RESUMO
Smoking during adolescence may increase the likelihood to develop nicotine dependence and to abuse other drugs such as cocaine. Despite great efforts to understand underlying neurobiological mechanisms of this progression, less attention has been paid to the role of genetic factors. Here, we investigated the influence of both genetic background and age at first nicotine exposure in the long-lasting effects on mesolimbic dopamine transmission including the increased cocaine-rewarding effect. Mid-adolescent and adult rats of inbred strains Lewis (addiction prone) and Fischer 344 (addiction resistant) were administered nicotine (0.4 mg/kg) or vehicle once daily for 5 days. Changes in dopamine transmission were investigated by in vivo microdialysis and electrophysiology after 30 days of withdrawal, whereas changes in cocaine-rewarding effect were assessed via conditioned place preference paradigm. Nicotine pre-exposure differentially changed mesolimbic dopamine transmission depending on strain and age of pre-exposure. A potentiation of dopamine response to nicotine was observed in nucleus accumbens (NAc) core of both strains and age groups, whereas dopamine response in NAc shell was enhanced exclusively in Lewis rats exposed to nicotine during adolescence. A similar response was observed following cocaine challenge at adulthood. Changes in VTA dopamine cell population and activity were observed only in adolescent nicotine-pretreated Lewis rats, which also showed an increased cocaine-rewarding effect at adulthood. These results highlight the influence of genetic background in the long-lasting effects of nicotine exposure and suggest that exposure during adolescence might increase nicotine and cocaine-rewarding properties in genetically vulnerable individuals, thereby facilitating progression toward dependence.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/genética , Dopamina/metabolismo , Patrimônio Genético , Nicotina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Fatores Etários , Animais , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos , Masculino , Microdiálise , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos LewRESUMO
BACKGROUND: Thalidomide and closely related analogues are used clinically for their immunomodulatory and antiangiogenic properties mediated by the inhibition of the proinflammatory cytokine tumor necrosis factor α. Neuroinflammation and angiogenesis contribute to classical neuronal mechanisms underpinning the pathophysiology of l-dopa-induced dyskinesia, a motor complication associated with l-dopa therapy in Parkinson's disease. The efficacy of thalidomide and the more potent derivative 3,6'-dithiothalidomide on dyskinesia was tested in the 6-hydroxydopamine Parkinson's disease model. METHODS: Three weeks after 6-hydroxydopamine infusion, rats received 10 days of treatment with l-dopa plus benserazide (6 mg/kg each) and thalidomide (70 mg/kg) or 3,6'-dithiothalidomide (56 mg/kg), and dyskinesia and contralateral turning were recorded daily. Rats were euthanized 1 hour after the last l-dopa injection, and levels of tumor necrosis factor-α, interleukin-10, OX-42, vimentin, and vascular endothelial growth factor immunoreactivity were measured in their striatum and substantia nigra reticulata to evaluate neuroinflammation and angiogenesis. Striatal levels of GLUR1 were measured as a l-dopa-induced postsynaptic change that is under tumor necrosis factor-α control. RESULTS: Thalidomide and 3,6'-dithiothalidomide significantly attenuated the severity of l-dopa-induced dyskinesia while not affecting contralateral turning. Moreover, both compounds inhibited the l-dopa-induced microgliosis and excessive tumor necrosis factor-α in the striatum and substantia nigra reticulata, while restoring physiological levels of the anti-inflammatory cytokine interleukin-10. l-Dopa-induced angiogenesis was inhibited in both basal ganglia nuclei, and l-dopa-induced GLUR1 overexpression in the dorsolateral striatum was restored to normal levels. CONCLUSIONS: These data suggest that decreasing tumor necrosis factor-α levels may be useful to reduce the appearance of dyskinesia, and thalidomide, and more potent derivatives may provide an effective therapeutic approach to dyskinesia. © 2019 International Parkinson and Movement Disorder Society.
Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/terapia , Fatores Imunológicos/uso terapêutico , Levodopa/efeitos adversos , Doença de Parkinson/complicações , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Animais , Citocinas/metabolismo , Discinesia Induzida por Medicamentos/psicologia , Interleucina-10/metabolismo , Masculino , Neostriado/metabolismo , Oxidopamina , Doença de Parkinson/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Substância Negra/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Neuroinflammation is a main component of Parkinson's disease (PD) neuropathology, where unremitting reactive microglia and microglia-secreted soluble molecules such as cytokines, contribute to the neurodegenerative process as part of an aberrant immune reaction. Besides, pro-inflammatory cytokines, predominantly TNF-α, play an important neuromodulatory role in the healthy and diseased brain, being involved in neurotransmitter metabolism, synaptic scaling and brain plasticity. Recent preclinical studies have evidenced an exacerbated neuroinflammatory reaction in the striatum of parkinsonian rats that developed dyskinetic responses following L-DOPA administration. These findings prompted investigation of non-neuronal mechanisms of L-DOPA-induced dyskinesia (LID) involving glial cells and glial-secreted soluble molecules. Hence, besides the classical mechanisms of LID that include abnormal corticostriatal neurotransmission and maladaptive changes in striatal medium spiny neurons (MSNs), here we review studies supporting a role of striatal neuroinflammation in the development of LID, with a focus on microglia and the pro-inflammatory cytokine TNF-α. Moreover, we discuss several mechanisms that have been involved in the development of LID, which are directly or indirectly under the control of TNF-α, and might be abnormally affected by its chronic overproduction and release by microglia in PD. It is proposed that TNF-α may contribute to the altered neuronal responses occurring in LID by targeting receptor trafficking and function in MSNs, but also dopamine synthesis in preserved dopaminergic terminals and serotonin metabolism in serotonergic neurons. Therapeutic approaches specifically targeting glial-secreted cytokines may represent a novel target for preventing or treating LID.
Assuntos
Discinesia Induzida por Medicamentos/imunologia , Inflamação/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/patologia , Humanos , Inflamação/patologia , Levodopa/efeitos adversosRESUMO
Adolescent Cannabis exposure has been hypothesized to act as a gateway to opiate abuse. In order to investigate the role of genetic background in cannabinoid-opiate interactions, we studied the effect of Δ(9) -tetrahydrocannabinol (THC) exposure of adolescent Lewis and Fischer 344 rats on the responsiveness of accumbens shell and core dopamine (DA), as monitored by microdialysis, to THC and heroin at adulthood. Heroin reward and reinstatement by heroin priming were studied by conditioned place preference (CPP) and cognitive and emotional functions by object recognition, Y maze and elevated plus maze paradigms. THC stimulated shell DA in Lewis but not in Fischer 344 rats. Adolescent THC exposure potentiated DA stimulant effects of heroin in the shell and core of Lewis and only in the core of Fischer 344 rats. Control Lewis rats developed stronger CPP to heroin and resistance to extinction compared with Fischer 344 strain. In Lewis rats, THC exposure did not affect heroin CPP but potentiated the effect of heroin priming. In Fischer 344 rats, THC exposure increased heroin CPP and made it resistant to extinction. Lewis rats showed seeking reactions during extinction and hedonic reactions in response to heroin priming. Moreover, adolescent THC exposure affected emotional function only in Lewis rats. These observations suggest that long-term effects of Cannabis exposure on heroin addictive liability and emotionality are dependent on individual genetic background.
Assuntos
Comportamento Animal/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/farmacologia , Dopamina/metabolismo , Dronabinol/farmacologia , Dependência de Heroína/genética , Heroína/farmacologia , Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Animais , Masculino , Microdiálise , Núcleo Accumbens/metabolismo , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Recompensa , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genéticaRESUMO
Genetic background and age at first exposure have been identified as critical variables that contribute to individual vulnerability to drug addiction. Evidence shows that genetic factors may account for 40-70% of the variance in liability to addiction. Alcohol consumption by young people, especially in the form of binge-drinking, is becoming an alarming phenomenon predictive of future problems with drinking. Thus, the literature indicates the need to better understand the influence of age and genetic background on the development of alcohol dependence. To this aim, the inbred rat strains Lewis (LEW, addiction prone) and Fischer 344 (F344, addiction resistant) were used as a model of genetic vulnerability to addiction and compared with the outbred strain Sprague-Dawley (SD) in a two-bottle choice paradigm as a model of alcohol abuse. During a 9-week period, adolescent and adult male rats of the three strains were intermittently exposed to ethanol (20%) and water during three 24-h sessions/week. Adult and adolescent SD and LEW rats escalated their alcohol intake over time reaching at stable levels, while F344 rats did not escalate their intake, regardless of age at drinking onset. Among adolescents, only F344 rats consumed a higher total amount of ethanol than adults, although only SD and LEW rats escalated their intake. Adult LEW rats, albeit having a lower ethanol consumption as compared to SD rats but greater than F344, showed a more compulsive intake, consuming higher amounts of ethanol during the first hour of exposure, reaching a higher degree of ethanol preference when start drinking as adolescents. Behavioral analysis during the first hour of ethanol consumption revealed significant strain differences, among which noticeable the lack of sedative effect in the LEW strain, at variance with F344 and SD strains, and highest indices of withdrawal (most notable jumping) in LEW rats during the first hour of abstinence days. The present results underscore the importance of individual genetic background and early onset of alcohol use in the progression toward abuse and development of alcohol addiction.
