Foliglurax, a positive allosteric modulator of the metabotrophic glutamate receptor 4, protects dopaminergic neurons in MPTP-lesioned male mice.

Overactivity of the corticostriatal glutamatergic pathway is documented in Parkinson's disease (PD) and stimulation of presynaptic metabotropic glutamate (mGlu) receptors 4 on these striatal afferents inhibits glutamate release normalizing neuronal activity in the basal ganglia. Moreover, mGlu4 receptors are also expressed in glial cells and are able to modulate glial function making this receptor a potential target for neuroprotection. Hence, we investigated whether foliglurax, a positive allosteric modulator of mGlu4 receptors with high brain exposure after oral administration, has neuroprotective effects in MPTP mice to model early PD. Male mice were treated daily from day 1 to 10 with 1, 3 or 10 mg/kg of foliglurax and administered MPTP on the 5th day then euthanized on the 11th day. Dopamine neuron integrity was assessed with measures of striatal dopamine and its metabolites levels, striatal and nigral dopamine transporter (DAT) binding and inflammation with markers of striatal astrocytes (GFAP) and microglia (Iba1). MPTP lesion produced a decrease in dopamine, its metabolites and striatal DAT specific binding that was prevented by treatment with 3 mg/kg of foliglurax, whereas 1 and 10 mg/kg had no beneficial effect. MPTP mice had increased levels of GFAP; foliglurax treatment (3 mg/kg) prevented this increase. Iba1 levels were unchanged in MPTP mice compared to control mice. There was a negative correlation between dopamine content and GFAP levels. Our results show that positive allosteric modulation of mGlu4 receptors with foliglurax provided neuroprotective effects in the MPTP mouse model of PD.

Neuroprotective effects of indole-3-carbinol on the rotenone rat model of Parkinson's disease: Impact of the SIRT1-AMPK signaling pathway.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder. Although mounting studies have been conducted, no effective therapy is available to halt its progression. Indole-3-carbinol (I3C) is a naturally occurring compound obtained by ß-thioglucosidase-mediated autolysis of glucobrassicin in cruciferous vegetables. Besides its powerful antioxidant activity, I3C has shown neuroprotection against depression and chemically induced neurotoxicity via its anti-inflammatory and antiapoptotic effects. This study aimed to investigate the neuroprotective effects of I3C against rotenone (ROT)-induced PD in male albino rats. The possible protective mechanisms were also explored. PD was induced by subcutaneous administration of ROT (2 mg/kg) for 28 days. The effects of I3C (25, 50, and 100 mg/kg/day) were assessed by catalepsy test (bar test), spontaneous locomotor activity, rotarod test, weight change, tyrosine hydroxylase (TH) expression, α-synuclein (α-Syn) expression, striatal dopamine (DA) content, and histological examination. The highest dose of I3C (100 mg/kg) was the most effective to prevent ROT-mediated motor dysfunctions and amend striatal DA decrease, weight loss, neurodegeneration, TH expression reduction, and α-Syn expression increase in both the midbrain and striatum. Further mechanistic investigations revealed that the neuroprotective effects of I3C are partially attributed to its anti-inflammatory and antiapoptotic effects and the activation of the sirtuin 1/AMP-activated protein kinase pathway. Altogether, these results suggested that I3C could attenuate biochemical, molecular, and functional changes in a rat PD model with following repeated rotenone exposures.

Activation of dopamine D2 receptors in the shell of nucleus accumbens triggers conditioned avoidance responses in rats.

