RESUMO
BACKGROUND: Chronic opioid exposure is common world-wide, but behavioural performance remains under-investigated. This study aimed to investigate visuospatial memory performance in opioid-exposed and dependent clinical populations and its associations with measures of intelligence and cognitive impulsivity. METHODS: We recruited 109 participants: (i) patients with a history of opioid dependence due to chronic heroin use (n = 24), (ii) heroin users stabilised on methadone maintenance treatment (n = 29), (iii) participants with a history of chronic pain and prescribed tramadol and codeine (n = 28) and (iv) healthy controls (n = 28). The neuropsychological tasks from the Cambridge Neuropsychological Test Automated Battery included the Delayed Matching to Sample (DMS), Pattern Recognition Memory, Spatial Recognition Memory, Paired Associate Learning, Spatial Span Task, Spatial Working Memory and Cambridge Gambling Task. Pre-morbid general intelligence was assessed using the National Adult Reading Test. RESULTS: As hypothesised, this study identified the differential effects of chronic heroin and methadone exposures on neuropsychological measures of visuospatial memory (p < 0.01) that were independent of injecting behaviour and dependence status. The study also identified an improvement in DMS performance (specifically at longer delays) when the methadone group was compared with the heroin group and also when the heroin group was stabilised onto methadone. Results identified differential effects of chronic heroin and methadone exposures on various neuropsychological measures of visuospatial memory independently from addiction severity measures, such as injecting behaviour and dependence status.
Assuntos
Agnosia/induzido quimicamente , Analgésicos Opioides/efeitos adversos , Dependência de Heroína/diagnóstico , Transtornos da Memória/induzido quimicamente , Rememoração Mental/efeitos dos fármacos , Adulto , Agnosia/diagnóstico , Agnosia/psicologia , Dor Crônica/tratamento farmacológico , Dor Crônica/psicologia , Codeína/efeitos adversos , Codeína/uso terapêutico , Feminino , Dependência de Heroína/complicações , Dependência de Heroína/psicologia , Dependência de Heroína/reabilitação , Humanos , Masculino , Transtornos da Memória/diagnóstico , Transtornos da Memória/psicologia , Metadona/efeitos adversos , Metadona/uso terapêutico , Testes Neuropsicológicos , Fatores de Risco , Tramadol/efeitos adversos , Tramadol/uso terapêutico , Reino UnidoRESUMO
BACKGROUND: Previous studies have provided inconsistent evidence that chronic exposure to opioid drugs, including heroin and methadone, may be associated with impairments in executive neuropsychological functioning, specifically cognitive impulsivity. Further, it remains unclear how such impairments may relate of the nature, level and extent of opioid exposure, the presence and severity of opioid dependence, and hazardous behaviours such as injecting. METHOD: Participants with histories of illicit heroin use (n = 24), former heroin users stabilized on prescribed methadone (methadone maintenance treatment; MMT) (n = 29), licit opioid prescriptions for chronic pain without history of abuse or dependence (n = 28) and healthy controls (n = 28) were recruited and tested on a task battery that included measures of cognitive impulsivity (Cambridge Gambling Task, CGT), motor impulsivity (Affective Go/NoGo, AGN) and non-planning impulsivity (Stockings of Cambridge, SOC). RESULTS: Illicit heroin users showed increased motor impulsivity and impaired strategic planning. Additionally, they placed higher bets earlier and risked more on the CGT. Stable MMT participants deliberated longer and placed higher bets earlier on the CGT, but did not risk more. Chronic opioid exposed pain participants did not differ from healthy controls on any measures on any tasks. The identified impairments did not appear to be associated specifically with histories of intravenous drug use, nor with estimates of total opioid exposure. CONCLUSION: These data support the hypothesis that different aspects of neuropsychological measures of impulsivity appear to be associated with exposure to different opioids. This could reflect either a neurobehavioural consequence of opioid exposure, or may represent an underlying trait vulnerability to opioid dependence.
