RESUMO
Hypodopaminergia in the ventral striatum is a putative neurobiological correlate of withdrawal in opioid-dependent individuals. This perspective stands in contrast to brain imaging studies with chronic opioid users showing that naloxone-enhanced dopamine (DA) release in the dorsal striatum is positively correlated with withdrawal aversion. Here, we examined regional differences in striatal DA function associated with opioid withdrawal in rats exposed to intermittent morphine injections for 31 days. Basal concentrations of DA were reduced (i.e., indicating a hypodopaminergic state) in the ventral striatum on Day 10 of morphine exposure, whereas a more prolonged period of morphine treatment was required to reveal hypodopaminergia in the dorsal striatum on Day 31. The ventral striatum consistently exhibited naloxone-induced transient reductions in DA below the hypodopaminergic basal levels, whereas morphine enhanced DA efflux. In the dorsal striatum, DA responsivity to naloxone shifted from a significant decrease on Day 10 to a notable increase above hypodopaminergic basal levels on Day 31, corroborating the findings in the human dorsal striatum. Unexpectedly, the magnitude of morphine-evoked increases in DA efflux on Day 31 was significantly blunted relative to values on Day 10. These findings indicate that prolonged-intermittent access to morphine results in a sustained hypodopaminergic state as reflected in basal levels in the striatum, which is accompanied by regional differences in DA responsivity to naloxone and morphine. Overall, our findings suggest that prolonging the duration of morphine exposure to 31 days is sufficient to reveal neuroadaptations that may underlie the transition from initial drug exposure to opioid dependence.
Assuntos
Naloxona , Estriado Ventral , Humanos , Ratos , Animais , Naloxona/farmacologia , Morfina/farmacologia , Dopamina , Analgésicos Opioides/farmacologia , Corpo EstriadoRESUMO
Hippocampal hyperexcitability is a promising therapeutic target to prevent Aß deposition in AD since enhanced neuronal activity promotes presynaptic Aß production and release. This article highlights the potential application of perampanel (PER), an AMPA receptor (AMPAR) antagonist approved for partial seizures, as a therapeutic agent for AD. Using transgenic AD mice combined with in vivo brain microdialysis and primary neurons under oligomeric Aß-evoked neuronal hyperexcitability, the acute effects of PER on Aß metabolism were investigated. A single oral administration of PER rapidly decreased ISF Aß40 and Aß42 levels in the hippocampus of J20, APP transgenic mice, without affecting the Aß40 /Aß42 ratio; 5 mg/kg PER resulted in declines of 20% and 31%, respectively. Moreover, PER-treated J20 manifested a marked decrease in hippocampal APP ßCTF levels with increased FL-APP levels. Consistently, acute treatment of PER reduced sAPPß levels, a direct byproduct of ß-cleavage of APP, released to the medium in primary neuronal cultures under oligomeric Aß-induced neuronal hyperexcitability. To further evaluate the effect of PER on ISF Aß clearance, a γ-secretase inhibitor was administered to J20 1 h after PER treatment. PER did not influence the elimination of ISF Aß, indicating that the acute effect of PER is predominantly on Aß production. In conclusion, acute treatment of PER reduces Aß production by suppressing ß-cleavage of amyloid-ß precursor protein effectively, indicating a potential effect of PER against Aß pathology in AD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Camundongos , Animais , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Receptores de AMPA , Piridonas/farmacologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Camundongos Transgênicos , Secretases da Proteína Precursora do Amiloide/metabolismoRESUMO
Alcohol Use Disorder (AUD) is a relapsing brain disorder that involves perturbations of brain dopamine (DA) systems, and combined treatment with varenicline + bupropion produces additive effects on accumbal DA output and abolishes the alcohol deprivation effect (ADE) in rats. Also, direct and indirect glycine receptor (GlyR) agonists raise basal DA, attenuate alcohol-induced DA release in the nucleus Accumbens (nAc) and reduce alcohol consumption in rats. This study in rats examines whether the GlyT1-inhibitor Org 24598, an indirect GlyR agonist, enhances the ADE-reducing and DA elevating action of the combined administration of varenicline + bupropion in lower doses than previously applied. Effects on voluntary alcohol consumption, the ADE and extracellular levels of glycine and DA in nAc were examined following treatment with Org 24598 6 and 9 mg/kg i.p., bupropion 3.75 mg/kg i.p. and varenicline 1.5 mg/kg s.c., in monotherapy or combined, using a two-bottle, free-choice alcohol consumption paradigm with an ADE paradigm, and in vivo microdialysis in male Wistar rats. Notably, all treatment regimens appeared to abolish the ADE but only the effect produced by the triple combination (Org24598 + varenicline + bupropion) was significant compared to vehicle. Hence, addition of Org 24598 may enhance the ADE-reducing action of varenicline + bupropion and appears to allow for a dose reduction of bupropion. Treatment with Org 24598 raised accumbal glycine levels but did not significantly alter DA output in monotherapy. Varenicline + bupropion produced a substantial elevation in accumbal DA output that was slightly enhanced following addition of Org 24598. Conceivably, the blockade of the ADE is achieved by the triple combination enhancing accumbal DA transmission in complementary ways, thereby alleviating a hypothesized hypodopaminergia and negative reinforcement to drink. Ultimately, combining an indirect or direct GlyR agonist with varenicline + bupropion may constitute a new pharmacological treatment principle for AUD, although further refinement in dosing and evaluation of other glycinergic compounds are warranted.
