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1.
J Neural Transm (Vienna) ; 131(1): 83-94, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37500938

RESUMO

Epidemiological studies and clinical observations suggest that nicotine, a major contributor of the global burden of disease, acts in a partially sex specific manner. Still, preclinical research has primarily been conducted in males. More research is thus required to define the effects displayed by nicotine on the female brain. To this end, female rats received 15 injections of either nicotine (0.36mg/kg) or saline, over a 3-week period and were then followed for up to 3 months. Behavioral effects of nicotine were assessed using locomotor activity measurements and elevated plus maze, while neurophysiological changes were monitored using ex vivo electrophysiological field potential recordings conducted in subregions of the dorsal and ventral striatum. Behavioral assessments demonstrated a robust sensitization to the locomotor stimulatory properties of nicotine, but monitored behaviors on the elevated plus maze were not affected during acute (24 h) or protracted (3 months) withdrawal. Electrophysiological recordings revealed a selective increase in excitatory neurotransmission in the nucleus accumbens shell and dorsomedial striatum during acute withdrawal. Importantly, accumbal neuroadaptations in nicotine-treated rats correlated with locomotor behavior, supporting a role for the nucleus accumbens in behavioral sensitization. While no sustained neuroadaptations were observed following 3 months withdrawal, there was an overall trend towards reduced inhibitory tone. Together, these findings suggest that nicotine produces selective transformations of striatal brain circuits that may drive specific behaviors associated with nicotine exposure. Furthermore, our observations suggest that sex-specificity should be considered when evaluating long-term effects by nicotine on the brain.


Assuntos
Corpo Estriado , Nicotina , Masculino , Ratos , Feminino , Animais , Nicotina/farmacologia , Ratos Wistar , Neostriado , Transmissão Sináptica/fisiologia
2.
J Neural Transm (Vienna) ; 131(1): 95-106, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37773223

RESUMO

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 Glicina
3.
Int J Mol Sci ; 25(1)2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38203752

RESUMO

Astrocytes are pivotal for synaptic transmission and may also play a role in the induction and expression of synaptic plasticity, including endocannabinoid-mediated long-term depression (eCB-LTD). In the dorsolateral striatum (DLS), eCB signaling plays a major role in balancing excitation and inhibition and promoting habitual learning. The aim of this study was to outline the role of astrocytes in regulating eCB signaling in the DLS. To this end, we employed electrophysiological slice recordings combined with metabolic, chemogenetic and pharmacological approaches in an attempt to selectively suppress astrocyte function. High-frequency stimulation induced eCB-mediated LTD (HFS-LTD) in brain slices from both male and female rats. The metabolic uncoupler fluorocitrate (FC) reduced the probability of transmitter release and depressed synaptic output in a manner that was independent on cannabinoid 1 receptor (CB1R) activation. Fluorocitrate did not affect the LTD induced by the CB1R agonist WIN55,212-2, but enhanced CB1R-dependent HFS-LTD. Reduced neurotransmission and facilitated HFS-LTD were also observed during chemogenetic manipulation using Gi-coupled DREADDs targeting glial fibrillary acidic protein (GFAP)-expressing cells, during the pharmacological inhibition of connexins using carbenoxolone disodium, or during astrocytic glutamate uptake using TFB-TBOA. While pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid (APV) failed to prevent synaptic depression induced by FC, it blocked the facilitation of HFS-LTD. While the lack of tools to disentangle astrocytes from neurons is a major limitation of this study, our data collectively support a role for astrocytes in modulating basal neurotransmission and eCB-mediated synaptic plasticity.