Assuntos
Analgésicos/efeitos adversos , Função Executiva/efeitos dos fármacos , Heroína/efeitos adversos , Comportamento Impulsivo/efeitos dos fármacos , Metadona/efeitos adversos , Adolescente , Adulto , Dependência de Heroína/tratamento farmacológico , Humanos , Masculino , Tratamento de Substituição de Opiáceos , Adulto JovemRESUMO
AIMS/HYPOTHESIS: We previously demonstrated that animals fed a high-fat (HF) diet for 10 weeks developed insulin resistance and behavioural inflexibility. We hypothesised that intervention with metformin would diminish the HF-feeding-evoked cognitive deficit by improving insulin sensitivity. METHODS: Rats were trained in an operant-based matching and non-matching to position task (MTP/NMTP). Animals received an HF (45% of kJ as lard; n = 24), standard chow (SC; n = 16), HF + metformin (144 mg/kg in diet; n = 20) or SC + metformin (144 mg/kg in diet; n = 16) diet for 10 weeks before retesting. Body weight and plasma glucose, insulin and leptin were measured. Protein lysates from various brain areas were analysed for alterations in intracellular signalling or production of synaptic proteins. RESULTS: HF-fed animals developed insulin resistance and an impairment in switching task contingency from matching to non-matching paradigm. Metformin attenuated the insulin resistance and weight gain associated with HF feeding, but had no effect on performance in either MTP or NMTP tasks. No major alteration in proteins associated with insulin signalling or synaptic function was detected in response to HF diet in the hypothalamus, hippocampus, striatum or cortex. CONCLUSIONS/INTERPRETATION: Metformin prevented the metabolic but not cognitive alterations associated with HF feeding. The HF diet protocol did not change basal insulin signalling in the brain, suggesting that the brain did not develop insulin resistance. These findings indicate that HF diet has deleterious effects on neuronal function over and above those related to insulin resistance and suggest that weight loss may not be sufficient to reverse some damaging effects of poor diet.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/metabolismo , Gorduras na Dieta/farmacologia , Resistência à Insulina/fisiologia , Metformina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Modelos Animais de Doenças , Hormônios/sangue , Hipoglicemiantes/farmacologia , Leptina/sangue , Masculino , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Falha de TratamentoRESUMO
Exposure to aversive environmental stimuli stimulates the serotonergic neurones that project to the forebrain and inhibit spontaneous activity when studied in a simple maze. This study explored the putative role of the principal 5-hydroxytryptamine (5-HT) neurones that project to the hippocampus from the median raphe nucleus in this response to an aversive environment by lesioning the 5-HT fibres that project through the fornix/fimbria and cingulum bundles. The effects of the lesions were investigated in independent groups of animals tested in an enclosed four-arm maze and a more aversive elevated maze of the same dimensions composed entirely of four open arms. The rats were significantly less active in the open maze, the principal effect of maze design being observed during the first 5 min sub-trial of a 15 min trial. This response to the more aversive environment was totally abolished by the lesion. It is concluded that exposure to an explicitly aversive environment elicits a brief stimulation of the 5-HT neurones that project to the hippocampus from the median raphe nucleus and that this stimulation inhibits the initial burst of exploratory activity that is observed in animals placed in a less aversive novel environment.
Assuntos
5,7-Di-Hidroxitriptamina/toxicidade , Comportamento Exploratório/efeitos dos fármacos , Fórnice/efeitos dos fármacos , Serotoninérgicos/toxicidade , Animais , Química Encefálica/efeitos dos fármacos , Corticosterona/sangue , Fórnice/citologia , Fórnice/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/patologia , Neurônios/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/patologia , Ratos , Ratos Wistar , Reforço Psicológico , Serotonina/metabolismoRESUMO
INTRODUCTION: There is a presumption that neurocognition is commonly impaired in chronic methadone exposed individuals (CM) when compared with healthy controls (HP). Additionally, it remains unclear if short term (<1year) abstinence (AP) is associated with an altered cognitive profile when compared with CM. METHOD: A random effect model approach was used on data assembled into the Comprehensive Meta-Analysis programme. Cohen's d effect sizes and a significance levels of p<0.01 were calculated for each domain. RESULTS: Data from a total cohort of 1063 CM, 412 AP and 879 HP participants, from 23 independent studies indicate global impairments in neurocognitive function in CM relative to HP participants. The smaller body of evidence comparing CM to AP participants is inconclusive. CONCLUSION: Methodological issues such as small sample sizes, heterogeneity and poor quality limited the interpretation of the results and does not address whether the observed impairments reflect co-morbid functioning, methadone-related sedation and/or other factors. Only higher quality longitudinal studies will permit confident interpretation of the results observed in this meta-analysis.