Conditioned avoidance responses (CAR) behavior is a classical instrumental response paradigm, which is widely used to study aversive conditioning and defensive motivation behavior. Previous studies have shown that dopamine D1 and D2 receptors are involved in CAR behavior; however, it is unclear in which brain regions that dopamine evokes CAR behavior. The aim of the study is to investigate whether dopamine triggers CAR behavior via activating dopamine D1 or D2 receptors in the shell of nucleus accumbens or dorsolateral striatum. The present study found that infusion of the dopamine D2 receptor agonist quinpirole, but not D1 receptor agonist SKF38393, into the shell of nucleus accumbens evoked CAR behavior in reserpine-treated rats. Whereas, infusion of neither SKF38393 nor quinpirole into the dorsolateral striatum evoked CAR behavior. In addition, infusion of quinpirole into the shell of nucleus accumbens enhanced CAR behavior in the unsuccessful trained rats without affecting the motor function in the balance beam and locomotor tests. In conclusion, activation of dopamine D2, but not D1 receptors in the shell of nucleus accumbens evokes CAR behavior. However, activation of dopamine D1 and D2 receptors in the dorsolateral striatum does not evoke CAR behavior. It is suggested that the shell of nucleus accumbens is the critical brain region for dopamine to invoke CAR behavior, and activation of dopamine D2 receptors in the shell of nucleus accumbens is sufficient and necessary to evoke CAR behavior.

Susceptibility to express amphetamine locomotor sensitization correlates with dorsolateral striatum bursting activity and GABAergic synapses in the globus pallidus.

Repeated psychostimulant administration results in behavioral sensitization, a process that is relevant in the early phases of drug addiction. Critically, behavioral sensitization is not observed in all subjects. Evidence shows that differential neuronal activity in the dorsolateral striatum (DLS) accompanies the expression of amphetamine (AMPH) locomotor sensitization. However, whether individual differences in DLS activity previous to AMPH administration can predict the expression of locomotor sensitization has not been assessed. Here, we examined DLS neuronal activity before and after repeated AMPH administration and related it to the susceptibility of rats to sensitize. For that, single-unit recordings on DLS medium spiny neurons (MSNs) were carried out in freely moving male Sprague Dawley rats during repeated AMPH administration. We also examined differences in neurostructure that could accompany sensitization. We quantified the density of the inhibitory postsynaptic marker gephyrin (Geph) in the entopeduncular nucleus (EP) and globus pallidus (GP). A higher burst firing and a lower percentage of correlation between MSNs post-Saline firing rate vs. locomotion predicted the expression of locomotor sensitization. Moreover, during the AMPH challenge, we observed that burst firing decreased in sensitized rats, in contrast to non-sensitized rats in which burst firing was maintained. Finally, a higher Geph density on GP but not EP was observed in non-sensitized rats after AMPH challenge. These results indicate that initial differences in DLS burst firing might underlie the susceptibility to express locomotor sensitization and suggest that the potentiation of dorsal striatum indirect pathway could be considered a protective mechanism to locomotor sensitization.

Intra-dorsal striatal acetylcholine M1 but not dopaminergic D1 or glutamatergic NMDA receptor antagonists inhibit consolidation of duration memory in interval timing.

The striatal beat frequency model assumes that striatal medium spiny neurons encode duration via synaptic plasticity. Muscarinic 1 (M1) cholinergic receptors as well as dopamine and glutamate receptors are important for neural plasticity in the dorsal striatum. Therefore, we investigated the effect of inhibiting these receptors on the formation of duration memory. After sufficient training in a peak interval (PI)-20-s procedure, rats were administered a single or mixed infusion of a selective antagonist for the dopamine D1 receptor (SCH23390, 0.5 µg per side), N-methyl-D-aspartic acid (NMDA)-type glutamate receptor (D-AP5, 3 µg), or M1 receptor (pirenzepine, 10 µg) bilaterally in the dorsal striatum, immediately before initiating a PI-40 s session (shift session). The next day, the rats were tested for new duration memory (40 s) in a session in which no lever presses were reinforced (test session). In the shift session, the performance was comparable irrespective of the drug injected. However, in the test session, the mean peak time (an index of duration memory) of the M1 + NMDA co-blockade group, but not of the D1 + NMDA co-blockade group, was lower than that of the control group (Experiments 1 and 2). In Experiment 3, the effect of the co-blockade of M1 and NMDA receptors was replicated. Moreover, sole blockade of M1 receptors induced the same effect as M1 and NMDA blockade. These results suggest that in the dorsal striatum, the M1 receptor, but not the D1 or NMDA receptors, is involved in the consolidation of duration memory.

