Role of the MicroRNAs in the Pathogenic Mechanism of Painful Symptoms in Long COVID: Systematic Review.

The ongoing pandemic of COVID-19 has caused more than 6.7 million tragic deaths, plus, a large percentage of people who survived it present a myriad of chronic symptoms that last for at least 6 months; this has been named as long COVID. Some of the most prevalent are painful symptoms like headache, joint pain, migraine, neuropathic-like pain, fatigue and myalgia. MicroRNAs are small non-coding RNAs that regulate genes, and their involvement in several pathologies has been extensively shown. A deregulation of miRNAs has been observed in patients with COVID-19. The objective of the present systematic review was to show the prevalence of chronic pain-like symptoms of patients with long COVID and based on the expression of miRNAs in patients with COVID-19, and to present a proposal on how they may be involved in the pathogenic mechanisms of chronic pain-like symptoms. A systematic review was carried out in online databases for original articles published between March 2020 to April 2022; the systematic review followed the PRISMA guidelines, and it was registered in PROSPERO with registration number CRD42022318992. A total of 22 articles were included for the evaluation of miRNAs and 20 regarding long COVID; the overall prevalence of pain-like symptoms was around 10 to 87%, plus, the miRNAs that were commonly up and downregulated were miR-21-5p, miR-29a,b,c-3p miR-92a,b-3p, miR-92b-5p, miR-126-3p, miR-150-5p, miR-155-5p, miR-200a, c-3p, miR-320a,b,c,d,e-3p, and miR-451a. The molecular pathways that we hypothesized to be modulated by these miRNAs are the IL-6/STAT3 proinflammatory axis and the compromise of the blood-nerve barrier; these two mechanisms could be associated with the prevalence of fatigue and chronic pain in the long COVID population, plus they could be novel pharmacological targets in order to reduce and prevent these symptoms.

Controlling the diversity of ion-induced fragmentation pathways by N-methylation of amino acids.

We present a combined experimental and theoretical study of the fragmentation of singly and doubly N-methylated glycine (sarcosine and N,N-dimethyl glycine, respectively) induced by low-energy (keV) O6+ ions. Multicoincidence mass spectrometry techniques and quantum chemistry simulations (ab initio molecular dynamics and density functional theory) allow us to characterise different fragmentation pathways as well as the associated mechanisms. We focus on the fragmentation of doubly ionised species, for which coincidence measurements provide unambiguous information on the origin of the various charged fragments. We have found that single N-methylation leads to a larger variety of fragmentation channels than in no methylation of glycine, while double N-methylation effectively closes many of these fragmentation channels, including some of those appearing in pristine glycine. Importantly, the closure of fragmentation channels in the latter case does not imply a protective effect by the methyl group.

Glutamate, Glutamine, GABA and Oxidative Products in the Pons Following Cortical Injury and Their Role in Motor Functional Recovery.

Brain injury leads to an excitatory phase followed by an inhibitory phase in the brain. The clinical sequelae caused by cerebral injury seem to be a response to remote functional inhibition of cerebral nuclei located far from the motor cortex but anatomically related to the injury site. It appears that such functional inhibition is mediated by an increase in lipid peroxidation (LP). To test this hypothesis, we report data from 80 rats that were allocated to the following groups: the sham group (n = 40), in which rats received an intracortical infusion of artificial cerebrospinal fluid (CSF); the injury group (n = 20), in which rats received CSF containing ferrous chloride (FeCl2, 50 mM); and the recovery group (n = 20), in which rats were injured and allowed to recover. Beam-walking, sensorimotor and spontaneous motor activity tests were performed to evaluate motor performance after injury. Lipid fluorescent products (LFPs) were measured in the pons. The total pontine contents of glutamate (GLU), glutamine (GLN) and gamma-aminobutyric acid (GABA) were also measured. In injured rats, the motor deficits, LFPs and total GABA and GLN contents in the pons were increased, while the GLU level was decreased. In contrast, in recovering rats, none of the studied variables were significantly different from those in sham rats. Thus, motor impairment after cortical injury seems to be mediated by an inhibitory pontine response, and functional recovery may result from a pontine restoration of the GLN-GLU-GABA cycle, while LP may be a primary mechanism leading to remote pontine inhibition after cortical injury.

Porous Silicon Gas Sensors: The Role of the Layer Thickness and the Silicon Conductivity.