RESUMO
Over the last decade, evidence has emerged linking disorders in the impulsive-compulsive spectrum in Parkinson's disease to dopamine receptor agonist treatment. These disorders include hypersexuality, gambling and, to a minor extent, compulsive shopping and eating, as well as dopamine dysregulation syndrome, characterized by an addictive pattern toward dopamine replacement therapy and stereotyped behaviors, such as punding. These syndromes, which have only recently been recognized and are still underdiagnosed, have deleterious social consequences that warrant interventions at the clinical level and promotion of research at the preclinical level. In this review, we first provide a summary of features of Parkinson's disease and current pharmacological therapies associated with the development of dopamine dysregulation syndrome and impulsive-compulsive disorders. We also examine the dopamine receptors and brain areas important in reward and compulsive behaviors. We then critically examine the neuroadaptations in dopaminergic circuitries and the literature concerning gambling, hypersexuality, and other addictive behaviors in parkinsonian patients. Finally, we focus on suggestions pointing to a role for dopamine D(3) receptors and sensitization phenomena as the main factors which may be the origin of these disorders.
Assuntos
Transtornos Disruptivos, de Controle do Impulso e da Conduta/metabolismo , Agonistas de Dopamina/uso terapêutico , Dopamina/metabolismo , Doenças Metabólicas/metabolismo , Doença de Parkinson/tratamento farmacológico , Animais , Transtornos Disruptivos, de Controle do Impulso e da Conduta/etiologia , Humanos , Doenças Metabólicas/complicações , Doença de Parkinson/complicaçõesRESUMO
Conditioned saccharin avoidance (CSA) can be produced when either lithium chloride (LiCl) or a reinforcing drug, such as morphine, is administered following exposure to the taste of saccharin. In this study we investigated the involvement of dopamine (DA) transmission in the acquisition of morphine and LiCl-CSA. CSA was evaluated in a two-bottle choice paradigm with two conditioning pairings between saccharin and morphine or LiCl as unconditioned stimulus (US). Morphine hydrochloride (7.5 mg/kg s.c.) or LiCl (40 mg/kg i.p.), administered 45 and 120' respectively after saccharin-drinking session, induced strong CSA. The DA D(1) receptor antagonist, SCH 39166 (0.1 mg/kg s.c.), impaired morphine-CSA if administered 15' and, to a lesser extent, 30' but not 45' before the drug (i.e immediately after saccharin drinking). In contrast SCH 39166 reduced LiCl-CSA when administered 45' before the drug and even more so when administered 105' before LiCl i.e. immediately after saccharin drinking. Therefore SCH 39166 impaired morphine-CSA when given shortly before the drug, while it impaired LiCl-CSA when given shortly after saccharin. Raclopride, a specific antagonist of D(2) receptors, failed to affect LiCl- and morphine-CSA. These results are consistent with the idea that DA, acting on D(1) receptors, plays a differential role in morphine- and LiCl-CSA. In LiCl-CSA DA is necessary for the processing (consolidation) of the short-term memory trace of the saccharin taste to be associated with the lithium-induced aversive state, while in morphine CSA contributes to mediate the appetitive properties of the drug.
Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Operante/fisiologia , Cloreto de Lítio/administração & dosagem , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Receptores de Dopamina D1/fisiologia , Sacarina/administração & dosagem , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Benzazepinas/farmacologia , Condicionamento Operante/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Preferências Alimentares/efeitos dos fármacos , Masculino , Racloprida/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Privação de ÁguaRESUMO
RATIONALE: A large body of evidence indicates an involvement of the mesolimbic dopamine (DA) pathway innervating the ventral striatum in the motivational effects of drug abuse. OBJECTIVE: The goal of the study is to clarify the role of DA D1 and D2 receptors of the rat nucleus accumbens (NAc) shell and core in the motivational effects of morphine as studied by conditioned place preference (CPP). METHODS: The effect of the intracerebral infusion of DA antagonists specific for DA D1 (SCH 39166) and D2 receptors (L-sulpiride) was studied in a single-trial place conditioning paradigm with fixed assignment of the drug to the unpreferred compartment. RESULTS: Morphine induced significant CPP at all the doses tested (0.5, 1.0, and 2.0 mg/kg, subcutaneously). A dose of 1.0 mg/kg was selected for further studies. Intra-NAc shell infusion of SCH 39166 and L-sulpiride at doses of 25 and 50 ng/1 microl per side impaired the acquisition of CPP by morphine. No effect was observed at 12.5 ng/1 microl per side. Intra-NAc core infusion of SCH 39166 (12.5, 25, and 50 ng/1 microl per side) did not affect the acquisition of morphine-induced CPP, while L-sulpiride (12.5, 25, and 50 ng/1 microl per side) impaired CPP acquisition only at the dose of 50 ng/1 microl per side. No effect on morphine-induced CPP was observed when the DA antagonists were infused into the NAc shell or core 10 min before the test session. CONCLUSION: These results indicate that DA D1 and D2 receptors in the NAc shell are involved in the acquisition of morphine-induced CPP.
Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Morfina/farmacologia , Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Mapeamento Encefálico , Antagonistas dos Receptores de Dopamina D2 , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inibidores , Meio Social , Sulpirida/farmacologiaRESUMO
RATIONALE: Experimental evidence indicates that the mesolimbic dopamine (DA) pathway innervating the ventral striatum is critically involved in the motivational effects of drug abuse. However, the role of DA transmission of the two main subdivisions of the nucleus accumbens (NAc), the shell and the core, in the motivational properties of nicotine is unknown. OBJECTIVES: The aim of this study was to investigate the role of DA D1 and D2 receptors of the rat NAc shell and core in the motivational effects of nicotine using a conditioned place preference (CPP) paradigm. METHODS: The effect of the intracerebral infusion of DA antagonists specific for DA D1 (SCH 39166) and D2 receptors (L-sulpiride) was studied in a single-trial place-conditioning paradigm with fixed assignment of the drug to the unpreferred compartment. RESULTS: Nicotine induced significant CPP at the dose of 0.4 and 0.6 mg/kg subcutaneously (s.c.). Intra-NAc shell infusion of SCH 39166 (6.25, 12.5, 25 and 50 ng bilaterally, 10 min before nicotine administration), impaired in a dose-dependent manner the acquisition of CPP by nicotine (0.4 mg/kg s.c.). SCH 39166 failed to affect nicotine CPP when infused into the NAc core. L-sulpiride (25 and 50 ng bilaterally) had no effect on acquisition after intra-Nac shell infusion. SCH 39166 and L-sulpiride were ineffective after infusion in the NAc shell and core 10 min before the test session. CONCLUSIONS: The results indicate that dopamine D1 but not D2 receptors of the NAc shell are specifically involved in the acquisition of nicotine-induced CPP.
Assuntos
Comportamento de Escolha/fisiologia , Condicionamento Clássico/fisiologia , Nicotina/farmacologia , Núcleo Accumbens/fisiologia , Núcleo Accumbens/fisiopatologia , Receptores de Dopamina D1/fisiologia , Meio Social , Tabagismo/fisiopatologia , Animais , Aprendizagem por Associação/fisiologia , Mapeamento Encefálico , Relação Dose-Resposta a Droga , Injeções Intravenosas , Masculino , Motivação , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/fisiologiaRESUMO
Preclinical evidence strongly indicate that adenosine A(2A) receptor antagonists represent a promising class of drugs for the treatment of motor deficits associated to Parkinson's disease. The effects of adenosine A(2A) receptor antagonists were here assessed in a rat model of parkinsonian tremor induced by cholinomimetic drugs by evaluating the counteraction of tremulous jaw movements. Systemic administration of the A(2A) antagonist SCH 58261 dose-dependently reduced the magnitude of perioral tremor induced by the acetylcholinesterase inhibitor tacrine (2.5 mg/kg). Furthermore, intrastriatal infusion of SCH BT2 (5 microg/microl), a water-soluble analogue of SCH 58261, antagonized tacrine-induced jaw movements with a maximal effect in the ventrolateral striatum. On the other hand, SCH 58261 (5 mg/kg) was ineffective in blocking tremulous jaw movements stimulated by the direct muscarinic agonist pilocarpine (1 mg/kg). Taken together, these results indicate that A(2A) antagonists reduce parkinsonian tremor stimulated in rats by tacrine and that the striatum is deeply involved in the observed effect. Moreover, the ineffectiveness of SCH 58261 in blocking pilocarpine-stimulated perioral tremor suggests that the antitremorigenic effects of A(2A) antagonists described here are not related to a direct action on muscarinic receptor. The prospective of providing additional antitremor benefits considerably enhances the therapeutic potential of A(2A) antagonists.
