50-kHz ultrasonic vocalizations in hemiparkinsonian rats repeatedly treated with dopaminomimetic drugs as a possible behavioral marker of the affective properties of dopamine-replacing therapy in Parkinson's disease

The current leading therapeutic strategy used to manage Parkinson’s disease (PD) is the so-called dopamine replacement therapy (DRT). However, the prolonged use of DRT is associated with the onset of both motor and non-motor complications. The latter include alterations in the emotional state and iatrogenic psychiatric-like disturbances. As of today, the preclinical investigation of iatrogenic psychiatric-like disturbances in PD is limited, due to a substantial lack of effective experimental models that allow studying the affective properties of dopaminomimetic drugs in parkinsonian animals. In this regard, this study evaluated the emission of 50-kHz ultrasonic vocalizations (USVs), a behavioral marker of positive affect, in rats bearing a unilateral lesion with 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle. Apomorphine (2 or 4 mg/kg, i.p.), L-3,4-dihydroxyphenilalanine (L-DOPA, 6 or 12 mg/kg, i.p.), or pramipexole (2 or 4 mg/kg, i.p.) were administered in a test cage (× 5 administrations) on alternate days. Seven days after treatment discontinuation, rats were re-exposed to the test cage to measure conditioned calling behavior and thereafter received a drug challenge. The total numbers of 50-kHz USVs and the numbers of “flat”, “trill” and “frequency modulated” (FM) calls were scored, to ascertain whether apomorphine, L-DOPA and pramipexole influenced general calling behavior and/or the emission of specific categories of calls that are thought to possess dissimilar behavioral significance. Moreover, the presence of correlations between the numbers of calls emitted and the numbers of contralateral rotations performed was evaluated, to disclose the presence of similarities and/or differences in the effects that apomorphine, L-DOPA and pramipexole elicited on emotional state and motor function. Furthermore, since the nucleus accumbens (NAc) plays a key role in the initiation of 50-kHz USVs in rats, this study evaluated the levels of Zif-268 (a marker of neuronal activation) in the NAc, to further clarify which neuronal circuits regulate the emission of 50-kHz USVs in hemiparkinsonian rats treated with dopaminomimetic drugs. Hemiparkinsonian rats treated with either apomorphine or L-DOPA, but not pramipexole, markedly vocalized during repeated treatment and after drug challenge, and showed conditioned calling behavior. Moreover, apomorphine, L-DOPA and pramipexole elicited different patterns of 50-kHz USV emissions and contralateral rotational behavior, suggesting that 50-kHz USV emissions and rotational behavior are not interchangeable measures in the study of the affective properties of dopaminomimetic drugs. Furthermore, hemiparkinsonian rats treated with either apomorphine or L-DOPA displayed modifications in the emission of categorized calls that varied with the drug, dose, and administration day considered, leaving the question open as to whether it is general calling behavior or the emission of categorized calls that marks the effects of dopaminomimetic drugs on the emotional state of hemiparkinsonian rats. Finally, the results of the present study also suggest that NAc is a brain region involved in the vocal expression of positive affect in hemiparkinsonian rats treated with dopaminomimetic drugs used in the DRT of PD. Taken together, these results suggest that measuring the emission of 50-kHz USVs may be a relevant experimental tool for: i) further characterizing at the preclinical level the effects that dopaminomimetic drugs used in the DRT of PD elicit on the emotional state, and ii) study how these effects may favor the manifestation of behavioral modifications that mimic in experimental rats the behavioral abnormalities featuring the iatrogenic psychiatric-like disturbances that may occur in PD patients

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

Lack of drug- and cue-stimulated emissions of ultrasonic vocalizations in C57BL/6 J mice repeatedly treated with amphetamine

The emission of ultrasonic vocalizations (USVs) is thought to communicate the behavioral and emotional states elicited in rodents by social and non-social stimuli. On this basis, studies of psychopharmacology in rats are increasingly utilizing USVs as a behavioral marker to evaluate the effects of drugs on the emotional state. Conversely, very limited information is available as to whether psychoactive drugs influence USV emissions in mice. To provide new insights in this respect, we evaluated the emission of USVs in C57BL/6 J mice subjected to repeated treatment with the dopaminergic psychostimulant of abuse amphetamine. Mice were first allowed to perform social contacts in dyads, and 2 days later they received amphetamine (1-4 mg/kg, i.p.) in a test cage (× 5 administrations) on alternate days. Seven days after treatment discontinuation, mice were re-exposed to the test cage to evaluate whether the presentation of drug-paired environmental cues elicited calling behavior, and thereafter received an amphetamine challenge. An additional group of animals received the dopamine receptor agonist apomorphine (1-4 mg/kg, i.p.), to further clarify the role of dopamine transmission in calling behavior of mice. C57BL/6 J mice emitted USVs during social contacts, but did not significantly vocalize after amphetamine administration, in response to amphetamine-paired environmental cues, and after apomorphine administration. These results indicate that C57BL/6 J mice may respond differently to social and pharmacological stimuli in terms of USV emissions, and may lay the foundation for future studies aimed at clarifying whether USVs may be a useful behavioral marker in studies of psychopharmacology in mice