Assuntos
Metadona/farmacologia , Humanos , Estudos LongitudinaisRESUMO
Increased psychophysiological resistance to chronic stress has been related to increased 5-HT release in the dorsal hippocampus. This study investigated the changes in 5-HT release and turnover in the hippocampus evoked by acute and repeated exposure to an inescapable stressor, an elevated open platform, and compared them to the changes evoked in the frontal cortex. Repeated exposure to this stressor results in habituation of the plasma corticosterone response to the test, with full habituation being observed after 20 trials. Repeated exposure to the stressor for 5 or 10 occasions increased 5-HT turnover in the hippocampus. By contrast, 5-HT turnover in frontal cortex was increased by acute exposure to the stressor. Microdialysis studies showed that acute stress increased 5-HT overflow in prefrontal cortex but not dorsal hippocampus whereas repeated daily (10 days) exposure to the stressor increased basal extracellular 5-HT in the dorsal hippocampus, but not the prefrontal cortex. Prior exposure to the stressor on up to 10 occasions enhanced the plasma corticosterone response to a challenge in an elevated plus-maze performed 24h later whereas repeated, but not acute, exposure to the stressor, elicited anxiolytic-like behavioural responses in this test. It is concluded that acute exposure to this form of inescapable stress selectively stimulates the 5-HT projections to the frontal cortex; repeated stress elicits a sustained increase in 5-HT release and turnover in the hippocampus. The data are consistent with the hypothesis that increased 5-HT release in the hippocampus may be implicated in the mechanisms underlying habituation to inescapable stress.
Assuntos
Química Encefálica/fisiologia , Comportamento Exploratório/fisiologia , Aprendizagem em Labirinto/fisiologia , Estresse Fisiológico/fisiopatologia , Animais , Comportamento Animal , Cromatografia Líquida de Alta Pressão/métodos , Corticosterona/sangue , Hipocampo/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Modelos Lineares , Masculino , Microdiálise/métodos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Estresse Fisiológico/etiologia , Estresse Fisiológico/psicologia , Fatores de TempoRESUMO
Previous studies have shown that rats fed a high calorie diet rich in saturated fat for 12weeks exhibit peripheral insulin resistance and impairments of behavioural flexibility when switched from an operant delayed matching to place (DMTP) schedule to a delayed non-matching to place (DNMTP) schedule. However, the metabolic changes evoked by feeding a high fat (HF) diet can be observed within two weeks of commencing the diet. The current study has confirmed that 4weeks exposure to an HF diet resulted in increased body weight, peripheral insulin resistance and plasma leptin. Studies performed during weeks 3 and 4 on the HF diet revealed suppressed lever pressing rates and impaired behavioural flexibility in the operant DMTP/DNMTP task. When animals fed the HF diet were then returned to a standard chow (SC) diet for 5weeks their weight and blood biochemistry no longer differed from those measured in animals that had never been exposed to the HF diet. The animals restored to the SC diet exhibited a clear ability to acquire the DNMTP schedule of reinforcement although these animals continued to lever press at a lower rate when compared with animals that received the SC diet throughout. The data suggest that exposure to an HF diet diminishes the motivation to respond for a reward and, thus, the capacity to adapt behavioural performance. This deficit was ameliorated, but not totally reversed, by the dietary intervention. If also true for humans, the results suggest that deficits in behavioural flexibility develop after only a short period on a high calorie diet but may be largely reversible through simple dietary intervention, at least in the early stages of deficit development. However, the putative effects of short-term exposure to an HF diet on behavioural motivation may persist for some time after switching to a healthier low fat diet and remain a problem for those seeking to adopt a healthier diet.