We studied the influences of the thickness of the porous silicon layer and the conductivity type on the porous silicon sensors response when exposed to ethanol vapor. The response was determined at room temperature (27 ∘C) in darkness using a horizontal aluminum electrode pattern. The results indicated that the intensity of the response can be directly or inversely proportional to the thickness of the porous layer depending on the conductivity type of the semiconductor material. The response of the porous sensors was similar to the metal oxide sensors. The results can be used to appropriately select the conductivity of semiconductor materials and the thickness of the porous layer for the target gas.

Molecular Modelling of the H2 -Adsorptive Properties of Tetrazolate-Based Metal-Organic Frameworks: From the Cluster Approach to Periodic Simulations.

Hydrogen has been proposed as a long-term non-fossil fuel to be used in a future ideal carbon-neutral energetic economy. However, its low volumetric energy density hinders its storage and transportation. Metal-organic frameworks (MOFs) represent very promising materials for this purpose due to their very extended surface areas. Azolates, in particular tetrazolates, are - together with carboxylate functionalities - very common organic linkers connecting metallic secondary building units in MOFs. This study addresses, from a theoretical perspective, the H2 adsorptive properties of tetrazolate linkers at the molecular level, following a size-progressive approach. Specifically, we have investigated how the physisorption energies and geometries are affected when changing the environment of the linker by considering the azolates in the gas phase, immersed in a finite cluster, or being part of an infinite extended crystal material. Furthermore, we also study the H2 adsorptive capacity of these linkers within the cluster model.

Dopamine D1 receptor activation maintains motor coordination and balance in rats.

Dopamine (DA) modulates motor coordination, and its depletion, as in Parkinson's disease, produces motor impairment. The basal ganglia, cerebellum and cerebral cortex are interconnected, have functional roles in motor coordination, and possess dopamine D1 receptors (D1Rs), which are expressed at a particularly high density in the basal ganglia. In this study, we examined whether the activation of D1Rs modulates motor coordination and balance in the rat using a beam-walking test that has previously been used to detect motor coordination deficits. The systemic administration of the D1R agonist SKF-38393 at 2, 3, or 4 mg/kg did not alter the beam-walking scores, but the subsequent administration of the D1R antagonist SCH-23390 at 1 mg/kg did produce deficits in motor coordination, which were reversed by the full agonist SKF-82958. The co-administration of SKF-38393 and SCH-23390 did not alter the beam-walking scores compared with the control group, but significantly prevented the increase in beam-walking scores induced by SCH-23390. The effect of the D1R agonist to prevent and reverse the effect of the D1R antagonist in beam-walking scores is an indicator that the function of D1Rs is necessary to maintain motor coordination and balance in rats. Our results support that D1Rs mediate the SCH-23390-induced deficit in motor coordination.

Sensorimotor Intervention Recovers Noradrenaline Content in the Dentate Gyrus of Cortical Injured Rats.

Nowadays, a consensus has been reached that designates the functional and structural reorganization of synapses as the primary mechanisms underlying the process of recovery from brain injury. We have reported that pontine noradrenaline (NA) is increased in animals after cortical ablation (CA). The aim of the present study was to explore the noradrenergic and morphological response after sensorimotor intervention (SMI) in rats injured in the motor cortex. We used male Wistar adult rats allocated in four conditions: sham-operated, injured by cortical ablation, sham-operated with SMI and injured by cortical ablation with SMI. Motor and somatosensory performance was evaluated prior to and 20 days after surgery. During the intervening period, a 15-session, SMI program was implemented. Subsequently, total NA analysis in the pons and dentate gyrus (DG) was performed. All groups underwent histological analysis. Our results showed that NA content in the DG was reduced in the injured group versus control, and this reduction was reverted in the injured group that underwent SMI. Moreover, injured rats showed reduction in the number of granule cells in the DG and decreased dentate granule cell layer thickness. Notably, after SMI, the loss of granule cells was reverted. Locus coeruleus showed turgid cells in the injured rats. These results suggest that SMI elicits biochemical and structural modifications in the hippocampus that could reorganize the system and lead the recovery process, modulating structural and functional plasticity.

D1 Antagonists and D2 Agonists Have Opposite Effects on the Metabolism of Dopamine in the Rat Striatum.