Assuntos
Dopamina/fisiologia , Doença de Parkinson/fisiopatologia , Receptores Purinérgicos P1/fisiologia , Análise de Variância , Animais , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Interações Medicamentosas , Arcada Osseodentária/efeitos dos fármacos , Arcada Osseodentária/fisiopatologia , Masculino , Movimento/efeitos dos fármacos , Movimento/fisiologia , Doença de Parkinson/terapia , Pilocarpina , Piperazinas/administração & dosagem , Antagonistas de Receptores Purinérgicos P1 , Pirimidinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Tacrina , Tremor/induzido quimicamente , Tremor/tratamento farmacológico , Triazóis/administração & dosagemRESUMO
Rotigotine acts in vitro as a full agonist of dopamine D1 receptors at concentrations almost superimposable to those at which it acts on D2 receptors. However in vivo evidence of the differences between the agonist activity of rotigotine at D1 receptors from that on the D2 receptors has not been provided yet. In order to test the ability of rotigotine to stimulate dopamine D1 and D2 receptors in vivo, we studied the effect of SCH39166 and eticlopride, selective dopamine D1 and D2/D3 receptor antagonists respectively, on rotigotine-induced contralateral turning behavior in 6-hydroxydopamine lesioned rats. Furthermore, the expression of the immediate-early gene c-fos in the caudate-putamen, was evaluated. As a comparison, we tested the D2/D3 agonist pramipexole. In primed rats, rotigotine (0.035, 0.1 and 0.35mg/kg) induced dose-dependent contralateral turning. Turning induced by 0.1mg/kg of rotigotine was reduced by pretreatment with the D1 antagonist SCH39166 and the D2 antagonist eticlopride. In drug-naive rats, rotigotine was less effective in eliciting turning but SCH39166 still reduced turning induced by rotigotine (0.35mg/kg). Pramipexole induced contralateral turning only in primed rats. SCH39166 potentiated and eticlopride abolished pramipexole-induced turning. Rotigotine induced Fos expression in the caudate-putamen and SCH39166 completely blocked it. Pramipexole failed to induce Fos. These results indicate that rotigotine acts in vivo as an agonist of D1 and D2 receptors while pramipexole is devoid of D1 activity in vivo. Given their differing DA receptor profiles, rotigotine and pramipexole might differ in their spectrum of application to the therapy of Parkinson's disease.
Assuntos
Agonistas de Dopamina/farmacologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Tetra-Hidronaftalenos/farmacologia , Tiofenos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzotiazóis/farmacologia , Dopamina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Oxidopamina/farmacologia , Pramipexol , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos Sprague-DawleyRESUMO
RATIONALE: Despite the critical role attributed to phosphorylated extracellular signal regulated kinase (pERK1/2) in the nucleus accumbens (Acb) in the actions of addictive drugs, the effects of morphine on ERK1/2 phosphorylation in this area are still controversial. OBJECTIVES: In order to investigate further this issue, we studied (1) the ability of morphine to affect ERK1/2 phosphorylation in the shell (AcbSh) and core (AcbC) of Sprague-Dawley and Wistar rats and of CD-1 and C57BL/6J mice and (2) the role of dopamine D1 and µ-opioid receptors in Sprague-Dawley rats and CD-1 mice. METHODS: The pERK1/2 expression was assessed by immunohistochemistry. RESULTS: In rats, morphine decreased AcbSh and AcbC pERK1/2 expression, whereas in mice, increased it preferentially in the AcbSh compared with the AcbC. Systemic SCH 39166 decreased pERK1/2 expression on its own in the AcbSh and AcbC of Sprague-Dawley rats and CD-1 mice; furthermore, in rats, SCH 39166 disclosed the ability of morphine to stimulate pERK1/2 expression. Systemic (rats and mice) and intra-Acb (rats) naltrexone prevented both decreases, in rats, and increases, in mice. CONCLUSIONS: These findings confirm the differential effects of morphine in rats and mice Acb and that D1 receptors exert a facilitatory role on ERK1/2 phosphorylation; furthermore, they indicate that, in rats, removal of the D1-dependent pERK1/2 expression discloses the stimulatory influence of morphine on ERK1/2 phosphorylation and that the morphine's ability to decrease pERK1/2 expression is mediated by Acb µ-opioid receptors. Future experiments may disentangle the psychopharmacological significance of the effects of morphine on pERK1/2 in the Acb.