Assuntos
Alcoolismo , Dopamina , Ratos , Masculino , Animais , Ratos Wistar , Vareniclina/farmacologia , Bupropiona/farmacologia , Glicina/farmacologia , Etanol , Receptores de GlicinaRESUMO
Nitric oxide (NO) is involved in the pathogenesis of cerebral ischemic injury. Here, we investigated the effects of aging on NO production during cerebral ischemia-reperfusion (IR). Male Wister rats (WRs) were assigned to 12-month-old (older; n = 5) and 3-month-old (younger; n = 7) groups. Similarly, male spontaneous hypertensive rats (SHRs) were allocated to 12-month-old (older; n = 6) and 3-month-old (younger; n = 8) groups. After anesthesia, their NO production was monitored using in vivo microdialysis probes inserted into the left striatum and hippocampus. Forebrain cerebral IR injuries were produced via ligation of the bilateral common carotid arteries, followed by reperfusion. The change in the NO3- of the older rats in the SHR groups in the striatum was less compared to that of the younger rats before ischemia, during ischemia, and after reperfusion (p < 0.05). In the hippocampus, the change in the NO3- of the older rats in the SHR groups was lower compared to that of the younger rats after reperfusion (p < 0.05). There were no significant differences between the two WR groups. Our findings suggested that aging in SHRs affected NO production, especially in the striatum, before and during cerebral ischemia, and after reperfusion. Hypertension and aging may be important factors impacting NO production in brain IR injury.
Assuntos
Lesões Encefálicas , Traumatismo por Reperfusão , Masculino , Ratos , Animais , Ratos Wistar , Óxido Nítrico , Microdiálise , Infarto Cerebral , Ratos Endogâmicos SHR , Reperfusão , Envelhecimento , ProsencéfaloRESUMO
Preclinical and clinical studies support a strong association between mutations in the GBA1 gene that encodes beta-glucocerebrosidase (GCase) (EC 3.2.1.45; glucosylceramidase beta) and Parkinson's disease (PD). Alpha-synuclein (AS), a key player in PD pathogenesis, and GBA1 mutations may independently and synergistically cause lysosomal dysfunction and thus, embody clinically well-validated targets of the neurodegenerative disease process in PD. However, in vivo models, recapitulating pathological features of PD that can be used to dissect the nature of the complex relationship between GCase and AS on the nigrostriatal axis, the region particularly vulnerable in PD, are direly needed. To address this, we implemented a bidirectional approach in mice to examine the effects of: 1) GCase overexpression (wild-type and mutant N370S GBA) on endogenous AS levels and 2) downregulation of endogenous GCase (Gba) combined with AS overexpression. Striatal delivery of viral-mediated GCase overexpression revealed minimal effects on cortical and nigrostriatal AS tissue levels and no significant effect on dopaminergic system integrity. On the other hand, microRNA (miR)-mediated Gba1 downregulation (miR Gba), combined with virus-mediated human AS overexpression (+AS), yields decreased GCase activity in the cortex, mimicking levels seen in GBA1 heterozygous carriers (30-40%), increased astrogliosis and microgliosis, decreased striatal dopamine levels (50% compared to controls) and loss of nigral dopaminergic neurons (~33%)- effects that were all reversible with miR rescue. Most importantly, the synergistic neurodegeneration of miR Gba + AS correlated with augmented AS accumulation and extracellular release in the striatum. Collectively, our results suggest that GCase downregulation alone is not sufficient to recapitulate key pathological features of PD in vivo, but its synergistic interplay with AS, via increased AS levels and extracellular release, drives nigrostriatal neurodegeneration. Furthermore, we report a novel double-hit GBA-AS model that can be used to identify putative mechanisms driving PD pathophysiology and can be subsequently used to test novel therapeutic approaches.