Assuntos
Astrócitos , Citratos , Endocanabinoides , Feminino , Masculino , Animais , Ratos , Endocanabinoides/farmacologia , Corpo Estriado , Neostriado
4.
Addict Biol ; 28(12): e13349, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-38017639

RESUMO

Alcohol use disorder is one of the major psychiatric disorders worldwide, and there are many factors and effects contributing to the disorder, for example, the experience of ethanol reward. The rewarding and reinforcing properties of ethanol have been linked to activation of the mesolimbic dopamine system, an effect that appears to involve glycine receptors (GlyRs) in the nucleus accumbens. On which neuronal subtypes these receptors are located is, however, not known. The aim of this study was to explore the role of GlyRs on cholinergic interneurons (CIN) in sustaining extracellular dopamine levels and in ethanol-induced dopamine release. To this end, CIN were ablated by anti-choline acetyltransferase-saporin administered locally in the nucleus accumbens of male Wistar rats. Changes in dopamine levels induced by ablation, ethanol and/or a GlyR antagonist were monitored using in vivo microdialysis. The GlyRs antagonist strychnine depressed extracellular dopamine in a similar manner independent on local ablation, suggesting that GlyRs on CIN are not important for sustaining the extracellular dopamine tone. However, a low concentration of strychnine hampered ethanol-induced dopamine release in sham-treated animals, whilst no reduction was seen in ablated animals, suggesting that GlyRs located on CIN are involved in ethanol-induced dopamine release. Further, in ablated rats, ethanol-induced increases of the extracellular levels of the GlyR agonists glycine and taurine were attenuated. In conclusion, this study suggests that CIN are not important for GlyR-mediated regulation of basal dopamine output, but that CIN ablation blunts the ethanol-induced dopamine release, putatively by reducing the release of GlyR agonists.


Assuntos
Receptores de Glicina , Estricnina , Humanos , Ratos , Masculino , Animais , Receptores de Glicina/metabolismo , Ratos Wistar , Estricnina/farmacologia , Etanol/farmacologia , Núcleo Accumbens , Dopamina , Interneurônios/metabolismo , Colinérgicos/farmacologia , Microdiálise
5.
J Neural Transm (Vienna) ; 129(4): 395-407, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35322277

RESUMO

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 Glicina
6.
Addict Biol ; 27(5): e13224, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36001425

RESUMO

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/farmacologia
7.
J Neural Transm (Vienna) ; 128(1): 83-94, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33351169

RESUMO

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 Wistar
8.
Addict Biol ; 26(3): e12959, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32789970

RESUMO

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/metabolismo
9.
Addict Biol ; 25(5): e12807, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31293045

RESUMO

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 Wistar
10.
Addict Biol ; 25(3): e12761, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31099157

RESUMO

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 , Autoadministração
11.
Addict Biol ; 25(3): e12757, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-30969011

RESUMO

Nicotine is recognized as one of the most addictive drugs, which in part could be attributed to progressive neuroadaptations and rewiring of dorsal striatal circuits. Since motor-skill learning produces neuroplasticity in the same circuits, we postulate that rotarod training could be sufficient to block nicotine-induced rewiring and thereby prevent long-lasting impairments of neuronal functioning. To test this hypothesis, Wistar rats were subjected to 15 days of treatment with either nicotine (0.36 mg/kg) or vehicle. After treatment, a subset of animals was trained on the rotarod. Ex vivo electrophysiology was performed 1 week after the nicotine treatment period and after up to 3 months of withdrawal to define neurophysiological transformations in circuits of the striatum and amygdala. Our data demonstrate that nicotine alters striatal neurotransmission in a distinct temporal and spatial sequence, where acute transformations are initiated in dorsomedial striatum (DMS) and nucleus accumbens (nAc) core. Following 3 months of withdrawal, synaptic plasticity in the form of endocannabinoid-mediated long-term depression (eCB-LTD) is impaired in the dorsolateral striatum (DLS), and neurotransmission is altered in DLS, nAc shell, and the central nucleus of the amygdala (CeA). Training on the rotarod, performed after nicotine treatment, blocks neurophysiological transformations in striatal subregions, and prevents nicotine-induced impairment of eCB-LTD. These datasets suggest that nicotine-induced rewiring of striatal circuits can be extinguished by other behaviors that induce neuroplasticity. It remains to be determined if motor-skill training could be used to prevent escalating patterns of drug use in experienced users or facilitate the recovery from addiction.