Assuntos
Analgésicos Opioides/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/efeitos dos fármacos , Morfina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Receptores de Dopamina D1/efeitos dos fármacos , Receptores Opioides mu/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Antagonistas de Dopamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Núcleo Accumbens/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores de Dopamina D1/metabolismo , Receptores Opioides mu/metabolismoRESUMO
Neuroinflammation is associated with l-DOPA treatment in Parkinson's disease (PD), suggesting a role in l-DOPA-induced dyskinesia (LID), however it is unclear whether increased inflammation is specifically related to the dyskinetic outcome of l-DOPA treatment. Diversely from oral l-DOPA, continuous intrajejunal l-DOPA infusion is associated with very low dyskinetic outcome in PD patients. We reproduced these regimens of administration in 6-OHDA-lesioned hemiparkinsonian rats, where dyskinetic responses and striatal neuroinflammation induced by chronic pulsatile (DOPAp) or continuous (DOPAc) l-DOPA were compared. Moreover, we investigated the contribution of a peripheral inflammatory challenge with lipopolysaccharide (LPS), to DOPAp-induced dyskinetic and neuroinflammatory responses. Rats 6-OHDA-infused in the medial forebrain bundle received two weeks treatment with DOPAp, DOPAc via subcutaneous osmotic minipumps, or DOPAp followed by DOPAc. l-DOPA plasma levels were measured in all experimental groups. An independent group of rats received one peripheral dose of LPS 24h before DOPAp treatment. Abnormal involuntary movements (AIMs) were evaluated as a rat model of LID. Immunoreactivity (IR) for OX-42, microglial and neuronal TNF-α, iNOS and GFAP was quantified in denervated and contralateral striatum. In addition, serum TNF-α was measured. The 6-OHDA denervation induced a mild microgliosis in the striatum two weeks after neurotoxin infusion, and increased TNF-α IR in microglia. Rats receiving the DOPAp treatment developed AIMs and displayed increased striatal OX-42, microglial TNF-α, iNOS and GFAP. Moreover, TNF-α IR was also increased in a subpopulation of striatal neurons. Conversely, DOPAc did not induce AIMs or inflammatory responses in either drug-naïve animals or rats that were previously dyskinetic when exposed to DOPAp. Serum TNF-α was not altered by any l-DOPA treatment. LPS pre-treatment increased the degree of DOPAp-induced AIMs and striatal IR for OX-42, TNF-α, iNOS and GFAP. Altogether the present findings indicate that in the 6-OHDA model, chronic l-DOPA induces striatal inflammatory responses, which however depend upon the administration regimen and the dyskinetic outcome of drug treatment. The potentiation of dyskinetic responses by LPS suggests a reciprocal causal link between neuroinflammation and LID.
Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/etiologia , Encefalite/induzido quimicamente , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/sangue , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/efeitos adversos , Lateralidade Funcional/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Levodopa/administração & dosagem , Levodopa/sangue , Lipopolissacarídeos/farmacologia , Masculino , Proteínas do Tecido Nervoso/metabolismo , Oxidopamina/toxicidade , Doença de Parkinson/sangue , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Simpatolíticos/toxicidade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Microdialysis studies in animals have shown that addictive drugs preferentially increase extracellular dopamine (DA) in the n. accumbens (NAc). Brain imaging studies, while extending these finding to humans, have shown a correlation between psychostimulant-induced increase of extracellular DA in the striatum and self-reported measures of liking and 'high' (euphoria). Although a correlate of drug reward independent from associative learning and performance is difficult to obtain in animals, conditioned taste avoidance (CTA) might meet these requirements. Addictive drugs induce CTA to saccharin most likely as a result of anticipatory contrast of saccharin over drug reward. Consistently with a role of DA in drug reward, D2 or combined D1/D2 receptor blockade abolishes cocaine, amphetamine and nicotine CTA. Intracranial self-administration studies with mixtures of D1 and D2 receptor agonists point to the NAc shell as the critical site of DA reward. NAc shell DA acting on D1 receptors is also involved in Pavlovian learning through pre-trial and post-trial consolidation mechanisms and in the utilization of spatial short-term memory for goal-directed behavior. Stimulation of NAc shell DA transmission by addictive drugs is shared by a natural reward like food but lacks its adaptive properties (habituation and inhibition by predictive stimuli). These peculiarities of drug-induced stimulation of DA transmission in the NAc shell result in striking differences in the impact of drug-conditioned stimuli on DA transmission. It is speculated that drug addiction results from the impact exerted on behavior by the abnormal DA stimulant properties acquired by drug-conditioned stimuli as a result of their association with addictive drugs.