Assuntos
Glucosilceramidase/metabolismo , Doenças Neurodegenerativas/metabolismo , alfa-Sinucleína/metabolismo , Animais , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Regulação para Baixo , Glucosilceramidase/genética , Lisossomos/metabolismo , Camundongos , Mutação , Doenças Neurodegenerativas/patologia , alfa-Sinucleína/genéticaRESUMO
Interventions that elevate glycine levels and target the glycine receptor (GlyR) in the nucleus Accumbens (nAc) reduce ethanol intake in rats, supposedly by acting on the brain reward system via increased basal and attenuated ethanol-induced nAc dopamine release. Glycine transport across the blood brain barrier (BBB) appears inefficient, but glycine-containing dipeptides elevate whole brain tissue dopamine levels in mice. This study explores whether treatment with the glycine-containing dipeptides leucine-glycine (Leu-Gly) and glycine-leucine (Gly-Leu) by means of a hypothesized, facilitated BBB passage, alter nAc glycine and dopamine levels and locomotor activity in two rodent models. The acute effects of Leu-Gly and Gly-Leu (1-1000 mg/kg, i.p.) alone or Leu-Gly in combination with ethanol on locomotion in male NMRI mice were examined in locomotor activity boxes. Striatal and brainstem slices were obtained for ex vivo HPLC analyses of tissue levels of glycine and dopamine. Furthermore, the effects of Leu-Gly i.p. (1-1000 mg/kg) on glycine and dopamine output in the nAc were examined using in vivo microdialysis coupled to HPLC in freely moving male Wistar rats. Leu-Gly and Gly-Leu did not significantly alter locomotion, ethanol-induced hyperlocomotor activity or tissue levels of glycine or dopamine, apart from Gly-Leu 10 mg/kg that slightly raised nAc dopamine. Microdialysis revealed no significant alterations in nAc glycine or dopamine levels when regarding all rats as a homogenous group. In a subgroup of rats defined as dopamine responders, a significant elevation of nAc dopamine (20%) was seen following Leu-Gly 10-1000 mg/kg i.p, and this group of animals presented lower baseline dopamine levels compared to dopamine non-responders. To conclude, peripheral injection of glycine-containing dipeptides appears inefficient in elevating central glycine levels but raises accumbal dopamine levels in a subgroup of rats with a lower endogenous dopamine tone. The tentative relationship between dopamine baseline and ensuing response to glycinergic treatment and presumptive direct interactions between glycine-containing dipeptides and the GlyR bear insights for refinement of the glycinergic treatment concept for alcohol use disorder (AUD).
Assuntos
Dopamina , Glicina , Animais , Dipeptídeos , Etanol , Glicina/farmacologia , Leucina , Masculino , Camundongos , Microdiálise , Ratos , Ratos Wistar , Receptores de GlicinaRESUMO
Acamprosate (Campral® - calcium-bis[N-acetylhomotaurinate]) is one of few available pharmacotherapies for individuals suffering from alcohol use disorder. Previously, we suggested that acamprosate reduces ethanol intake by increasing dopamine in the nucleus accumbens (nAc), thereby partly substituting for alcohol's dopamine releasing effect. An experimental study suggested the calcium moiety of acamprosate to be the active component of the drug and to mediate the relapse preventing effect. The aim of the present study was to, by means of reversed in vivo microdialysis, elucidate if the dopamine elevating properties of acamprosate are mediated by N-acetylhomotaurine or by the calcium moiety. Male rats were equipped with a microdialysis probe in the nAc and received acute local treatment with regular acamprosate (CaAcamp 0.5 mM), calcium chloride (CaCl2 0.5 mM), sodium acamprosate (NaAcamp 0.5-1 mM), the glycine receptor (GlyR) antagonist strychnine (Stry 20 µM), or vehicle. In all experiments, extracellular levels of dopamine and taurine were examined. We found that local perfusion with both CaAcamp and CaCl2 increased dopamine levels in a GlyR-dependent manner. NaAcamp did not influence dopamine levels, but concomitant administration with CaCl2 resulted in an additive dopamine output compared to the drugs administrated alone. We also found CaAcamp and the combination of CaCl2 and NaAcamp to increase accumbal taurine levels, suggesting that CaAcamp may act indirectly on GlyRs via taurine release. The present results indicate that both N-acetylhomotaurine and the calcium moiety of acamprosate have dopamine elevating properties within the nAc and that, in this respect, these substances are beneficial in combination.