Assuntos
Aprendizagem/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Destreza Motora , Neostriado/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Animais , Corpo Estriado/efeitos dos fármacos , Endocanabinoides , Masculino , Neostriado/metabolismo , Neurônios/metabolismo , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Teste de Desempenho do Rota-Rod , Transmissão Sináptica/efeitos dos fármacos
12.
Alcohol Clin Exp Res ; 43(5): 803-811, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30860600

RESUMO

BACKGROUND: Addiction has been conceptualized as a shift from controlled recreational use toward compulsive and habitual drug-taking behavior. Although the brain reward system is vital for alcohol reward and reinforcement, other neuronal circuits may be involved in controlling long-term alcohol-seeking and drug-taking behaviors. The aim of this study was to outline alcohol-induced neuroplasticity in defined cortical and striatal subregions, previously implicated in alcohol use disorder. METHODS: Male Wistar rats were allowed to voluntarily consume ethanol (EtOH) in an intermittent manner for 2 months, after which ex vivo electrophysiological recordings were performed and data compared with isolated water controls housed in parallel. RESULTS: Field potential recordings revealed an increase in field excitatory postsynaptic potentials (fEPSPs) in the dorsomedial striatum (DMS) of rats consuming EtOH, while a depression of evoked potentials was detected in the dorsolateral striatum (DLS). Mean activity in cortical (medial prefrontal cortex, lateral orbitofrontal cortex [OFC]), and accumbal regions (nucleus accumbens [nAc] core/shell) was not significantly altered as compared to water-drinking controls, but a correlation between the amount of alcohol consumed and evoked potentials could be found in both dorsal striatal subregions, OFC, and nAc core. Removal of EtOH for 1 to 2 days was sufficient to restore neurotransmission in the DLS, while the increase in fEPSP amplitude sustained in the DMS. CONCLUSIONS: These preclinical findings are in line with clinical observations indicating that alcohol produces neurophysiological transformations in dorsal striatal circuits, which in turn may lead to disruptions in decision-making processes that could further promote alcohol misuse.


Assuntos
Adaptação Fisiológica/fisiologia , Consumo de Bebidas Alcoólicas/fisiopatologia , Corpo Estriado/fisiologia , Etanol/administração & dosagem , Córtex Pré-Frontal/fisiologia , Adaptação Fisiológica/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/tendências , Animais , Corpo Estriado/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Masculino , Técnicas de Cultura de Órgãos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar , Autoadministração
13.
Addict Biol ; 24(3): 355-363, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29292565

RESUMO

The endocannabinoid (eCB) system modulates several phenomena related to addictive behaviors, and drug-induced changes in eCB signaling have been postulated to be important mediators of physiological and pathological reward-related synaptic plasticity. Here, we studied eCB-mediated long-term depression (eCB-LTD) in the dorsolateral striatum, a brain region critical for acquisition of habitual and automatic behavior. We report that nicotine differentially affects ex vivo eCB signaling depending on previous exposure in vivo. In the nicotine-naïve brain, nicotine facilitates eCB-signaling and LTD, whereas tolerance develops to this facilitating effect after subchronic exposure in vivo. In the end, a progressive impairment of eCB-induced LTD is established after protracted withdrawal from nicotine. Endocannabinoid-LTD is reinstated 6 months after the last drug injection, but a brief period of nicotine re-exposure is sufficient to yet again impair eCB-signaling. LTD induced by the cannabinoid 1 receptor agonist WIN55,212-2 is not affected, suggesting that nicotine modulates eCB production or release. Nicotine-induced facilitation of eCB-LTD is occluded by the dopamine D2 receptor agonist quinpirole, and by the muscarinic acetylcholine receptor antagonist scopolamine. In addition, the same compounds restore eCB-LTD during protracted withdrawal. Nicotine may thus modulate eCB-signaling by affecting dopaminergic and cholinergic neurotransmission in a long-lasting manner. Overall, the data presented here suggest that nicotine facilitates eCB-LTD in the initial phase, which putatively could promote neurophysiological and behavioral adaptations to the drug. Protracted withdrawal, however, impairs eCB-LTD, which may influence or affect the ability to maintain cessation.