Emission of 50-kHz ultrasonic vocalizations stimulated by antiparkinsonian dopaminomimetic drugs in hemiparkinsonian rats is associated with neuronal activation in subcortical regions that regulate the affective state

Dopamine replacement therapy (DRT) of Parkinson's disease (PD) may trigger non-motor complications, some of which affect hedonic homeostatic regulation. Management of iatrogenic alterations in the affective state in PD is unsatisfactory, partly because of the limitations in the experimental models that are used in the preclinical investigation of the neurobiology and therapy of these alterations. In this connection, we recently employed a new experimental approach consisting in measuring the emission of 50-kHz ultrasonic vocalizations (USVs), a marker of positive affect, in hemiparkinsonian rats treated with drugs used in the DRT of PD. To further strengthen our approach, we here evaluated how the acute and repeated (× 5, on alternate days) administration of apomorphine (2 mg/kg, i.p.) or L-3,4-dihydroxyphenilalanine (L-DOPA, 12 mg/kg, i.p.) modified the immunoreactivity for Zif-268, a marker of neuronal activation, in the nucleus accumbens (NAc), caudate-putamen (CPu) and medial prefrontal cortex (mPFC), which are brain regions that regulate emotional states and drugs' affective properties. Acute and repeated treatment with either apomorphine or L-DOPA stimulated the emission of 50-kHz USVs in hemiparkinsonian rats, and this effect was paired with increased Zif-268 immunoreactivity in the NAc and CPu, but not mPFC. These findings indicate that subcortical and cortical regions may differently regulate the emission of 50-kHz USVs in hemiparkinsonian rats treated with dopaminergic drugs used in the DRT of PD. Moreover, they provide further evidence that measuring 50-kHz USV emissions in hemiparkinsonian rats may be a relevant approach to investigate at the preclinical level the affective properties of antiparkinsonian drugs

Increased emissions of 50-kHz ultrasonic vocalizations in hemiparkinsonian rats repeatedly treated with dopaminomimetic drugs: A potential preclinical model for studying the affective properties of dopamine replacement therapy in Parkinson's disease

Dopamine replacement therapy used in Parkinson's disease (PD) may induce alterations in the emotional state that can underlie the manifestation of iatrogenic psychiatric-like disturbances. The preclinical investigation of these disturbances is limited, also because few reliable paradigms are available to study the affective properties of dopaminomimetic drugs in parkinsonian animals. To provide a relevant experimental tool in this respect, we evaluated whether dopaminomimetic drugs modified the emission of 50-kHz ultrasonic vocalizations (USVs), a behavioral marker of positive affect, in rats bearing a unilateral lesion with 6-hydroxydopamine in the medial forebrain bundle. Apomorphine (2 or 4 mg/kg, i.p.), L-3,4-dihydroxyphenilalanine (L-DOPA, 6 or 12 mg/kg, i.p.), or pramipexole (2 or 4 mg/kg, i.p.) were administered in a test cage (× 5 administrations) on alternate days. Seven days after treatment discontinuation, rats were re-exposed to the test cage to measure conditioned calling behavior and thereafter received a drug challenge. Hemiparkinsonian rats treated with either apomorphine or L-DOPA, but not pramipexole, markedly vocalized during repeated treatment and after challenge, and showed conditioned calling behavior. Moreover, apomorphine, L-DOPA and pramipexole elicited different patterns of 50-kHz USV emissions and rotational behavior, indicating that calling behavior in hemiparkinsonian rats treated with dopaminomimetic drugs is not a byproduct of motor activation. Taken together, these results suggest that measuring 50-kHz USV emissions may be a relevant experimental tool for studying how dopaminomimetic drugs modify the affective state in parkinsonian rats, with possible implications for the preclinical investigation of iatrogenic psychiatric-like disturbances in PD

Influence of dopamine transmission in the medial prefrontal cortex and dorsal striatum on the emission of 50-kHz ultrasonic vocalizations in rats treated with amphetamine: Effects on drug-stimulated and conditioned calls