Assuntos
Dopamina , Núcleo Accumbens , Acamprosato/farmacologia , Animais , Cálcio , Cloreto de Cálcio/farmacologia , Masculino , Microdiálise , Ratos , Ratos Wistar , Receptores de Glicina , Sódio/farmacologia , Taurina/farmacologiaRESUMO
The brain is a critical target for the toxic action of organophosphorus (OP) inhibitors of acetylcholinesterase (AChE) such as the nerve agent sarin. However, the available oxime antidote 2-PAM only reactivates OP-inhibited AChE in peripheral tissues. Monoisonitrosoacetone (MINA), a tertiary oxime, reportedly reactivates AChE in the central nervous system (CNS). The current study investigated whether MINA would be beneficial as a supplemental oxime treatment in preventing lethality and reducing morbidity following lethal sarin exposure, MINA supplement would improve AChE recovery in the body, and MINA would be detectable in the CNS. Guinea pigs were exposed to sarin and treated with atropine sulfate and 2-PAM at one minute. Additional 2-PAM or MINA was administered at 3, 5, 15, or 30 min after sarin exposure. Survival and morbidity were assessed at 2 and 24 h. AChE activity in brain and peripheral tissues was evaluated one hour after MINA and 2-PAM treatment. An in vivo microdialysis technique was used to determine partitioning of MINA into the brain. A liquid chromatography-tandem mass spectrometry method was developed for the analysis of MINA in microdialysates. MINA-treated animals exhibited significantly higher survival and lower morbidity compared to 2-PAM-treated animals. 2-PAM was significantly more effective in reactivating AChE in peripheral tissues, but only MINA reactivated AChE in the CNS. MINA was found in guinea pig brain microdialysate samples beginning at ~10 min after administration in a dose-related manner. The data strongly suggest that a centrally penetrating oxime could provide significant benefit as an adjunct to atropine and 2-PAM therapy for OP intoxication.
Assuntos
Acetilcolinesterase/metabolismo , Antídotos/farmacologia , Encéfalo/efeitos dos fármacos , Reativadores da Colinesterase/farmacologia , Intoxicação por Organofosfatos/prevenção & controle , Oximas/farmacologia , Sarina , Animais , Antídotos/metabolismo , Encéfalo/enzimologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ativação Enzimática , Cobaias , Masculino , Microdiálise , Intoxicação por Organofosfatos/enzimologia , Oximas/metabolismo , Permeabilidade , Compostos de Pralidoxima/metabolismo , Compostos de Pralidoxima/farmacologia , Distribuição TecidualRESUMO
Approved medications for alcohol use disorder (AUD) display modest effect sizes. Pharmacotherapy aimed at the mechanism(s) by which ethanol activates the dopamine reward pathway may offer improved outcomes. Basal and ethanol-induced accumbal dopamine release in the rat involve glycine receptors (GlyR) in the nucleus accumbens (nAc). Glycine transporter 1 (GlyT-1) inhibitors, which raise extracellular glycine levels, have repeatedly been shown to decrease ethanol intake in the rat. To further explore the rational for elevating glycine levels in the treatment of AUD, this study examined accumbal extracellular glycine and dopamine levels and voluntary ethanol intake and preference in the rat, after systemic treatment with glycine. The effects of three different doses of glycine i.p. on accumbal glycine and dopamine levels were examined using in vivo microdialysis in Wistar rats. In addition, the effects of the intermediate dose of glycine on voluntary ethanol intake and preference were examined in a limited access two-bottle ethanol/water model in the rat. Systemic glycine treatment increased accumbal glycine levels in a dose-related manner, whereas accumbal dopamine levels were elevated in a subpopulation of animals, defined as dopamine responders. Ethanol intake and preference decreased after systemic glycine treatment. These results give further support to the concept of elevating central glycine levels to reduce ethanol intake and indicate that targeting the glycinergic system may represent a pharmacologic treatment principle for AUD.
Assuntos
Dopamina , Glicina , Animais , Etanol , Masculino , Microdiálise , Núcleo Accumbens , Ratos , Ratos WistarRESUMO
Alcohol use disorder is a chronic, relapsing brain disorder causing substantial morbidity and mortality. Cholinergic interneurons (CIN) within the nucleus accumbens (nAc) have been suggested to exert a regulatory impact on dopamine (DA) neurotransmission locally, and defects in CIN have been implied in several psychiatric disorders. The aim of this study was to investigate the role of CIN in regulation of basal extracellular levels of DA and in modulation of nAc DA release following ethanol administration locally within the nAc of male Wistar rats. Using reversed in vivo microdialysis, the acetylcholinesterase inhibitor physostigmine was administered locally in the nAc followed by addition of either the muscarinic acetylcholine (ACh) receptor antagonist scopolamine or the nicotinic ACh receptor antagonist mecamylamine. Further, ethanol was locally perfused in the nAc following pretreatment with scopolamine and/or mecamylamine. Lastly, ethanol was administered locally into the nAc of animals with accumbal CIN-ablation induced by anticholine acetyl transferase-saporin. Physostigmine increased accumbal DA levels via activation of muscarinic ACh receptors. Neither scopolamine and/or mecamylamine nor CIN-ablation altered basal DA levels, suggesting that extracellular DA levels are not tonically controlled by ACh in the nAc. In contrast, ethanol-induced DA elevation was prevented following coadministration of scopolamine and mecamylamine and blunted in CIN-ablated animals, suggesting involvement of CIN-ACh in ethanol-mediated DA signaling. The data presented in this study suggest that basal extracellular levels of DA within the nAc are not sustained by ACh, whereas accumbal CIN-ACh is involved in mediating ethanol-induced DA release.