Assuntos
Corpo Estriado/efeitos dos fármacos , Endocanabinoides/farmacologia , Estimulantes Ganglionares/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Nicotina/farmacologia , Análise de Variância , Animais , Masculino , Ratos Wistar , Receptores de Dopamina D2/efeitos dos fármacos , Reforço Psicológico
14.
J Neural Transm (Vienna) ; 124(5): 607-619, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28161754

RESUMO

The glycine transporter-1 inhibitor Org25935 is a promising candidate in a treatment concept for alcohol use disorder targeting the glycine system. Org25935 inhibits ethanol-induced dopamine elevation in brain reward regions and reduces ethanol intake in Wistar rats. This study aimed to further characterise the compound and used ethanol consumption, behavioral measures, and gene expression as parameters to investigate the effects in Wistar rats and, as pharmacogenetic comparison, Alko-Alcohol (AA) rats. Animals were provided limited access to ethanol in a two-bottle free-choice paradigm with daily drug administration. Acute effects of Org25935 were estimated using locomotor activity and neurobehavioral status. Effects on gene expression in Wistar rats were measured with qPCR. The higher but not the lower dose of Org25935 reduced alcohol intake in Wistar rats. Unexpectedly, Org25935 reduced both ethanol and water intake and induced strong CNS-depressive effects in AA-rats (withdrawn from further studies). Neurobehavioral effects by Org25935 differed between the strains (AA-rats towards sedation). Org25935 did not affect gene expression at the mRNA level in the glycine system of Wistar rats. The data indicate a small therapeutic range for the anti-alcohol properties of Org25935, a finding that may guide further evaluations of the clinical utility of GlyT-1 inhibitors. The results point to the importance of pharmacogenetic considerations when developing drugs for alcohol-related medical concerns. Despite the lack of successful clinical outcomes, to date, the heterogeneity of drug action of Org25935 and similar agents and the unmet medical need justify further studies of glycinergic compounds in alcohol use disorder.


Assuntos
Dissuasores de Álcool/farmacologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Neurotransmissores/farmacologia , Tetra-Hidronaftalenos/farmacologia , Dissuasores de Álcool/química , Consumo de Bebidas Alcoólicas/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressores do Sistema Nervoso Central/administração & dosagem , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Etanol/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Predisposição Genética para Doença , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Neurotransmissores/química , RNA Mensageiro/metabolismo , Ratos Wistar , Tetra-Hidronaftalenos/química
15.
Alcohol Clin Exp Res ; 41(11): 1816-1830, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28833225

RESUMO

Identification of ethanol's (EtOH) primary molecular brain targets and determination of their functional role is an ongoing, important quest. Pentameric ligand-gated ion channels, that is, the nicotinic acetylcholine receptor, the γ-aminobutyric acid type A receptor, the 5-hydroxytryptamine3 , and the glycine receptor (GlyR), are such targets. Here, aspects of the structure and function of these receptors and EtOH's interaction with them are briefly reviewed, with special emphasis on the GlyR and the importance of this receptor and its ligands for EtOH pharmacology. It is suggested that GlyRs are involved in (i) the dopamine-activating effect of EtOH, (ii) regulating EtOH intake, and (iii) the relapse preventing effect of acamprosate. Exploration of the GlyR subtypes involved and efforts to develop subtype specific agonists or antagonists may offer new pharmacotherapies for alcohol use disorders.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Etanol/administração & dosagem , Etanol/metabolismo , Receptores de Glicina/fisiologia , Acamprosato , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Animais , Dopamina/metabolismo , Humanos , Naltrexona/administração & dosagem , Naltrexona/metabolismo , Taurina/administração & dosagem , Taurina/análogos & derivados , Taurina/metabolismo
16.
Addict Biol ; 22(1): 93-102, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26365786