Rat ultrasonic vocalizations (USVs) of 50-kHz are increasingly being evaluated as a behavioral marker of the affective properties of drugs. Studies in amphetamine-treated rats have shown that activation of dopamine transmission in the nucleus accumbens (NAc) initiates the emission of 50-kHz USVs, but little is known on how dopamine transmission in other brain regions modulates the effects of drugs on calling behavior. To clarify this issue, we evaluated 50-kHz USV emissions in rats subjected to dopaminergic denervation of either the medial prefrontal cortex (mPFC) or the dorsal striatum (DS) and treated with amphetamine. Rats received amphetamine (1 mg/kg, i.p. × 5) on alternate days in a test cage; 7 days later, they were re-exposed to the test cage, to measure calling behavior that may reflect drug conditioning, and then challenged with amphetamine (1 mg/kg, i.p.). The numbers of total and categorized 50-kHz USVs emitted were evaluated, along with immunofluorescence for Zif-268 in the NAc. Dopamine-denervated and sham-operated rats displayed comparable patterns of calling behavior during amphetamine treatment and after amphetamine challenge. Conversely, rats that were dopamine-denervated in the mPFC, but not DS, emitted low numbers of 50-kHz USVs on test cage re-exposure. Finally, dopamine-denervated rats displayed a less marked increase in Zif-268-positive neurons in the NAc shell after amphetamine challenge, compared with sham-operated rats. These results may be relevant to identify the neuronal circuits that modulate 50-kHz USV emissions in rats treated with amphetamine, as well as the interplay between calling behavior and affective properties of drugs

Protective Agents in Parkinson’s Disease: Caffeine and Adenosine A2A Receptor Antagonists

Based on several findings suggesting that the adenosinergic system is one of the most interesting in the field of neuroprotection in Parkinson’s disease, this chapter describes the functions of the purine adenosine and its A2A receptors in the central nervous system, with emphasis on their role in neuroprotection. The neuromodulatory role of A2A receptors and the preclinical and epidemiological studies on the mechanisms of the neuroprotective role of caffeine and urate, the final product of purine catabolism, are extensively discussed in the light of their potential modifying effects on Parkinson’s disease

First report of digital skin ulcer with Stenotrophomonas maltophilia infection in an immunocompetent patient

Stenotrophomonas maltophilia is an aerobic Gram-negative bacillus that usually causes infection in immunocompromised patients. We present the case of an immunocompetent patient with a distal necrosis of the second and third fingers of the right hand caused by S. maltophilia infection. The patient underwent antibiotic therapy with trimethoprim/sulphamethoxazole on the basis of the susceptibility tests and underwent surgical debridement of the necrotic tissues, including of the distal phalanx bone, and further reconstruction with Atasoy flap. Stenotrophomonas maltophilia is emerging as an important cause of skin infection in immunoresponsive patients. Several community-acquired infections have been reported, however, as far as we are aware of, our case represents the first report of a digital wound of intact skin caused by community-acquired S. maltophilia infection in an immunocompetent patient

Characterization of Nasco grape pomace-loaded nutriosomes and their neuroprotective effects in the MPTP mouse model of Parkinson’s disease

Grape pomaces have recently received great attention for their richness in polyphenols, compounds known to exert anti-inflammatory and antioxidant effects. These pomaces, however, have low brain bioavailability when administered orally due to their extensive degradation in the gastrointestinal tract. To overcome this problem, Nasco pomace extract was incorporated into a novel nanovesicle system called nutriosomes, composed of phospholipids (S75) and water-soluble maltodextrin (Nutriose (R) FM06). Nutriosomes were small, homogeneously dispersed, had negative zeta potential, and were biocompatible with intestinal epithelial cells (Caco-2). Nasco pomace extract resulted rich in antioxidant polyphenols (gallic acid, catechin, epicatechin, procyanidin B2, and quercetin). To investigate the neuroprotective effect of Nasco pomace in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), Nasco nutriosomes or Nasco suspension was administered intragastrically and their neuroprotective effects were evaluated. Degeneration of nigro-striatal dopaminergic neurons induced by subacute MPTP treatment, the pathological hallmark of PD, was assessed through immunohistochemical evaluation of tyrosine hydroxylase (TH) in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc), and the dopamine transporter (DAT) in CPu. Immunohistochemical analysis revealed that Nasco nutriosomes significantly prevented the reduction in TH-and DATpositive fibres in CPu, and the number of TH-positive cells in SNc following subacute MPTP treatment, while Nasco suspension counteracted MPTP toxicity exclusively in SNc. Overall, these results highlight the therapeutic effects of Nasco pomace extract when administered in a nutriosome formulation in the subacute MPTP mouse model of PD and validate the effectiveness of the nutriosome preparation over suspension as an innovative nano-drug delivery system for in vivo administration