Assuntos
Acetilcolina/farmacologia , Dopamina/metabolismo , Etanol/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Antagonistas Colinérgicos/farmacologia , Masculino , Mecamilamina/farmacologia , Microdiálise , Antagonistas Nicotínicos/farmacologia , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar , Escopolamina/farmacologia , Área Tegmentar Ventral/metabolismoRESUMO
Selective antagonists of thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2), in order to enable a better understanding of this peptide's central functions, have not been identified. Using pGlu-Glu-Pro-NH2 ([Glu2]TRH) as a lead peptide and with modification at its central residue, our studies focused on some of its analogues synthesized as potential functional antagonists of TRH in the rodent brain. Among the peptides studied, the novel isomeric analogue [ß-Glu2]TRH was found to suppress the analeptic and antidepressant-like pharmacological activities of TRH without eliciting intrinsic effects in these paradigms. [ß-Glu2]TRH also completely reversed TRH's stimulation of acetylcholine turnover in the rat hippocampus without a cholinergic activity of its own, which was demonstrated through in vivo microdialysis experiments. Altogether, [ß-Glu2]TRH emerged as the first selective functional antagonist of TRH's prominent cholinergic actions, by which this endogenous peptide elicits a vast array of central effects.
Assuntos
Antidepressivos , Estimulantes do Sistema Nervoso Central , Hipocampo/metabolismo , Peptídeos , Hormônio Liberador de Tireotropina/antagonistas & inibidores , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/farmacologia , Hipocampo/patologia , Masculino , Camundongos , Peptídeos/química , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Hormônio Liberador de Tireotropina/metabolismoRESUMO
Identifying similarities and differences in the brain metabolome during different states of consciousness has broad relevance for neuroscience and state-dependent autonomic function. This study focused on the prefrontal cortex (PFC) as a brain region known to modulate states of consciousness. Anesthesia was used as a tool to eliminate wakefulness. Untargeted metabolomic analyses were performed on microdialysis samples obtained from mouse PFC during wakefulness and during isoflurane anesthesia. Analyses detected 2,153 molecules, 91 of which could be identified. Analytes were grouped as detected during both wakefulness and anesthesia (n = 61) and as unique to wakefulness (n = 23) or anesthesia (n = 7). Data were analyzed using univariate and multivariate approaches. Relative to wakefulness, during anesthesia there was a significant (q < 0.0001) fourfold change in 21 metabolites. During anesthesia 11 of these 21 molecules decreased and 10 increased. The Kyoto Encyclopedia of Genes and Genomes database was used to relate behavioral state-specific changes in the metabolome to metabolic pathways. Relative to wakefulness, most of the amino acids and analogs measured were significantly decreased during isoflurane anesthesia. Nucleosides and analogs were significantly increased during anesthesia. Molecules associated with carbohydrate metabolism, maintenance of lipid membranes, and normal cell functions were significantly decreased during anesthesia. Significant state-specific changes were also discovered among molecules comprising lipids and fatty acids, monosaccharides, and organic acids. Considered together, these molecules regulate point-to-point transmission, volume conduction, and cellular metabolism. The results identify a novel ensemble of candidate molecules in PFC as putative modulators of wakefulness and the loss of wakefulness.NEW & NOTEWORTHY The loss of wakefulness caused by a single concentration of isoflurane significantly altered levels of interrelated metabolites in the prefrontal cortex. The results support the interpretation that states of consciousness reflect dynamic interactions among cortical neuronal networks involving a humbling number of molecules that comprise the brain metabolome.