RESUMO

Drugs of abuse share the ability to increase extracellular dopamine (DA) levels in the mesolimbic DA system. This effect has been linked to positive and reinforcing experiences of drug consumption and is presumed to be of importance for continued use, as well as for the development of dependence and addiction. Previous rat studies from our lab have implicated a neuronal circuitry involving glycine receptors in nucleus accumbens (nAc) and, secondarily, nicotinic acetylcholine receptors in the ventral tegmental area (VTA) in ethanol's (EtOH) DA-elevating effect. The work presented here, performed in male Wistar rats, suggests that the lateral septum (LS), which has previously been associated with different aspects of EtOH-related behaviour, is involved as well. In vivo microdialysis methodology demonstrated that blocking the generation of action potentials in LS using tetrodotoxin prevented a DA increase in nAc after accumbal EtOH perfusion. Retrograde tracing and polymerase chain reaction (PCR) were used to identify and characterize cells projecting to VTA from nAc/LS and from LS to nAc. Based on the PCR results, cells projecting from both LS/nAc to anterior VTA and from LS to nAc were mainly GABAergic neurons expressing glycine receptors, and these cells are presumed to be involved in mediating the DA-elevating effect of EtOH. These results provide further evidence implicating LS in the reinforcing effects of EtOH. Additional studies are needed to investigate LS involvement in EtOH consumption behaviour and its potential role in the development of dependence and addiction.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Etanol/farmacologia , Núcleos Septais/efeitos dos fármacos , Núcleos Septais/metabolismo , Animais , Masculino , Modelos Animais , Ratos , Ratos Wistar
17.
Adv Exp Med Biol ; 975 Pt 1: 173-181, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28849453

RESUMO

In the search for the primary mechanism underlying the dopamine elevating properties of ethanol we have established that raised levels of taurine in the nucleus accumbens (nAc) is pivotal. In the nAc, the release of taurine appears to be connected to osmoregulation, and neither taurine nor dopamine is increased if ethanol is administered in a hypertonic saline solution. However, even though the nAc is important for drug-reinforcement, manifestation of addiction has been postulated to recruit the more dorsal parts of the striatum (DS). How ethanol influences dopamine and taurine in the DS and their role in addiction is thus far poorly understood. By means of in vivo microdialysis in freely moving rats we concomitantly monitored extracellular levels of dopamine and taurine in the DS following administration of ethanol diluted either in an isotonic or hypertonic saline solution. In a different set of rats, placed in a voluntary ethanol consumption paradigm (intermittent access to 20% ethanol for 2 months), taurine and dopamine were monitored following an acute injection of ethanol. We found that neither administration of ethanol diluted in a hypertonic saline solution, nor 2 months of moderate ethanol consumption, influence the ethanol-induced increase of taurine in the DS. We propose that there may be regional differences in the relationship between taurine, dopamine and ethanol in the nAc and in the DS. It remains to be determined if this subregion-specificity is important for the transition from recreational drug use to a compulsive habit.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Etanol/farmacologia , Taurina/metabolismo , Animais , Dopamina/metabolismo , Masculino , Microdiálise , Ratos , Ratos Wistar
18.
Adv Exp Med Biol ; 975 Pt 1: 217-224, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28849457

RESUMO

Alcohol dependence is a puzzling brain disorder causing enormous suffering and financial costs world-wide. One of the few common denominators of all addictive drugs is activation of the mesolimbic dopamine system resulting in increased dopamine levels in the nucleus accumbens. In order to understand the development of addiction and find new efficient treatment strategies we need to understand how addictive drugs increase dopamine following acute and chronic administration of drugs. In the search for mechanisms underlying ethanol's ability to increase dopamine in the nucleus accumbens we have found taurine to be of major importance, although the complete picture remains to be disclosed. The aim of the present study was to explore whether chronic voluntary ethanol intake influences the ethanol-induced elevation of taurine. By means of in vivo micro-dialysis we found that voluntary intake of large amounts of ethanol for 12 weeks only had a modest influence on ethanol-induced elevations of taurine in the rat.


