critically influences the behavioural effects of amphetamine

Role of movement in long-term basal ganglia changes: implications for abnormal motor responses

Abnormal involuntary movements (AIMs) and dyskinesias elicited by drugs that stimulate dopamine receptors in the basal ganglia are a major issue in the management of Parkinson’s disease (PD). Preclinical studies in dopamine-denervated animals have contributed to the modeling of these abnormal movements, but the precise neurochemical and functional mechanisms underlying these untoward effects are still elusive. It has recently been suggested that the performance of movement may itself promote the later emergence of drug-induced motor complications, by favoring the generation of aberrant motor memories in the dopamine-denervated basal ganglia. Our recent results from hemiparkinsonian rats subjected to the priming model of dopaminergic stimulation are in agreement with this. These results demonstrate that early performance of movement is crucial for the manifestation of sensitized rotational behavior, indicative of an abnormal motor response, and neurochemical modifications in selected striatal neurons following a dopaminergic challenge. Building on this evidence, this paper discusses the possible role of movement performance in drug-induced motor complications, with a look at the implications for PD management

Divergent acute and enduring changes in 50-kHz ultrasonic vocalizations in rats repeatedly treated with amphetamine and dopaminergic antagonists: new insights on the role of dopamine in calling behavior

Background: Rats emit 50-kHz ultrasonic vocalizations (USVs) in response to non-pharmacological and pharmacological stimuli, with addictive psychostimulants being the most effective drugs that elicit calling behavior in rats. Earlier investigations found that dopamine D1-like and D2-like receptors modulate the emission of 50-kHz USVs stimulated in rats by the acute administration of addictive psychostimulants. Conversely, information is lacking on how dopamine D1-like and D2-like receptors modulate calling behavior in rats that are repeatedly treated with addictive psychostimulants. Methods: We evaluated the emission of 50-kHz USVs in rats repeatedly treated (×5 on alternate days) with amphetamine (1 mg/kg, i.p.), either alone or together with: i) SCH 23390 (0.1-1 mg/kg, s.c.), a dopamine D1 receptor antagonist, ii) raclopride (0.3-1 mg/kg, s.c.), a selective dopamine D2 receptor antagonist, or iii) a combination of SCH 23390 and raclopride (0.1 + 0.3 mg/kg, s.c.). Calling behavior of rats was recorded following pharmacological treatment, as well as in response to the presentation of amphetamine-paired cues and to amphetamine challenge (both performed 7 days after treatment discontinuation). Results: Amphetamine-treated rats displayed a sensitized 50-kHz USV emission during repeated treatment, as well as marked calling behavior in response to amphetamine-paired cues and to amphetamine challenge. Antagonism of D1 or D2 receptors either significantly suppressed or attenuated the emission of 50-kHz USVs in amphetamine-treated rats, with a maximal effect after synergistic antagonism of both receptors. Conclusions: These results shed further light on how dopamine transmission modulates the emission of 50-kHz USVs in rats treated with psychoactive drugs

A2A Receptor Antagonism and Dyskinesia in Parkinson's Disease

Dyskinesia, a major complication of treatment of Parkinson's disease (PD), involves two phases: induction, which is responsible for dyskinesia onset, and expression, which underlies its clinical manifestation. The unique cellular and regional distribution of adenosine A2A receptors in basal ganglia areas that are richly innervated by dopamine, and their antagonistic role towards dopamine receptor stimulation, have positioned A2A receptor antagonists as an attractive nondopaminergic target to improve the motor deficits that characterize PD. In this paper, we describe the biochemical characteristics of A2A receptors and the effects of adenosine A2A antagonists in rodent and primate models of PD on L-DOPA-induced dyskinesia, together with relevant biomarker studies. We also review clinical trials of A2A antagonists as adjuncts to L-DOPA in PD patients with motor fluctuations. These studies have generally demonstrated that the addition of an A2A antagonist to a stable L-DOPA regimen reduces OFF time and mildly increases dyskinesia. However, limited clinical data suggest that the addition of an A2A antagonist along with a reduction of L-DOPA might maintain anti-Parkinsonian benefit and reduce dyskinesia. Whether A2A antagonists might reduce the development of dyskinesia has not yet been tested clinically

Brain dysfunctions and neurotoxicity induced by psychostimulants in experimental models and humans: an overview of recent findings

Preclinical and clinical studies indicate that psychostimulants, in addition to having abuse potential, may elicit brain dysfunctions and/or neurotoxic effects. Central toxicity induced by psychostimulants may pose serious health risks since the recreational use of these substances is on the rise among young people and adults. The present review provides an overview of recent research, conducted between 2018 and 2023, focusing on brain dysfunctions and neurotoxic effects elicited in experimental models and humans by amphetamine, cocaine, methamphetamine, 3,4-methylenedioxymethamphetamine, methylphenidate, caffeine, and nicotine. Detailed elucidation of factors and mechanisms that underlie psychostimulant-induced brain dysfunction and neurotoxicity is crucial for understanding the acute and enduring noxious brain effects that may occur in individuals who use psychostimulants for recreational and/or therapeutic purposes

Mouse and rat ultrasonic vocalizations in neuroscience and neuropharmacology: State of the art and future applications

Mice and rats emit ultrasonic vocalizations (USVs), which may express their arousal and emotional states, to communicate with each other. There is continued scientific effort to better understand the functions of USVs as a central element of the rodent behavioral repertoire. However, studying USVs is not only important because of their ethological relevance, but also because they are widely applied as a behavioral readout in various fields of biomedical research. In mice and rats, a large number of experimental models of brain disorders exist and studying the emission of USVs in these models can provide valuable information about the health status of the animals and the effectiveness of possible interventions, both environmental and pharmacological. This review (i) provides an updated overview of the contexts in which ultrasonic calling behaviour of mice and rats has particularly high translational value, and (ii) gives some examples of novel approaches and tools used for the analysis of USVs in mice and rats, combining qualitative and quantitative methods. The relevance of age and sex differences as well as the importance of longitudinal evaluations of calling and non-calling behaviour is also discussed. Finally, the importance of assessing the communicative impact of USVs in the receiver, that is, through playback studies, is highlighted

Neuronal and peripheral damages induced by synthetic psychoactive substances: an update of recent findings from human and animal studies

Preclinical and clinical studies indicate that synthetic psychoactive substances, in addition to having abuse potential, may elicit toxic effects of varying severity at the peripheral and central levels. Nowadays, toxicity induced by synthetic psychoactive substances poses a serious harm for health, since recreational use of these substances is on the rise among young and adult people. The present review summarizes recent findings on the peripheral and central toxicity elicited by "old" and "new" synthetic psychoactive substances in humans and experimental animals, focusing on amphetamine derivatives, hallucinogen and dissociative drugs and synthetic cannabinoids