Assuntos
Anestesia , Anestésicos Inalatórios/farmacologia , Estado de Consciência/efeitos dos fármacos , Isoflurano/farmacologia , Metaboloma/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Vigília/efeitos dos fármacos , Anestésicos Inalatórios/administração & dosagem , Animais , Cromatografia Líquida , Isoflurano/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microdiálise , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Espectrometria de Massas em TandemRESUMO
Background: Surgical decompression after acute spinal cord injury has become the consensus of orthopaedic surgeons. However, the choice of surgical decompression time window after acute spinal cord injury has been one of the most controversial topics in orthopaedics. Objective: We apply an online electrochemical system (OECS) for continuously monitoring the ascorbate of the rats' spinal cord to determine the extent to which ascorbate levels were influenced by contusion or sustained compression. Methods: Adult Sprague-Dawley rats (n=10) were instrumented for ascorbate concentration recording and received T11 drop spinal cord injury (SCI). The Group A (n=5) were treated with immediately decompression after SCI. The Group B (n=5) were contused and oppressed until 1 h after the injury to decompress. Results: The ascorbate level of spinal cord increased immediately by contusion injury and reached to 1.62 µmol/L ± 0.61 µmol/L (217.30% ± 95.09% of the basal level) at the time point of 60 min after the injury. Compared with the Group A, the ascorbate level in Group B increased more significantly at 1 h after the injury, reaching to 3.76 µmol/L ± 1.75 µmol/L (430.25% ± 101.30% of the basal level). Meanwhile, we also found that the decompression after 1 hour of continuous compression will cause delayed peaks of ascorbate reaching to 5.71 µmol/L ± 2.69 µmol/L (627.73% ± 188.11% of the basal level). Conclusion: Our study provides first-hand direct experimental evidence indicating ascorbate is directly involved in secondary spinal cord injury and exhibits the dynamic time course of microenvironment changes after continuous compression injury of the spinal cord.
Assuntos
Ácido Ascórbico/análise , Medula Espinal/metabolismo , Animais , Modelos Animais de Doenças , Eletroquímica/métodos , Masculino , Microdiálise , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/metabolismo , Ferimentos e Lesões/metabolismoRESUMO
Excessive alcohol use causes considerable morbidity and mortality worldwide. Changes in the mesolimbic dopamine system have been postulated as a neurobiological underpinning of excessive alcohol consumption, and recent research also suggests that the amino acid taurine plays a central role in ethanol-induced dopamine elevation. The aim of this study was to further outline the role of dopamine and taurine in regulating alcohol consumption. In this study, a choice between ethanol (20%) and water was administered to Wistar rats in an intermittent manner (three times/week) for seven consecutive weeks. In vivo microdialysis was used to explore baseline levels as well as ethanol-induced increases of extracellular dopamine and taurine, in the nucleus accumbens (nAc) of Wistar rats voluntarily consuming large or small amounts of ethanol. Basal levels of taurine were also measured in cerebrospinal fluid (CSF) and serum in a subset of rats. Ethanol-induced increases in nAc dopamine and taurine did not differ between alcohol-consuming and naïve rats. However, when categorized based on ethanol intake, rats consuming larger amounts of ethanol exhibited a lower dopamine tone in the nucleus accumbens and responded to ethanol with a slower elevation of extracellular taurine levels, as compared with low-consuming animals. Basal levels of taurine in nAc, CSF, or serum did not differ between ethanol high- and low-consuming rats. Our data support previous studies claiming an association between low endogenous dopamine levels and excessive alcohol intake.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Depressores do Sistema Nervoso Central/administração & dosagem , Dopamina/metabolismo , Etanol/administração & dosagem , Núcleo Accumbens/metabolismo , Taurina/metabolismo , Animais , Comportamento Animal , Líquido Cefalorraquidiano/química , Microdiálise , Ratos , Ratos Wistar , AutoadministraçãoRESUMO
Alcohol use disorder (AUD) is detrimental to health and causes preterm death. Unfortunately, available pharmacological and nonpharmacological treatments have small effect sizes, and improved treatments are needed. Smoking and AUD share heritability and are pharmacologically associated, since drug-induced dopamine (DA) output in nucleus accumbens (nAc) involves nicotinic acetylcholine receptors (nAChRs) in both cases. Smoking therapy agents, such as the partial nAChR agonist varenicline or the DA/noradrenaline transporter inhibitor bupropion, could potentially also be used for AUD. To investigate this hypothesis, the effects of varenicline, bupropion, or a combination of the two on nAc DA levels, ethanol intake, and the alcohol deprivation effect (ADE) were examined. In vivo microdialysis showed that varenicline (1.5 mg/kg) and bupropion (2.5, 5, or 10 mg/kg) elevated nAc DA levels and that the combination produced additive effects. Five days treatment with varenicline, bupropion, or the combination did not suppress ethanol consumption, as compared with vehicle-treated control. However, combined administration of varenicline and bupropion completely blocked the ADE when readministering ethanol following 14 days of abstinence. Since ADE is considered highly predictive for the clinical outcome in man, our data suggest that the combination of varenicline and bupropion could be a promising treatment for AUD.