Assuntos
Condicionamento Operante/fisiologia , Dieta Hiperlipídica/efeitos adversos , Transtornos Mentais/etiologia , Transtornos Mentais/reabilitação , Doenças Metabólicas/etiologia , Doenças Metabólicas/reabilitação , Análise de Variância , Animais , Glicemia , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Jejum , Insulina/sangue , Leptina/sangue , Masculino , Ratos , Ratos Wistar , Reforço Psicológico , Fatores de TempoRESUMO
During the last decade, nicotine has been used increasingly as an aid to smoking cessation and has been found to be a safe and efficacious treatment for the symptoms of nicotine withdrawal. This period has also seen significant advances in our understanding of the mechanisms underlying the psychopharmacological responses to nicotine, including, particularly, those that have been implicated in nicotine addiction. This paper reviews this decade of progress in the specific context of the therapeutic application of nicotine to the treatment of smoking cessation. Other putative future applications, particularly in the treatment of neurodegenerative disorders, are also reviewed.
Assuntos
Nicotina/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Receptores Nicotínicos/efeitos dos fármacos , Abandono do Hábito de Fumar , Doença de Alzheimer/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Ensaios Clínicos como Assunto , Portadores de Fármacos , Humanos , Nicotina/administração & dosagem , Nicotina/metabolismo , Nicotina/farmacocinética , Nicotina/farmacologia , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacologia , Doença de Parkinson/tratamento farmacológico , Receptores Nicotínicos/metabolismo , Síndrome de Abstinência a Substâncias , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológicoRESUMO
The renal effects of incremental infusions of norepinephrine (placebo, 0.025 mu/kg/min), 0.075 micrograms/kg/min, phenylephrine (placebo, 0.5 micrograms/kg/min, 2.5 micrograms/kg/min), and tyramine (placebo, 2 micrograms/kg/min, 15 micrograms/kg/min) were examined in three respective groups (n = 9, 8, and 8) of normotensive male subjects undergoing water diuresis. Tyramine is an indirect sympathetic agent that causes neuronal release of endogenous norepinephrine. Increases in mean arterial pressure during each high-dose infusion were comparable in all three groups. Both norepinephrine and phenylephrine caused a decrease in urinary sodium excretion and effective renal plasma flow, with no changes in glomerular filtration rate. Proximal tubular sodium reabsorption, as assessed by both lithium clearance and solute-free water clearance methods, was increased by pressor doses of norepinephrine and phenylephrine. In contrast, a similar pressor dose of tyramine was associated with a pressure natriuresis, an increase in effective renal plasma flow, and a decrease in proximal tubular sodium reabsorption. Our data indicate that, in normotensive humans, circulating catecholamines (norepinephrine and phenylephrine) have opposite effects on renal sodium handling from neuronally released norepinephrine (tyramine).
Assuntos
Natriurese/fisiologia , Neurônios/metabolismo , Norepinefrina/fisiologia , Adulto , Humanos , Masculino , Norepinefrina/farmacologia , Fenilefrina/farmacologia , Valores de Referência , TiraminaRESUMO
The effect of post-mortem treatment on the binding of d, I-[3H]nicotine, to rat cerebrocortical membranes, has been evaluated. Neither freezing [-70 degrees C] and thawing, a four hour post-mortem period at room temperature, nor refrigeration for up to 96 hrs at 4 degrees C caused any significant changes in the density or properties of nicotine binding sites in cerebrocortical membranes. The results suggest that nicotine binding to membranes in brain is unlikely to be affected by the usual postmortem delays experienced before human necropsies.
Assuntos
Receptores Nicotínicos/metabolismo , Animais , Córtex Cerebral/metabolismo , Cinética , Masculino , Membranas/metabolismo , Modelos Biológicos , Mudanças Depois da Morte , Ratos , Ratos EndogâmicosRESUMO
Low-dose (0.025 micrograms/kg per min) noradrenaline infusion, resulting in a physiological plasma increment (280 pg/ml), was antinatriuretic in normal salt-replete male subjects. The reduction in sodium excretion (-20%, P less than 0.01) occurred without any change in the glomerular filtration rate but was associated with a significant (P less than 0.02) decline in lithium clearance. These results suggest that changes in circulating noradrenaline, within the physiological range, can decrease sodium excretion in man by enhancing proximal tubular sodium reabsorption. These findings extend previous investigations in man which used pharmacological doses of noradrenaline and are in agreement with animal evidence for a renal tubular antinatriuretic effect of the sympathetic nervous system.