The striatum is known to possess high levels of D1-like and D2-like receptors (D1Rs and D2Rs, respectively). We have previously shown that selective inhibition of D1Rs increases the dopaminergic metabolic response and proposed that this effect is associated with the concomitant activation of postsynaptic D2Rs by endogenous dopamine (DA). Here, we examined whether activation of D2Rs modulates the metabolism and synthesis of DA in the striatum. We used male Wistar rats to evaluate the effects of the systemic administration of a D2R agonist (bromocriptine), a D1R antagonist (SCH-23390), and the co-administration of these compounds with pargyline on the inhibition of monoamine oxidase. DA and L-3,4-dihidroxyphenylacetic acid (DOPAC) levels and 3,4-dihydroxy-L-phenylalanine (L-DOPA) content were measured using high performance liquid chromatography. The systemic administration of SCH-23390 alone, at 0.25, 0.5, 1 or 2 mg/kg, significantly (P < 0.05) increased DOPAC levels and the DOPAC/DA ratio. At 2, 4 and 8 mg/kg, the administration of bromocriptine alone significantly (P < 0.05) decreased DOPAC levels, L-DOPA content and the DOPAC/DA ratio, whereas at 2 mg/kg, it decreased DA levels. In both groups, co-administration of either SCH-23390 or bromocriptine with pargyline decreased DOPAC levels and the DOPAC/DA ratio by approximately 70 % compared to the levels observed in the control groups. In conclusion, administration of the D2R agonist bromocriptine decreased dopaminergic synthesis and metabolism in the striatum; in contrast, administration of the D1R antagonist SCH-23390 induced the opposite effects.

Lipase-catalyzed synthesis of hyperbranched poly-L-lactide in an ionic liquid.

Hyperbranched poly-L-lactides have been synthesized by eROP in [C4MIM][PF6] media. The bis(hydroxymethyl)butyric acid molecule was used as the AB2 core co-monomer and immobilized lipase B from Candida antarctica as biocatalyst. The degree of branching could be controlled by the reaction conditions, with the maximum achieved being 0.21. The successful achievement of the hyperbranched structure is attributed to the high solvent power of substrates and products in the ionic liquid besides sustained lipase activity.

Chronic H3R activation reduces L-Dopa-induced dyskinesia, normalizes cortical GABA and glutamate levels, and increases striatal dopamine D1R mRNA expression in 6-hydroxydopamine-lesioned male rats.

RATIONALE: Dyskinesias induced by L-3,4-dihydroxyphenylalanine, L-Dopa (LIDs), are the major complication in the pharmacological treatment of Parkinson's disease. LIDs induce overactivity of the glutamatergic cortico-striatal projections, and drugs that reduce glutamatergic overactivity exert antidyskinetic actions. Chronic administration of immepip, agonist at histamine H3 receptors (H3R), reduces LIDs and diminishes GABA and glutamate content in striatal dialysates (Avila-Luna et al., Psychopharmacology 236: 1937-1948, 2019). OBJECTIVES AND METHODS: In rats unilaterally lesioned with 6-hydroxydopamine in the substantia nigra pars compacta (SNc), we examined whether the chronic administration of immepip and their withdrawal modify LIDs, the effect of L-Dopa on glutamate and GABA content, and mRNA levels of dopamine D1 receptors (D1Rs) and H3Rs in the cerebral cortex and striatum. RESULTS: The administration of L-Dopa for 21 days induced LIDs. This effect was accompanied by increased GABA and glutamate levels in the cerebral cortex ipsi and contralateral to the lesioned SNc, and immepip administration prevented (GABA) or reduced (glutamate) these actions. In the striatum, GABA content increased in the ipsilateral nucleus, an effect prevented by immepip. L-Dopa administration had no significant effects on striatal glutamate levels. In lesioned and L-Dopa-treated animals, D1R mRNA decreased in the ipsilateral striatum, an effect prevented by immepip administration. CONCLUSIONS: Our results indicate that chronic H3R activation reduces LIDs and the overactivity of glutamatergic cortico-striatal projections, providing further evidence for an interaction between D1Rs and H3Rs in the cortex and striatum under normal and pathological conditions.

Comparison of carbon content between plantation and natural regeneration seedlings in Durango, Mexico.