Assuntos
Transtornos Relacionados ao Uso de Álcool/prevenção & controle , Bupropiona/farmacologia , Dopamina/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Agentes de Cessação do Hábito de Fumar/farmacologia , Vareniclina/farmacologia , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Masculino , Ratos , Ratos WistarRESUMO
The functionally selective 5-HT2C receptor ligand SB242084 can increase motivation and have rapid onset anti-depressant-like effects. We sought to identify the specific behavioral effects of SB242084 treatment and elucidate the mechanism in female and male mice. Using a quantitative behavioral approach, we determined that SB242084 increases the vigor and persistence of goal-directed activity across different types of physical work, particularly when work requirements are demanding. We found this influence of SB242084 on effort, rather than reward to be reflected in striatal DA measured during behavior. Using in vivo fast scan cyclic voltammetry, we found that SB242084 has no effect on reward-related phasic DA release in the NAc. Using in vivo microdialysis to measure tonic changes in extracellular DA, we also found no changes in the NAc. In contrast, SB242084 treatment increases extracellular DA in the dorsomedial striatum, an area that plays a key role in response vigor. These findings have several implications. At the behavioral level, this work shows that the capacity to work in demanding situations can be increased, without a generalized increase in motor activity or reward value. At the circuit level, we identified a pathway restricted potentiation of DA release and showed that this was the reason for the increased response vigor. At the cellular level, we show that a specific serotonin receptor cross talks to the DA system. Together, this information provides promise for the development of treatments for apathy, a serious clinical condition that can afflict patients with psychiatric and neurological disorders.SIGNIFICANCE STATEMENT Motivated behaviors are modulated by reward value, effort demands, and cost-benefit computations. This information drives the decision to act, which action to select, and the intensity with which the selected action is performed. Because these behavioral processes are all regulated by DA signaling, it is very difficult to influence selected aspects of motivated behavior without affecting others. Here we identify a pharmacological treatment that increases the vigor and persistence of responding in mice, without increasing generalized activity or changing reactions to rewards. We show that the 5-HT2C-selective ligand boosts motivation by potentiating activity-dependent DA release in the dorsomedial striatum. These results reveal a novel strategy for treating patients with motivational deficits, avolition, or apathy.
Assuntos
Aminopiridinas/farmacologia , Encéfalo/efeitos dos fármacos , Dopamina/metabolismo , Indóis/farmacologia , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Receptor 5-HT2C de Serotonina/metabolismo , Animais , Apatia/efeitos dos fármacos , Apatia/fisiologia , Encéfalo/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Motivação/efeitos dos fármacos , Motivação/fisiologia , Recompensa , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
The faster drugs of abuse reach the brain, the greater is the risk of addiction. Even small differences in the rate of drug delivery can influence outcome. Infusing cocaine intravenously over 5 vs. 90-100 s promotes sensitization to the psychomotor and incentive motivational effects of the drug and preferentially recruits mesocorticolimbic regions. It remains unclear whether these effects are due to differences in how fast and/or how much drug reaches the brain. Here, we predicted that varying the rate of intravenous cocaine infusion between 5 and 90 s produces different rates of rise of brain drug concentrations, while producing similar peak concentrations. Freely moving male Wistar rats received acute intravenous cocaine infusions (2.0 mg/kg/infusion) over 5, 45 and 90 s. We measured cocaine concentrations in the dorsal striatum using rapid-sampling microdialysis (1 sample/min) and high-performance liquid chromatography-tandem mass spectrometry. We also measured extracellular concentrations of dopamine and other neurochemicals. Regardless of infusion rate, acute cocaine did not change concentrations of non-dopaminergic neurochemicals. Infusion rate did not significantly influence peak concentrations of cocaine or dopamine, but concentrations increased faster following 5-s infusions. We also assessed psychomotor activity as a function of cocaine infusion rate. Infusion rate did not significantly influence total locomotion, but locomotion increased earlier following 5-s infusions. Thus, small differences in the rate of cocaine delivery influence both the rate of rise of drug and dopamine concentrations, and psychomotor activity. A faster rate of rise of drug and dopamine concentrations might be an important issue in making rapidly delivered cocaine more addictive.
Assuntos
Cocaína/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/farmacologia , Atividade Motora/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Administração Intravaginal , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Cocaína/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Inibidores da Captação de Dopamina/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Ratos WistarRESUMO
Gulf War Illness (GWI) is characterized by a constellation of symptoms that includes cognitive dysfunction. While the causes for GWI remain unknown, prophylactic use of the acetylcholinesterase inhibitor pyridostigmine bromide (PB) in combination with the stress of deployment has been proposed to be among the causes of the cognitive dysfunction in GWI. Mechanistically, clinical studies suggest that altered immune function may be an underlying factor in the neurochemical and neurobehavioral complications of GWI. Accordingly, the goal of this study was to determine how responses to an immune challenge (lipopolysaccharide; LPS) or stress impacts inflammation, acetylcholine (ACh) neurochemistry and behavior in an experimental model of GWI. Rats with a history of PB treatment exhibited potentiated increases in C-reactive protein levels in response to a submaximal LPS challenge compared to control rats, indicating that prior treatment with this cholinesterase inhibitor leads to exacerbated inflammatory responses to a subsequent immune challenge. ACh responses to LPS administration were decreased in the hippocampus, but not prefrontal cortex (PFC), in rats with a prior history of PB treatment or stress exposure. Additionally, ACh release in response to acute immobilization stress was attenuated in the PFC and hippocampus in these groups. These attenuated cholinergic responses were accompanied by impairments in contextual and cue-based fear learning. The results of this study suggest that stress and LPS challenges adversely affect central ACh neurochemistry in a rodent model of GWI and support the hypothesis that dysregulated immune responses are mechanistically linked to the neurological complications of GWI.