Early life exposure to poly I:C impairs striatal DA-D2 receptor binding, myelination and associated behavioural abilities in rats.

Early-life viral infections critically influence the brain development and have been variously reported to cause neuropsychiatric diseases such as Schizophrenia, Parkinson's diseases, demyelinating diseases, etc. To investigate the alterations in the dopaminergic system, myelination and associated behavioral impairments following neonatal viral infection, the viral immune activation model was created by an intraperitoneal injection of Poly I:C (5 mg/kg bw/ip) to neonatal rat pups on PND-7. The DA-D2 receptor binding was assessed in corpus striatum by using 3H-Spiperone at 3, 6 and 12 weeks of age. MOG immunolabelling was performed to check myelination stature and myelin integrity, while corpus callosum calibre was assessed by Luxol fast blue staining. Relative behavioral tasks i.e., motor activity, motor coordination and neuromuscular strength were assessed by open field, rotarod and grip strength meter respectively at 3, 6 and 12 weeks of age. Following Poly I:C exposure, a significant decrease in DA-D2 receptor binding, reduction in corpus callosum calibre and MOG immunolabelling indicating demyelination and a significant decrease in locomotor activity, neuromuscular strength and motor coordination signify motor deficits and hypokinetic influence of early life viral infection. Thus, the findings suggest that early life poly I:C exposure may cause demyelination and motor deficits by decreasing DA-D2 receptor binding affinity.

Zonisamide attenuates the severity of levodopa-induced dyskinesia via modulation of the striatal serotonergic system in a rat model of Parkinson's disease.

Glutamate, GABA, acetylcholine, dopamine, and serotonin interact with each other to regulate the flow of neural information in the striatum. Serotonin type 1A receptor (5HT1A) is primarily expressed on glutamatergic nerve terminals, and 5HT1B is expressed on GABAergic medium spiny neurons (MSNs). Zonisamide (ZNS) reportedly improves the off period without worsening levodopa-induced dyskinesia (LID) in patients with advanced Parkinson's disease. In this study, LID model rats were prepared by administrating levodopa to unilaterally 6-OHDA-lesioned rats. We analyzed changes in serotonergic neurotransmission of LID model rats to elucidate the relationship between LID and the serotonergic system and pathomechanism of the anti-dyskinetic effects of ZNS. Abnormal involuntary movements (AIMs) were most severe in intermittently levodopa-treated rats but milder in rats intermittently medicated with levodopa and ZNS. Continuously levodopa-infused rats or intermittently ZNS-injected rats did not develop AIMs, and no differences in the expression of brain-derived neurotrophic factor, 5-HT transporter, 5HT1A, and 5HT1B mRNA between the lesioned striatum and normal side were observed. Expression of 5HT1B mRNA was elevated in the lesioned striatum of intermittently levodopa-treated rats, but this elevation was normalized by concomitant use of ZNS. The severity of AIMs was correlated with the ratio of 5HT1B to 5HT1A mRNA expression in the lesioned striatum, indicating that the anti-LID effect of ZNS is based on inhibition via 5HT1B receptors to direct pathway MSNs sensitized by intermittent levodopa treatment. Selectively acting serotonergic drugs, especially those that lower the 5HT1B to 5HT1A ratio, are promising new therapeutic agents to attenuate LID development.

Pitolisant, a wake-promoting agent devoid of psychostimulant properties: Preclinical comparison with amphetamine, modafinil, and solriamfetol.

Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models.

Behavioural and biochemical responses to methamphetamine are differentially regulated by mGlu2 and mGlu3 metabotropic glutamate receptors in male mice.