Assuntos
Dopamina/fisiologia , Núcleo Accumbens/fisiologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Animais , Nível de Alerta/fisiologia , Condicionamento Clássico/fisiologia , Condicionamento Operante/fisiologia , Dopamina/metabolismo , Espaço Extracelular/metabolismo , Espaço Extracelular/fisiologia , Humanos , Motivação , Núcleo Accumbens/metabolismo , Fosforilação , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
Several evidences indicate that the selective blockade of adenosine A(2A) receptors counteracts the motor activity impairment in experimental models of Parkinson's disease. In the present study, the effects of the adenosine A(2A) receptor antagonist, SCH 58261 (5-amino-7-(beta-phenylethyl)-2-(8-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine, were assessed following a repeated treatment schedule in the contralateral turning behavior rat model of Parkinson's disease. Unilateral lesions of the nigrostriatal pathway were induced by injecting 6-hydroxydopamine (6-OHDA) in medial forebrain bundle. Repeated administration of SCH 58261 was performed either alone (7 and 14 days repeated SCH 58261) or together with L-dopa (19 days repeated SCH 58261 plus L-dopa or L-dopa alone). After a 7- and 14-day repeated administration schedule, SCH 58261 (5 mg/kg) maintained its ability to potentiate the contralateral turning behavior induced by a subthreshold dose of L-dopa (2 mg/kg i.p.), showing no tolerance to its stimulant effects. SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) or L-dopa (6 mg/kg) alone induced, at these dosages, the same number of contralateral turnings after the first administration. While chronic intermittent SCH 58261 plus L-dopa did not lead to a modified turning behavior during treatment, L-dopa alone produced a progressive increase in turning behavior intensity and duration. These results provide evidence that SCH 58261 retains its ability to potentiate L-dopa effects in a validated rat model of Parkinson's disease even after repeated treatments. Moreover, these results suggest that adenosine A(2A) blockade prevents the appearance of motor response alterations in L-dopa-treated rats, supporting the concept that A(2A) receptor antagonists have a therapeutic potential for the treatment of Parkinson's disease. Copyright 2001 Wiley-Liss, Inc.
RESUMO
Conditioned taste aversion (CTA) can be applied to study associative learning and its relevant underpinning molecular mechanisms in discrete brain regions. The present study examined, by immunohistochemistry and immunocytochemistry, the effects of acquisition and expression of lithium-induced CTA on activated Extracellular signal Regulated Kinase (p-ERK) in the prefrontal cortex (PFCx) and nucleus accumbens (Acb) of male Sprague-Dawley rats. The study also examined, by immunoblotting, whether acquisition and expression of lithium-induced CTA resulted in modified levels of phosphorylation of glutamate receptor subunits (NR1 and GluR1) and Thr(34)- and Thr(75-Dopamine-and-cAMP-Regulated) PhosphoProtein (DARPP-32). CTA acquisition was associated with an increase of p-ERK-positive neurons and phosphorylated NR1 receptor subunit (p-NR1) in the PFCx, whereas p-GluR1, p-Thr(34)- and p-Thr(75)-DARPP-32 levels were not changed in this brain region. CTA expression increased the number of p-ERK-positive neurons in the shell (AcbSh) and core (AcbC) but left unmodified p-NR1, p-GluR1, p-Thr(34)- and p-Thr(75-DARPP-32) levels. Furthermore, post-embedding immunogold quantitative analysis in AcbSh revealed that CTA expression significantly increased nuclear p-ERK immunostaining as well as p-ERK-labeled axo-spinous contacts. Overall, these results indicate that ERK and NR1, but not GluR1 and DARPP-32, are differentially phosphorylated as a consequence of acquisition and expression of aversive associative learning. Moreover, these results confirm that CTA represents an useful approach to study the molecular basis of associative learning in rats and suggest the involvement of ERK cascade in learning-associated synaptic plasticity.