Assuntos
Acetilcolina/imunologia , Inibidores da Colinesterase/administração & dosagem , Inflamação/imunologia , Síndrome do Golfo Pérsico/imunologia , Brometo de Piridostigmina/administração & dosagem , Estresse Psicológico/imunologia , Animais , Comportamento Animal/efeitos dos fármacos , Proteína C-Reativa/imunologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Modelos Animais de Doenças , Medo/efeitos dos fármacos , Medo/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Inflamação/induzido quimicamente , Inflamação/complicações , Lipopolissacarídeos/administração & dosagem , Masculino , Síndrome do Golfo Pérsico/complicações , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/imunologia , Ratos Sprague-Dawley , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/complicaçõesRESUMO
Various small molecules act as neurotransmitters and orchestrate neural communication. Growing evidence suggests that not only classical neurotransmitters but also several small molecules, including amino acid derivatives, modulate synaptic transmission. As conditions of acute and chronic pain alter neuronal excitability in the nucleus accumbens, we hypothesized that small molecules released in the nucleus accumbens might play important roles in modulating the pain sensation. However, it is not easy to identify possible pain modulators owing to the absence of a method for comprehensively measuring extracellular small molecules in the brain. In this study, through the use of an emerging metabolomics technique, namely ion chromatography coupled with high-resolution mass spectrometry, we simultaneously analyzed the dynamics of more than 60 small molecules in brain fluids collected by microdialysis, under both the application of pain stimuli and the administration of analgesics. We identified N-acetylaspartylglutamate as a potential pain modulator that is endogenously released in the nucleus accumbens. Infusion of N-acetylaspartylglutamate into the nucleus accumbens significantly attenuated the pain induced by the activation of sensory nerves through optical stimulation. These findings suggest that N-acetylaspartylglutamate released in the nucleus accumbens could modulate pain sensation.
Assuntos
Dipeptídeos/metabolismo , Espaço Extracelular/metabolismo , Espectrometria de Massas , Microdiálise , Núcleo Accumbens/metabolismo , Dor/metabolismo , Sensação , Analgesia , Animais , Comportamento Animal , Líquidos Corporais/metabolismo , Channelrhodopsins/metabolismo , Dopamina/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Optogenética , Dor/patologia , Limiar da Dor , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologia , Bibliotecas de Moléculas Pequenas/metabolismoRESUMO
In neuronal plasma membrane, two syntaxin isoforms, HPC-1/syntaxin 1A (STX1A) and syntaxin 1B (STX1B), are predominantly expressed as soluble N-ethylmaleimide-sensitive fusion attachment protein receptors, also known as t-SNAREs. We previously reported that glutamatergic and GABAergic synaptic transmissions are impaired in Stx1b null mutant (Stx1b-/- ) mice but are almost normal in Stx1a null mutant (Stx1a-/- ) mice. These observations suggested that STX1A and STX1B have distinct functions in fast synaptic transmission in the central nervous system (CNS). Interestingly, recent studies indicated that Stx1a-/- or Stx1a+/- mice exhibit disruption in the monoaminergic system in the CNS, causing unusual behaviour that is similar to neuropsychological alterations observed in psychiatric patients. Here, we studied whether STX1B contributes to the regulation of monoaminergic system and if STX1B is related to neuropsychological properties in human neuropsychological disorders similar to STX1A. We found that monoamine release in vitro was normal in Stx1b+/- mice unlike Stx1a-/- or Stx1a+/- mice, but the basal extracellular dopamine (DA) concentration in the ventral striatum was increased. DA secretion in the ventral striatum is regulated by GABAergic neurons, and Stx1b+/- mice exhibited reduced GABA release both in vitro and in vivo, disrupting the DAergic system in the CNS of these mice. We also found that Stx1b+/- mice exhibited reduced pre-pulse inhibition (PPI), which is believed to represent one of the prominent schizotypal behavioural profiles of human psychiatric patients. The reduction in PPI was rescued by DA receptor antagonists. These observations indicated that STX1B contributes to excess activity of the DAergic system through regulation of GABAergic transmission.