Forest plantations and natural forests perform a relevant role in capturing CO2 and reducing greenhouse gas concentrations. The objective of this study was to compare the diameter increment, biomass and carbon accumulation in a plantation of Pinus durangensis and a naturally regenerated stand. The data were collected from 32 circular plots of 100 m2 (16 plots in the planted site and 16 in naturally regenerated area). At each plot, the diameter at the base (cm) and height (m) of all seedlings were measured using a Vernier and tape measure, and a seedling was destructively sampled collecting one cross-section at the base of the stump. The annual ring-width increment of each sampled seedling was recorded to obtain its diameter at the base and estimate annual aboveground biomass and carbon accumulation through allometric equations. The response variables were evaluated using mixed-effects ANOVA models. Results indicated that there were significant differences (P ≤ 0.05) on annual tree-ring width growth, biomass and carbon accumulation. The plantation seedlings showed significantly higher growth rates, biomass and carbon accumulation at most evaluated years. After 7 years of growth the lines of current annual increment (CAI) and mean annual increment (MAI) in basal diameter for both the plantation and the natural regeneration have not yet intersected. Both forest plantations and naturally regenerated stands of the studied tree species may be suitable alternatives to promote CO2 capture and increase timber production.

Traumatic brain injury extending to the striatum alters autonomic thermoregulation and hypothalamic monoamines in recovering rats.

The brain cortex is the structure that is typically injured in traumatic brain injury (TBI) and is anatomically connected with other brain regions, including the striatum and hypothalamus, which are associated in part with motor function and the regulation of body temperature, respectively. We investigated whether a TBI extending to the striatum could affect peripheral and core temperatures as an indicator of autonomic thermoregulatory function. Moreover, it is unknown whether thermal modulation is accompanied by hypothalamic and cortical monoamine changes in rats with motor function recovery. The animals were allocated into three groups: the sham group (sham), a TBI group with a cortical contusion alone (TBI alone), and a TBI group with an injury extending to the dorsal striatum (TBI + striatal injury). Body temperature and motor deficits were evaluated for 20 days post-injury. On the 3rd and 20th days, rats were euthanized to measure the serotonin (5-HT), noradrenaline (NA), and dopamine (DA) levels using high-performance liquid chromatography (HPLC). We observed that TBI with an injury extending to the dorsal striatum increased core and peripheral temperatures. These changes were accompanied by a sustained motor deficit lasting for 14 days. Furthermore, there were notable increases in NA and 5-HT levels in the brain cortex and hypothalamus both 3 and 20 days after injury. In contrast, rats with TBI alone showed no changes in peripheral temperatures and achieved motor function recovery by the 7th day post-injury. In conclusion, our results suggest that TBI with an injury extending to the dorsal striatum elevates both core and peripheral temperatures, causing a delay in functional recovery and increasing hypothalamic monoamine levels. The aftereffects can be attributed to the injury site and changes to the autonomic thermoregulatory functions.

Effects of oxcarbazepine on monoamines content in hippocampus and head and body shakes and sleep patterns in kainic acid-treated rats.

The aim of this work was to analyze the effect of oxcarbazepine (OXC) on sleep patterns, "head and body shakes" and monoamine neurotransmitters level in a model of kainic-induced seizures. Adult Wistar rats were administered kainic acid (KA), OXC or OXC + KA. A polysomnographic study showed that KA induced animals to stay awake for the whole initial 10 h. OXC administration 30 min prior to KA diminished the effect of KA on the sleep parameters. As a measure of the effects of the drug treatments on behavior, head and body shakes were visually recorded for 4 h after administration of KA, OXC + KA or saline. The presence of OXC diminished the shakes frequency. 4 h after drug application, the hippocampus was dissected out, and the content of monoamines was analyzed. The presence of OXC still more increased serotonin, 5-hidroxyindole acetic acid, dopamine, and homovanilic acid, induced by KA.

Role of the Dopaminergic System in the Striatum and Its Association With Functional Recovery or Rehabilitation After Brain Injury.

Disabilities are estimated to occur in approximately 2% of survivors of traumatic brain injury (TBI) worldwide, and disability may persist even decades after brain injury. Facilitation or modulation of functional recovery is an important goal of rehabilitation in all patients who survive severe TBI. However, this recovery tends to vary among patients because it is affected by the biological and physical characteristics of the patients; the types, doses, and application regimens of the drugs used; and clinical indications. In clinical practice, diverse dopaminergic drugs with various dosing and application procedures are used for TBI. Previous studies have shown that dopamine (DA) neurotransmission is disrupted following moderate to severe TBI and have reported beneficial effects of drugs that affect the dopaminergic system. However, the mechanisms of action of dopaminergic drugs have not been completely clarified, partly because dopaminergic receptor activation can lead to restoration of the pathway of the corticobasal ganglia after injury in brain structures with high densities of these receptors. This review aims to provide an overview of the functionality of the dopaminergic system in the striatum and its roles in functional recovery or rehabilitation after TBI.