Group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) shape mechanisms of methamphetamine addiction, but the individual role played by the two subtypes is unclear. We measured methamphetamine-induced conditioned place preference (CPP) and motor responses to single or repeated injections of methamphetamine in wild-type, mGlu2-/-, and mGlu3-/-mice. Only mGlu3-/-mice showed methamphetamine preference in the CPP test. Motor response to the first methamphetamine injection was dramatically reduced in mGlu2-/-mice, unless these mice were treated with the mGlu5 receptor antagonist, MTEP. In contrast, methamphetamine-induced sensitization was increased in mGlu3-/-mice compared to wild-type mice. Only mGlu3-/-mice sensitized to methamphetamine showed increases in phospho-ERK1/2 levels in the nucleus accumbens (NAc) and free radical formation in the NAc and medial prefrontal cortex. These changes were not detected in mGlu2-/-mice. We also measured a series of biochemical parameters related to the mechanism of action of methamphetamine in naïve mice to disclose the nature of the differential behavioural responses of the three genotypes. We found a reduced expression and activity of dopamine transporter (DAT) and vesicular monoamine transporter-2 in the NAc and striatum of mGlu2-/-and mGlu3-/-mice, whereas expression of the DAT adaptor, syntaxin 1A, was selectively increased in the striatum of mGlu3-/-mice. Methamphetamine-stimulated dopamine release in striatal slices was largely reduced in mGlu2-/-, but not in mGlu3-/-, mice. These findings suggest that drugs that selectively enhance mGlu3 receptor activity or negatively modulate mGlu2 receptors might be beneficial in the treatment of methamphetamine addiction and associated brain damage.

Corticosterone in the dorsolateral striatum facilitates the extinction of stimulus-response memory.

Glucocorticoid hormones are crucially involved in modulating mnemonic processing of stressful or emotionally arousing experiences. They are known to enhance the consolidation of new memories, including those that extinguish older memories. In this study, we investigated whether glucocorticoids facilitate the extinction of a striatum-dependent, and behaviorally more rigid, stimulus-response memory. For this, male rats were initially trained for six days on a stimulus-response task in a T-maze to obtain a reward after making an egocentric right-turn body response, regardless of the starting position in this maze. This training phase was followed by three extinction sessions in which right-turn body responses were not reinforced. Corticosterone administration into the dorsolateral region of the striatum after the first extinction session dose-dependently enhanced the consolidation of extinction memory: Rats administered the higher dose of corticosterone (30 ng), but not lower doses (5 or 10 ng), exhibited significantly fewer right-turn body responses and had longer latencies compared to vehicle-treated animals on the second and third extinction sessions. Co-administration of the glucocorticoid receptor antagonist RU 486 (10 ng) prevented the corticosterone effect, indicating that glucocorticoids enhance the extinction of stimulus-response memory via activation of the glucocorticoid receptor. Corticosterone administration into the dorsomedial striatum did not affect extinction memory. These findings indicate that stress-response mechanisms involving corticosterone actions in the dorsolateral striatum facilitate the extinction of stimulus-response memory that might allow for the development of an opportune behavioral strategy.

Bidirectional role of microtubule dynamics in the acquisition and maintenance of temporal information in dorsolateral striatum.