Assuntos
Natriurese , Norepinefrina/fisiologia , Adulto , Creatinina/metabolismo , Hemodinâmica , Humanos , Masculino , Norepinefrina/administração & dosagem , Norepinefrina/sangue , Postura , Distribuição Aleatória , Circulação RenalRESUMO
OBJECTIVE: The present study examines the effect of angiotensin converting enzyme inhibition on the renal haemodynamic and sodium excretory responses to noradrenaline in man. DESIGN: We studied the effects of intravenous noradrenaline (0.075 micrograms/kg per min) and enalapril pretreatment (5 mg/day for 5 days), alone and in combination, on urinary sodium excretion, effective renal plasma flow, glomerular filtration rate and segmental tubular function in nine normal subjects. METHODS: The subjects were studied during maximal water diuresis. The clearance of inulin and of para-aminohippurate were used to estimate the glomerular filtration rate and effective renal plasma flow, respectively. Segmental tubule handling of sodium was assessed by the lithium clearance method. RESULTS: Noradrenaline alone decreased urinary sodium excretion (P < 0.01) and the effective renal plasma flow (P < 0.01) without altering the glomerular filtration rate. Enalapril pretreatment significantly attenuated this fall in sodium excretion (P < 0.05) and effective renal plasma flow (P < 0.05), and had a similar attenuating effect on the noradrenaline-induced decrease in the fractional excretion of lithium. The pressor response to noradrenaline infusion was not, however, influenced by the enalapril pretreatment. CONCLUSIONS: Enalapril blunts the renal vasoconstrictive effect and the antinatriuretic effect of noradrenaline in man. Our results indicate that there is an important interaction between the sympathetic nervous system and the renin-angiotensin system in the kidneys in man.
Assuntos
Enalapril/farmacologia , Natriurese/efeitos dos fármacos , Norepinefrina/farmacologia , Adulto , Aldosterona/sangue , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Lítio/urina , Masculino , Sistema Renina-Angiotensina/fisiologia , Método Simples-Cego , Sistema Nervoso Simpático/fisiologiaRESUMO
The effect of a 20-min infusion of atrial natriuretic factor (ANF) 99-126, 0.4 microgram/kg per min, on both urinary albumin and beta 2-microglobulin excretion was examined in nine normal male subjects during stable water diuresis. ANF caused a rise in urinary albumin in excretion (from 4.19 +/- 0.66 to 13.49 +/- 3.07 ng/min, P less than 0.01) without any significant change in either creatinine clearance of beta 2-microglobulin excretion. These findings suggest that ANF may enhance glomerular permeability to albumin in man.
Assuntos
Albuminúria/urina , Fator Natriurético Atrial/farmacologia , Diuréticos/farmacologia , Fragmentos de Peptídeos/farmacologia , Microglobulina beta-2/urina , Adulto , Diurese , Humanos , Masculino , Estimulação QuímicaRESUMO
OBJECTIVE: The present study examines the role of alpha 1-adrenoceptors in determining the renal haemodynamic and sodium excretory responses to a physiological dose of angiotensin II in man. DESIGN: The effects of a low-dose infusion of angiotensin II (1 ng/kg per min) and a non-depressor dose of prazosin (0.25 mg), alone and in combination, on urinary sodium excretion (UNaV), effective renal plasma flow (ERPF), glomerular filtration rate (GFR) and segmental tubular function were studied in eight normal male subjects. METHODS: Subjects were studied undergoing maximal water diuresis. Clearances of inulin and para-aminohippurate were employed to estimate GFR and ERPF, respectively. Segmental tubular handling was assessed by both lithium clearance (CLi) and solute-free water methods. RESULTS: Angiotensin II decreased UNaV without altering ERPF and GFR. Angiotensin II caused a significant fall in fractional CLi, which may indicate a proximal tubular effect of angiotensin II. Angiotensin II alone also increased fractional reabsorption of sodium delivered to the distal nephron, as evaluated by both the CLi method and by estimation of solute-free water clearance. When angiotensin II was given in combination with prazosin, which on its own had no apparent effects on any renal parameters, the antinatriuretic and tubular effects of angiotensin II were significantly blunted. CONCLUSIONS: These findings suggest that low doses of circulating angiotensin II are able to modulate UNaV by increasing sodium reabsorption in the proximal and, to some extent, the distal nephron segment in man. The study also showed that a non-depressor dose of prazosin blunted the renal effects of angiotensin II, thereby providing tentative evidence of a renal interaction between alpha-adrenoceptors and angiotensin II in man.