Assuntos
Adaptação Fisiológica/fisiologia , Etanol/toxicidade , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Taurina/metabolismo , Alcoolismo/metabolismo , Animais , Masculino , Microdiálise , Ratos , Ratos Wistar
19.
Addict Biol ; 21(2): 397-406, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25581387

RESUMO

Tobacco use is often associated with long-term addiction as well as high risk of relapse following cessation. This is suggestive of persistent neural adaptations, but little is known about the long-lasting effects of nicotine on neural circuits. In order to investigate the long-term effects of nicotine exposure, Wistar rats were treated for 3 weeks with nicotine (0.36 mg/kg), and the duration of behavioral and neurophysiological adaptations was evaluated 7 months later. We found that increased drug-induced locomotion persisted 7 months after the initial behavioral sensitization. In vitro analysis of synaptic activity in the core and shell of the nucleus accumbens (nAc) revealed a decrease in input/output function in both regions of nicotine-treated rats as compared to vehicle-treated control rats. In addition, administration of the dopamine D2 receptor agonist quinpirole (5 µM) significantly increased evoked population spike amplitude in the nAc shell of nicotine-treated rats as compared to vehicle-treated control rats. To test whether nicotine exposure creates long-lasting malleable circuits, animals were re-exposed to nicotine 7 months after the initial exposure. This treatment revealed an increased sensitivity to nicotine among animals previously exposed to nicotine, with higher nicotine-induced locomotion responses than observed initially. In vitro electrophysiological recordings in re-exposed rats detected an increased sensitivity to dopamine D2 receptor activation. These results suggest that nicotine produces persistent neural adaptations that make the system sensitive and receptive to future nicotine re-exposure.


Assuntos
Comportamento Animal/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Antagonistas dos Receptores de Dopamina D2/farmacologia , Esquema de Medicação , Complexo de Golgi/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Núcleo Accumbens/efeitos dos fármacos , Quimpirol/farmacologia , Ratos Wistar , Coluna Vertebral/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
20.
Alcohol Clin Exp Res ; 39(12): 2364-74, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26614538

RESUMO

BACKGROUND: Alcohol acts on both inhibitory and excitatory receptor systems resulting in a net increase in dopamine output in the ventral striatum (nucleus accumbens [nAc]), which is implicated in drug reward. However, the dorsal striatum may also be involved in reward-related behaviors. The objectives of this study were to investigate the role of inhibitory receptors in modulating the acute effects of ethanol (EtOH) on dopamine release and synaptic activity in the shell region of the nAc (nAcS) and dorsolateral striatum (DLS). METHODS: EtOH (300 mM) was administered via reversed microdialysis in the nAcS or DLS of Wistar rats following pretreatment with glycine or GABAA receptor antagonist strychnine and bicuculline, respectively. Dopamine content in dialysate samples was quantified using high-performance liquid chromatography. In addition, local field potential recordings were performed in the nAcS and DLS in slices from Wistar rats. Population spike (PS) amplitude was measured following treatment with EtOH (50 mM) in slices pretreated with strychnine or bicuculline. RESULTS: Local EtOH increased dopamine levels in both regions, an effect that strychnine pretreatment inhibited in the nAcS. EtOH-induced increases in accumbal dopamine were not blocked by a low (5 µM) concentration of bicuculline, but were inhibited by pretreatment with higher bicuculline concentrations. None of the antagonists administered in the DLS prevented the EtOH-induced dopamine increase. Field potential recordings in the nAcS showed that acute EtOH produced an increase in PS amplitude which was blocked by both strychnine and bicuculline. In the DLS, EtOH induced a decrease in PS amplitude which was not influenced by strychnine or bicuculline. CONCLUSIONS: The current results show that changes in striatal dopamine output and synaptic activity induced by acute EtOH administration are modulated by inhibitory receptors in a subregion-specific manner.


Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Etanol/administração & dosagem , Receptores de GABA-B/metabolismo , Transdução de Sinais/fisiologia , Sinapses/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Corpo Estriado/efeitos dos fármacos , Etanol/toxicidade , Antagonistas de Receptores de GABA-A/farmacologia , Masculino , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos
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