Accurate and precise timing is crucial for complex and purposeful behaviors, such as foraging for food or playing a musical instrument. The brain is capable of processing temporal information in a coordinated manner, as if it contains an 'internal clock'. Similar to the need for the brain to orient itself in space in order to understand its surroundings, temporal orientation and tracking is an essential component of cognition as well. While there have been multiple models explaining the neural correlates of timing, independent lines of research appear to converge on the conclusion that populations of neurons in the dorsal striatum encode information relating to where a subject is in time relative to an anticipated goal. Similar to other learning processes, acquisition and maintenance of this temporal information is dependent on synaptic plasticity. Microtubules are cytoskeletal proteins that have been implicated in synaptic plasticity mechanisms and therefore are considered key elements in learning and memory. In this study, we investigated the role of microtubule dynamics in temporal learning by local infusions of microtubule stabilizing and destabilizing agents into the dorsolateral striatum. Our results suggested a bidirectional role for microtubules in timing, such that microtubule stabilization improves the maintenance of learned target durations, but impairs the acquisition of a novel duration. On the other hand, microtubule destabilization enhances the acquisition of novel target durations, while compromising the maintenance of previously learned durations. These findings suggest that microtubule dynamics plays an important role in synaptic plasticity mechanisms in the dorsolateral striatum, which in turn modulates temporal learning and time perception.

PPARγ receptors are involved in the effects of cannabidiol on orofacial dyskinesia and cognitive dysfunction induced by typical antipsychotic in mice.

Tardive dyskinesia (TD) is a movement disorder that appears after chronic use of drugs that block dopaminergic receptors such as antipsychotics. Besides the motor symptoms, patients with TD also present cognitive deficits. Neuroinflammatory mechanisms could be involved in the development of these symptoms. A previous study showed that cannabidiol (CBD), the major non-psychotomimetic compound of Cannabis sativa plant, prevents orofacial dyskinesia induced by typical antipsychotics by activating peroxisome proliferator-activated receptors gamma (PPARγ). Here, we investigated if CBD would also reverse haloperidol-induced orofacial dyskinesia and associated cognitive deficits. We also verified if these effects depend on PPARγ receptor activation. Daily treatment with haloperidol (3 mg/kg, 21 days) increased the frequency of vacuous chewing movements (VCM) and decreased the discrimination index in the novel object recognition test in male Swiss mice. CBD (60 mg/kg/daily) administered in the last 7 days of haloperidol treatment attenuated both behavioral effects. Furthermore, haloperidol increased IL-1ß and TNF-α levels in the striatum and hippocampus while CBD reverted these effects. The striatal and hippocampal levels of proinflammatory cytokines correlated with VCM frequency and discrimination index, respectively. Pretreatment with the PPARγ antagonist GW9662 (2 mg/kg/daily) blocked the behavioral effects of CBD. In conclusion, these results indicated that CBD could attenuate haloperidol-induced orofacial dyskinesia and improve non-motor symptoms associated with TD by activating PPARγ receptors.

Task-Dependent Effects of SKF83959 on Operant Behaviors Associated With Distinct Changes of CaMKII Signaling in Striatal Subareas.

BACKGROUND: SKF83959, an atypical dopamine (DA) D1 receptor agonist, has been used to test the functions of DA-related receptor complexes in vitro, but little is known about its impact on conditioned behavior. The present study examined the effects of SKF83959 on operant behaviors and assayed the neurochemical mechanisms involved. METHODS: Male rats were trained and maintained on either a fixed-interval 30-second (FI30) schedule or a differential reinforcement of low-rate response 10-second (DRL10) schedule of reinforcement. After drug treatment tests, western blotting assayed the protein expressions of the calcium-/calmodulin-dependent protein kinase II (CaMKII) and the transcription factor cyclic AMP response element binding protein (CREB) in tissues collected from 4 selected DA-related areas. RESULTS: SKF83959 disrupted the performance of FI30 and DRL10 behaviors in a dose-dependent manner by reducing the total number of responses in varying magnitudes. Moreover, the distinct profiles of the behavior altered by the drug were manifested by analyzing qualitative and quantitative measures on both tasks. Western-blot results showed that phospho-CaMKII levels decreased in the nucleus accumbens and the dorsal striatum of the drug-treated FI30 and DRL10 subjects, respectively, compared with their vehicle controls. The phospho-CREB levels decreased in the nucleus accumbens and the hippocampus of drug-treated FI30 subjects but increased in the nucleus accumbens of drug-treated DRL10 subjects. CONCLUSIONS: Our results provide important insight into the neuropsychopharmacology of SKF83959, indicating that the drug-altered operant behavior is task dependent and related to regional-dependent changes of CaMKII-CREB signaling in the mesocorticolimbic DA systems.