Assuntos
Angiotensina II/antagonistas & inibidores , Angiotensina II/fisiologia , Natriurese/fisiologia , Prazosina/farmacologia , Receptores Adrenérgicos alfa/fisiologia , Adulto , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Humanos , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/fisiologia , Masculino , Natriurese/efeitos dos fármacos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Circulação Renal/efeitos dos fármacos , Circulação Renal/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologiaRESUMO
1. The effects of acute and subchronic nicotine and (+)-amphetamine on the extracellular levels of dopamine and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus accumbens (NAc) have been studied in conscious, freely-moving rats by use of in vivo microdialysis. 2. In rats which had been habituated to the test apparatus for approximately 80 min, the acute subcutaneous (s.c.) administration of nicotine (0.1 or 0.4 mg kg-1) caused a dose-dependent increase (P less than 0.01) in spontaneous activity and evoked significant increases (P less than 0.05) in the extracellular levels of DOPAC and HVA. 3. Measurements made 24 h after the last injection of nicotine showed that pretreatment with the higher doses tested (0.4 mg kg-1) resulted in increased basal levels of dopamine (P less than 0.01) and decreased basal levels of DOPAC (P less than 0.05) in the NAc dialysates. 4. Pretreatment with nicotine (0.1 or 0.4 mg kg-1 daily for 5 days) enhanced the effects of the drug on spontaneous locomotor activity and enhanced the effects of the drug on extracellular levels of dopamine to the extent that the response became significant (P less than 0.05). 5. If a dopamine uptake inhibitor, nomifensine, was added to the Ringer solution used to dialyse the probe, the s.c. administration of both acute and subchronic nicotine (0.4 mg kg-1) resulted in significant increases (P less than 0.05) in the dopamine concentration in the dialysate. Under these conditions, pretreatment with nicotine prior to the test day prolonged (P less than 0.05) the dopamine response to a challenge dose of nicotine.6. Subcutaneous injections of (+)-amphetamine (0.2 or 0.5 mg kg-') evoked dose-dependent increases in both spontaneous activity and the concentration of dopamine in NAc dialysates. These responses were unaffected by 5 days pretreatment with the drug.7. The results of this study support the conclusion that the enhanced locomotor response to nicotine observed in animals pretreated with the drug prior to the test day is associated with potentiation of its effects on dopamine secretion in the NAc.
Assuntos
Dopamina/metabolismo , Atividade Motora/efeitos dos fármacos , Nicotina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Dextroanfetamina/administração & dosagem , Dextroanfetamina/farmacologia , Ácido Homovanílico/metabolismo , Masculino , Nicotina/administração & dosagem , Nomifensina/farmacologia , Núcleo Accumbens/fisiologia , Ratos , Ratos EndogâmicosRESUMO
In vivo brain microdialysis was used to investigate the influence of lobeline on dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) overflow in the core of the nucleus accumbens of freely-moving rats pretreated with nicotine (0.4 mg x kg(-1), s.c., once per day for 5 days). Locomotion was also recorded. Lobeline, at doses of 0.7, 4.0 and 10.0 mg x kg(-1), i.p., failed to elicit any significant changes in extracellular dopamine or dihydroxyphenylacetic acid levels during the 60 min following its administration and did not stimulate locomotor. The dopamine responses to nicotine (0.4 mg x kg(-1), s.c.), were abolished (P<0.01) if the nicotine challenge was administered 10 min but not 60 min, after lobeline doses of 4.0 and 10.0 mg kg(-1), i.p., but were unaffected following lobeline at the lowest dose tested (0.7 mg x kg(-1), i.p.) at either time. The increase in locomotor activity was significantly attenuated (P<0.01), to a similar extent, when the nicotine was injected 10 min, but not 60 min, after all three doses of lobeline (0.7, 4.0 and 10.0 mg kg(-1), i.p.) when compared with the saline-treated rats. The results suggest that lobeline is a short-acting antagonist of the nicotinic AChRs which mediate the effects of nicotine on mesolimbic dopamine activity and locomotor stimulation.