RESUMO
Significant evidence suggests that ultrasonic vocalizations (USVs) may index the emotional state in rats, and 50-kHz USVs have been proposed as a tool to investigate the rewarding properties of drugs. Apart from the evidence on some psychostimulants, little is known about the effects of other drugs with rewarding properties on emission of 50-kHz USVs. To further elucidate the neuropharmacology of 50-kHz USVs and their relevance in drug-induced reward, this study characterized the effects of different drugs possessing rewarding properties on 50-kHz USVs in adult male rats. Rats received the acute administration of 3,4-methylenedioxymethamphetamine (MDMA, 5-15 mg/kg, i.p.), methylphenidate (2.5-10 mg/kg, i.p.), morphine (1-5 mg/kg, s.c.), or nicotine (0.1-0.4 mg/kg, s.c.). The number and acoustic features of 50-kHz USVs and their subtypes were then measured. As a comparison, additional rats received the acute administration of amphetamine (2 mg/kg, i.p.), which strongly stimulates the emission of 50-kHz USVs. Methylphenidate, similar to amphetamine, increased the total number of 50-kHz USVs emitted by rats, and also modified their acoustic features. Conversely, MDMA, morphine, and nicotine did not elevate the total number of 50-kHz USVs. However, these drugs modified the acoustic features of 50-kHz USVs, as well as the number and acoustic features of specific subtypes of vocalizations. This study demonstrates that major differences exist in the effects of psychoactive drugs on 50-kHz USVs in rats. These findings provide a better understanding of psychoactive properties of drugs with rewarding properties and usefulness of 50-kHz USVs in assessment of these properties.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Metilfenidato/farmacologia , Morfina/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Nicotina/farmacologia , Psicotrópicos/farmacologia , Recompensa , Vocalização Animal/efeitos dos fármacos , Animais , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Parkinson's disease is a neurodegenerative pathology which affects the dopaminergic neurons in the mesencephalon, leading to a progressive and relentless motor disability and to non-motor symptoms of different severity. The aim of this review is to summarize the features of drugs currently used in the pharmacotherapy of Parkinson's disease, with a look at their beneficial effects and limitations. Drugs acting on dopamine transmission, as L-DOPA, direct dopaminergic agonists, inhibitors for either the MAO or COMT enzymes and drugs acting on neurotransmitters other than dopamine (e.g. acetylcholine, glutamate) will be covered. Investigational drugs currently under examination for their therapeutic potential in Parkinson's disease and recent patents which may be relevant to the field will be also discussed.
Assuntos
Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Desenho de Fármacos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Animais , Antiparkinsonianos/farmacocinética , Drogas em Investigação/farmacocinética , Humanos , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Patentes como AssuntoRESUMO
Saccharin avoidance conditioned by drugs of abuse (CSA) has been interpreted as an expression of the appetitive, dopamine-dependent, properties of the drug. Repeated exposure to these drugs induces an increase (sensitization) of their motor stimulant properties associated with differential changes in DA transmission in the NAc shell and core. The present study investigated the changes in drug CSA induced by schedules of repeated drug exposure that induce behavioral sensitization. CSA was performed in a two-bottle choice paradigm with two saccharin-drug associations in rats previously sensitized to morphine, cocaine, amphetamine and nicotine. In control rats morphine (1 and 5mg/kg s.c.), cocaine (5 and 10mg/kg i.p.), amphetamine (0.25 and 0.5mg/kg s.c.) and nicotine (0.4 mg/kg s.c.) induced dose-dependent CSA. Sensitization to morphine, cocaine and nicotine, which is known to reduce the responsiveness of NAc shell DA to the same drugs, also reduced CSA. In contrast, sensitization to amphetamine, that does not affect the responsiveness of NAc shell DA to the drug, failed to affect CSA. The results are consistent with the hypothesis that NAc shell DA is a substrate of the appetitive properties of drugs of abuse.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Drogas Ilícitas/farmacologia , Sacarina/farmacologia , Anfetamina/farmacologia , Animais , Cocaína/farmacologia , Relação Dose-Resposta a Droga , Masculino , Morfina/farmacologia , Nicotina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
We have recently demonstrated how antagonism of adenosine A(2A) receptors within the globus pallidus (GP) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor L-DOPA in 6-hydroxydopamine-lesioned hemiparkinsonian rats. To further characterize the influence of pallidal A(2A) receptor blockade on the motor stimulant effects elicited by dopamine receptor activation, hemiparkinsonian rats were infused with the water-soluble A(2A) antagonist SCH BT2 in the GP, alone or in combination with systemic administration of either SKF 38393 or quinpirole, to stimulate dopamine D(1) or D(2) receptors, respectively. SCH BT2 alone (5 mug/1 mul) neither altered motor behavior nor produced postural asymmetry. In contrast, the contralateral rotations elicited by SKF 38393 (1.5 mg/kg) as well as quinpirole (0.05 mg/kg) were potentiated by the concomitant intrapallidal infusion of SCH BT2. The results of this study demonstrate that blockade of pallidal A(2A) receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D(1) or D(2) dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A(2A) receptor antagonists.