Altered excitatory transmission in striatal neurons after chronic ethanol consumption in selectively bred crossed high alcohol-preferring mice.

Genetic predisposition to heavy drinking is a risk factor for alcohol misuse. We used selectively bred crossed high alcohol-preferring (cHAP) mice to study sex differences in alcohol drinking and its effect on glutamatergic activity in dorsolateral (DLS) and dorsomedial (DMS) striatum. We performed whole-cell patch-clamp recording in neurons from male and female cHAP mice with 5-week alcohol drinking history and alcohol-naïve controls. In DMS, alcohol-naïve males' neurons displayed lower cell capacitance and higher membrane resistance than females' neurons, both effects reversed by drinking. Conversely, in DLS neurons, drinking history increased capacitance only in males and changed membrane resistance only in females. Altered biophysical membrane properties were accompanied by disrupted glutamatergic transmission. Drinking history increased spontaneous excitatory postsynaptic current (sEPSC) amplitude in DMS and frequency in DLS female neurons, compared to alcohol-naïve females, without effect in males. Acute ethanol differentially impacted DMS and DLS neurons by sex and drinking history. In DMS, acute alcohol significantly increased sEPSC frequency only in neurons from alcohol-naïve females, an effect that disappeared after drinking history. In DLS, acute alcohol had opposing effects in males and females based on drinking history. Estrous cycle also impacted DMS and DLS neurons differently: sEPSC amplitudes were higher in DMS cells from drinking history than alcohol-naïve females, whereas estrous cycle, not drinking history, modified DLS firing rate. Our data show sex differences in cHAP ethanol consumption and neurophysiology, suggesting differential dysregulation of glutamatergic drive onto DMS and DLS after chronic ethanol consumption.

A New Tool to Study Parkinsonism in the Context of Aging: MPTP Intoxication in a Natural Model of Multimorbidity.

The diurnal rodent Octodon degus (O. degus) is considered an attractive natural model for Alzheimer's disease and other human age-related features. However, it has not been explored so far if the O. degus could be used as a model to study Parkinson's disease. To test this idea, 10 adult male O. degus were divided into control group and MPTP-intoxicated animals. Motor condition and cognition were examined. Dopaminergic degeneration was studied in the ventral mesencephalon and in the striatum. Neuroinflammation was also evaluated in the ventral mesencephalon, in the striatum and in the dorsal hippocampus. MPTP animals showed significant alterations in motor activity and in visuospatial memory. Postmortem analysis revealed a significant decrease in the number of dopaminergic neurons in the ventral mesencephalon of MPTP animals, although no differences were found in their striatal terminals. We observed a significant increase in neuroinflammatory responses in the mesencephalon, in the striatum and in the hippocampus of MPTP-intoxicated animals. Additionally, changes in the subcellular expression of the calcium-binding protein S100ß were found in the astrocytes in the nigrostriatal pathway. These findings prove for the first time that O. degus are sensitive to MPTP intoxication and, therefore, is a suitable model for experimental Parkinsonism in the context of aging.

Acrolein scavenger dimercaprol offers neuroprotection in an animal model of Parkinson's disease: implication of acrolein and TRPA1.