Graft survival of Pinus engelmannii Carr. in relation to two grafting techniques with dormant and sprouting buds.

Developing methods for successfully grafting forest species will be helpful for establishing asexual seed orchards and increasing the success of forest genetic improvement programs in Mexico. In this study we investigated the effects of two grafting techniques (side veneer and top cleft) and two phenological stages of the scion buds (end of latency and beginning of sprouting), in combination with other seven grafting variables, on the sprouting and survival of 120 intraspecific grafts of Pinus engelmannii Carr. The scions used for grafting were taken from a 5.5-year-old commercial forest plantation. The first grafting was performed on January 18 (buds at the end of dormancy) and the second on February 21 (buds at the beginning of sprouting). The data were examined by analysis of variance and a test of means and were fitted to two survival models (the Weibull's accelerated failure time and the Cox's proportional hazards model) and the respective hazard ratios were calculated. Survival was higher in the top cleft grafts made with buds at the end of latency, with 80% sprouting and an estimated average survival time of between 164 and 457 days after the end of the 6-month evaluation period. Four variables (grafting technique, phenological stage of the scion buds, scion diameter and rootstock height) significantly affected the risk of graft death in both survival models. Use of top cleft grafts with buds at the end of the latency stage, combined with scion diameters smaller than 11.4 mm and rootstock heights greater than 58.5 cm, was associated with a lower risk of death.

Catecholamine levels and gene expression of their receptors in tissues of adults with osteosarcoma.

AIM: The purpose of this work was to identify and measure catecholamines, their metabolites, and the gene expression of catecholamine receptors in osteosarcoma tissue. MATERIALS AND METHODS: The levels of 3,4-dihydroxyphenylacetic acid, norepinephrine, serotonin, and 5-hydroxyindoleacetic acid in cancer tissue and in adjacent and non-oncological bone tissue were analysed by high-performance liquid chromatography, and the gene expression of catecholamine receptors and of dopamine ß-hydroxylase, monoaminoxidase, ki67, and Runx2 in the osteosarcoma tissue, tissue adjacent to the tumour, non-oncological bone, and human brain tissue was analysed by RT-PCR. RESULTS: We found significantly higher levels of 3,4-dihydroxyphenylacetic acid and norepinephrine in the cancer sample than in adjacent and non-oncological bone. We found that ß-adrenergic receptors and dopaminergic receptors, dopamine ß-hydroxylase, ki67, Runx2, and serotonergic receptor gene expression were significantly higher in tumour tissue than in adjacent and non-oncological bone. CONCLUSION: Catecholamines and their receptors could be potential molecular markers for osteosarcoma progression.

Survival of side grafts with scions from pure species Pinus engelmannii Carr. and the P. engelmannii × P. arizonica Engelm. var. arizonica hybrid.

Grafting is one of the most widely used methods for vegetative propagation, particularly for multiplying trees considered important, but there has been little research done on the effect of hybridization on grafts from the genus Pinus. Sometimes hybrids show the ability to reproduce and adapt efficiently to the environment. However, they reduce the genetic gain of seed orchards. The objective in this research was to evaluate the effect of scion grafts from pure species donor Pinus engelmannii Carr. and from putative hybrid trees P. engelmannii × P. arizonica Engelm., grafted on rootstocks of pure species P. engelmannii, along with the effect of the position of the scion in the donor tree crown (upper third and middle third). The scions were collected from three trees of the pure species and three hybrids. In each tree, 20 scions were collected from each third of the crown evaluated. 120 side-veneer grafts were made at the beginning of spring (March) 2018. Variance analyses were performed to evaluate the treatments and adjustments of the Logit and Weibull models to obtain the probability of graft survival. Significant differences were found between the origins of scions (p < 0.0083, after Bonferroni correction), showing grafts with hybrid tree scions taking hold better. In addition, the probability of survival at 5 months after grafting with hybrid tree scions was greater (p < 0.0001) than in grafts with scions from trees of the pure species (Logit model), which coincides with the results of the Weibull model, which indicated that the probability of graft death with pure species donor tree scions is greater than for grafts with hybrid scions. There were no significant differences regarding the position of the scion in the donor tree crown.