BACKGROUND: The mechanisms underlying lesions of dopaminergic (DA) neurons, an essential pathology of Parkinson's disease (PD), are largely unknown, although oxidative stress is recognized as a key factor. We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in PD pathology, and that acrolein scavenger hydralazine can reduce the elevated acrolein, mitigate DA neuron death, and alleviate motor deficits in a 6-hydroxydopamine (6-OHDA) rat model. As such, we hypothesize that a structurally distinct acrolein scavenger, dimercaprol (DP), can also offer neuroprotection and behavioral benefits. METHODS: DP was used to lower the elevated levels of acrolein in the basal ganglia of 6-OHDA rats. The acrolein levels and related pathologies were measured by immunohistochemistry. Locomotor and behavioral effects of 6-OHDA injections and DP treatment were examined using the open field test and rotarod test. Pain was assessed using mechanical allodynia, cold hypersensitivity, and plantar tests. Finally, the effects of DP were assessed in vitro on SK-N-SH dopaminergic cells exposed to acrolein. RESULTS: DP reduced acrolein and reversed the upregulation of pain-sensing transient receptor potential ankyrin 1 (TRPA1) channels in the substantia nigra, striatum, and cortex. DP also mitigated both motor and sensory deficits typical of PD. In addition, DP lowered acrolein and protected DA-like cells in vitro. Acrolein's ability to upregulate TRPA1 was also verified in vitro using cell lines. CONCLUSIONS: These results further elucidated the acrolein-mediated pathogenesis and reinforced the critical role of acrolein in PD while providing strong arguments for anti-acrolein treatments as a novel and feasible strategy to combat neurodegeneration in PD. Considering the extensive involvement of acrolein in various nervous system illnesses and beyond, anti-acrolein strategies may have wide applications and broad impacts on human health.

Hydroxytyrosol as anti-parkinsonian molecule: Assessment using in-silico and MPTP-induced Parkinson's disease model.

3-Hydroxytyrosol (HXT) is a natural polyphenol present in extra virgin olive oil. It is a key component of Mediterranean diet and is known for its strong antioxidant activity. The present study evaluated the potential of HXT as an anti-parkinsonian molecule in terms of its ability to inhibit MAO-B and thereby maintaining dopamine (DA) levels in Parkinson's disease (PD). In-silico molecular docking study followed by MMGBSA binding free energy calculation revealed that HXT has a strong binding affinity for MAO-B in comparison to MAO-A. Moreover, rasagiline and HXT interacted with the similar binding sites and modes of interactions. Additionally, molecular dynamics simulation studies revealed stable nature of HXT-MAO-B interaction and also provided information about the amino acid residues involved in binding. Moreover, in vitro studies revealed that HXT inhibited MAO-B in human platelets with IC50 value of 7.78 µM. In vivo studies using MPTP-induced mouse model of PD revealed increase in DA levels with concomitant decrease in DA metabolites (DOPAC and HVA) on HXT treatment. Furthermore, MAO-B activity was also inhibited on HXT administration to PD mice. In addition, HXT treatment prevented MPTP-induced loss of DA neurons in substantia nigra and their nerve terminals in the striatum. HXT also attenuated motor impairments in PD mice assessed by catalepsy bar, narrow beam walk and open field tests. Thus, the present findings reveal HXT as a potential inhibitor of MAO-B, which may be used as a lead molecule for the development of therapeutics for PD.

Levodopa-Induced Dyskinesia in Parkinson Disease Specifically Associates With Dopaminergic Depletion in Sensorimotor-Related Functional Subregions of the Striatum.

PURPOSE: To determine whether the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) specifically relates to dopaminergic depletion in sensorimotor-related subregions of the striatum. METHODS: Our primary study sample consisted of 185 locally recruited PD patients, of which 73 (40%) developed LID. Retrospective 123I-FP-CIT SPECT data were used to quantify the specific dopamine transporter (DAT) binding ratio within distinct functionally defined striatal subregions related to limbic, executive, and sensorimotor systems. Regional DAT levels were contrasted between patients who developed LID (PD + LID) and those who did not (PD-LID) using analysis of covariance models controlled for demographic and clinical features. For validation of the findings and assessment of the evolution of LID-associated DAT changes from an early disease stage, we also studied serial 123I-FP-CIT SPECT data from 343 de novo PD patients enrolled in the Parkinson Progression Marker's Initiative using mixed linear model analysis. RESULTS: Compared with PD-LID, DAT level reductions in PD + LID patients were most pronounced in the sensorimotor striatal subregion (F = 5.99, P = 0.016) and also significant in the executive-related subregion (F = 5.30, P = 0.023). In the Parkinson Progression Marker's Initiative cohort, DAT levels in PD + LID (n = 161, 47%) were only significantly reduced compared with PD-LID in the sensorimotor striatal subregion (t = -2.05, P = 0.041), and this difference was already present at baseline and remained largely constant over time. CONCLUSION: Measuring DAT depletion in functionally defined sensorimotor-related striatal regions of interest may provide a more sensitive tool to detect LID-associated dopaminergic changes at an early disease stage and could improve individual prognosis of this common clinical complication in PD.