Sleep in the completely locked-in state (CLIS) in amyotrophic lateral sclerosis.

Persons in the completely locked-in state (CLIS) suffering from amyotrophic lateral sclerosis (ALS) are deprived of many zeitgebers of the circadian rhythm: While cognitively intact, they are completely paralyzed, eyes mostly closed, with artificial ventilation and artificial nutrition, and social communication extremely restricted or absent. Polysomnographic recordings in eight patients in CLIS, however, revealed the presence of regular episodes of deep sleep during night time in all patients. It was also possible to distinguish an alpha-like state and a wake-like state. Classification of rapid eye movement (REM) sleep is difficult because of absent eye movements and absent muscular activity. Four out of eight patients did not show any sleep spindles. Those who have spindles also show K-complexes and thus regular phases of sleep stage 2. Thus, despite some irregularities, we found a surprisingly healthy sleep pattern in these patients.

GABAergic imbalance is normalized by dopamine D1 receptor activation in the striatum contralateral to the cortical injury in motor deficit-recovered rats.

RATIONALE: The sensorimotor cortex and the striatum are interconnected by the corticostriatal pathway, suggesting that cortical injury alters the striatal function, which may be modulated by dopamine. OBJECTIVES: We studied whether the activation of dopamine D1 receptors (D1Rs) modulates the γ-aminobutyric acid (GABA) and glutamate levels in the striatum of recovered rats at 192 h after cortical injury. METHODS: The D1R agonist SKF-38393 (0, 2, 3, or 4 mg/kg) was administered at 24, 48, 96, and 192 h post-injury, and then rats were decapitated to determine GABA and glutamate levels and the levels of D1R mRNA on both sides of the striatum. RESULTS: GABAergic imbalance in the striatum contralateral to the injury site was normalized by the administration of the D1R agonist, but this treatment did not produce a significant effect on glutamate levels, suggesting that glutamate was metabolized into GABA. The administration of SKF-38393 (2 mg/kg) decreased the levels of D1R mRNA in the striatum contralateral to the injury, and this effect was blocked by the coadministration of the D1R antagonist SCH-23390 (2 mg/kg). In the striatum ipsilateral to the injury, the D1R agonist increased the D1R mRNA levels, an effect that was blocked by SCH-23390. CONCLUSION: The reversal of the GABAergic imbalance in the striatum contralateral to the cortical injury can be modulated by extrastriatal D1R activation, and the D1R agonist-induced increases in the D1R mRNA levels in the striatum ipsilateral to the injury suggest that the striatum may be necessary to achieve functional recovery.

Chronic administration of the histamine H3 receptor agonist immepip decreases L-Dopa-induced dyskinesias in 6-hydroxydopamine-lesioned rats.

RATIONALE: Histamine H3 receptors (H3Rs) are co-expressed with dopamine D1 receptors (D1Rs) by striato-nigral medium spiny GABAergic neurons, where they functionally antagonize D1R-mediated responses. OBJECTIVES AND METHODS: We examined whether the chronic administration of the H3R agonist immepip modifies dyskinesias induced by L-3,4-dihydroxyphenylalanine, L-Dopa (LIDs), in rats lesioned with 6-hydroxydopamine in the substantia nigra pars compacta, and the effect of D1R and H3R co-activation on glutamate and GABA content in dialysates from the dorsal striatum of naïve rats. RESULTS: The systemic administration (i.p.) of L-Dopa for 14 days significantly increased axial, limb, and orolingual abnormal involuntary movements (AIMs) compared with the vehicle group. The chronic administration of the H3R agonist immepip alongside L-Dopa significantly decreased axial, limb, and orolingual AIMs compared with L-Dopa alone, but AIMs returned to previous values on immepip withdrawal. Chronic immepip was ineffective when administered prior to L-Dopa. The chronic administration of immepip significantly decreased GABA and glutamate content in striatal dialysates, whereas the administration of L-Dopa alone increased GABA and glutamate content. CONCLUSIONS: These results indicate that chronic H3R activation reduces LIDs, and the effects on striatal GABA and glutamate release provide evidence for a functional interaction between D1Rs and H3Rs.