Comparison of the sensitizing effects of cocaine and ethanol on histone deacetylase isoforms in the rat brain.

Behavioral sensitization, an animal model of drug addiction, persists for a prolonged period after repeated exposure to drugs of abuse. The persistence of an addiction behavioral phenotype suggests long-lasting changes in gene regulation at the epigenetic level. We measured the expression of histone deacetylases (HDACs) isoforms in the prefrontal cortex and dorsal striatum following the development of sensitization to cocaine (15 mg/kg, administered five times) and ethanol (0.5 g/kg, administered 15 times) to investigate the epigenetic changes that mediate sensitization. Animals sensitized to ethanol exhibited augmented locomotor activity in response to the cocaine challenge. Similarly, those sensitized to cocaine exhibited increased locomotor activity in response to an ethanol challenge. These findings indicate cross-sensitization between ethanol and cocaine and suggest that a common molecular mechanism underlying the cross-sensitization. In animals sensitized to cocaine or ethanol, mRNA levels of class II HDACs (HDAC4 and HDAC5) were decreased in the prefrontal cortex and dorsal striatum, whereas acute treatments with either drug had no effect on the expression of class II HDACs. By contrast, class I HDACs (HDAC1 and HDAC2) responded to the acute cocaine challenge, whereas sensitization itself did not have a consistent effect on class I HDAC levels. These findings support the hypothesis of a common epigenetic mechanism underlying persistent behavioral sensitization induced by different drugs, which may be mediated by the altered expression of class II HDACs.

Voluntary binge-patterned alcohol drinking and sex-specific influences on monoamine-related neurochemical signatures in the mouse gut and brain.

BACKGROUND: Altered monoamine (i.e., serotonin, dopamine, and norepinephrine) activity following episodes of alcohol abuse plays key roles not only in the motivation to ingest ethanol, but also physiological dysfunction related to its misuse. Although monoamine activity is essential for physiological processes that require coordinated communication across the gut-brain axis (GBA), relatively little is known about how alcohol misuse may affect monoamine levels across the GBA. Therefore, we evaluated monoamine activity across the mouse gut and brain following episodes of binge-patterned ethanol drinking. METHODS: Monoamine and select metabolite neurochemical concentrations were analyzed by ultra-high-performance liquid chromatography in gut and brain regions of female and male C57BL/6J mice following "Drinking in the Dark" (DID), a binge-patterned ethanol ingestion paradigm. RESULTS: First, we found that alcohol access had an overall small effect on gut monoamine-related neurochemical concentrations, primarily influencing dopamine activity. Second, neurochemical patterns between the small intestine and the striatum were correlated, adding to recent evidence of modulatory activity between these areas. Third, although alcohol access robustly influenced activity in brain areas in the mesolimbic dopamine system, binge exposure also influenced monoaminergic activity in the hypothalamic region. Finally, sex differences were observed in the concentrations of neurochemicals within the gut, which was particularly pronounced in the small intestine. CONCLUSION: Together, these data provide insights into the influence of alcohol abuse and biological sex on monoamine-related neurochemical changes across the GBA, which could have important implications for GBA function and dysfunction.