Assuntos
Dopamina/fisiologia , Estimulantes Ganglionares/farmacologia , Lobelina/farmacologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Dopamina/metabolismo , Interações Medicamentosas , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
1. The effects of constant nicotine infusions (0.25, 1.0 and 4.0 mg kg-1 day-1) on extracellular dopamine levels in the nucleus accumbens (NAc) and on locomotor activity have been compared with the changes evoked by repeated daily injections (0.4 mg kg-1 day-1 for 5 days) of the drug. 2. The extracellular dopamine concentration in the NAc was significantly increased (P < 0.05) following a challenge dose of nicotine (0.4 mg kg-1, s.c.) in animals which had been pretreated with daily injections of the drug. This effect was accompanied by an enhanced locomotor response to nicotine. 3. The stimulant effects of nicotine on mesolimbic dopamine secretion and on locomotor activity were significantly inhibited (P < 0.01) by the prior administration of mecamylamine (2.0 mg kg-1, s.c.) but not by hexamethonium (2.0 mg kg-1, s.c.). 4. The constant infusion of nicotine at a rate of 1 and 4 but not 0.25 mg kg-1 day-1 abolished the sensitized dopamine response in the NAc to an injection of nicotine in animals pretreated with the drug. The locomotor responses to nicotine in the nicotine-pretreated rats were significantly attenuated by the infusion of nicotine at all 3 doses, although the nicotine induced locomotor activity, in the rats infused with 0.25 mg kg-1 day-1 was also significantly (P < 0.05) higher than that observed in the rats treated acutely with nicotine. 5. Significantly (P<0.01) enhanced mesolimbic dopamine responses, to a challenge injection of nicotine(0.4 mg kg-1, s.c.), were observed 2 and 7 days after termination of the infusion of nicotine (4 mg kg-1 day-1 for 14 days); locomotor responses were enhanced (P<0.01) 1, 2 and 7 days after termination of the infusion.6. The results suggest that sensitized mesolimbic dopamine responses to nicotine occur as a result of stimulation of centrally located nicotinic receptors but that these receptors may be desensitized during periods of chronic exposure to nicotine at doses which may be relevant to smoking.
Assuntos
Dopamina/metabolismo , Sistema Límbico/metabolismo , Nicotina/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Hexametônio/farmacologia , Ácido Homovanílico/metabolismo , Bombas de Infusão Implantáveis , Sistema Límbico/efeitos dos fármacos , Masculino , Mecamilamina/farmacologia , Microdiálise , Atividade Motora/efeitos dos fármacos , Nicotina/administração & dosagem , Nicotina/sangue , Ratos , Ratos Sprague-DawleyRESUMO
The effects of acute and subchronic (7) injections of nicotine (0.4 mg kg-1, s.c.) and of selective lesions of the 5-hydroxytryptaminergic (5-HTergic) pathways innervating the hippocampus on the spontaneous behaviour of rats in an elevated X-maze composed of two open and two enclosed runways have been examined. Subchronic, but not acute, nicotine increased total spontaneous activity. Neither acute nor subchronic nicotine altered the ratio of open:closed runway entries. Destruction of the 5-HTergic pathways innervating the hippocampus with 5,7-dihydroxytryptamine caused a reduction in the ratio of open:enclosed runway entries. Acute, but not subchronic, nicotine caused a significant increase in plasma corticosterone. The lesion had no effects on the plasma levels of this hormone. No significant interactions between the lesion and the responses to nicotine were observed. The data failed to provide any evidence that hippocampal 5-HTergic systems may be implicated in the effects of nicotine on the spontaneous behaviour of the rat.
Assuntos
Córtex Suprarrenal/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Neurônios/fisiologia , Nicotina/farmacologia , Serotonina/fisiologia , 5,7-Di-Hidroxitriptamina/farmacologia , Animais , Química Encefálica/efeitos dos fármacos , Corticosterona/sangue , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismoRESUMO
1. The repeated co-administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (0.1 and 0.3 mg kg-1, i.p.) with nicotine (0.4 mg kg-1, s.c.) attenuated the development of tolerance to the locomotor depressant effect of the nicotine in rats. 2. The repeated co-administration of the competitive NMDA antagonist D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid, 2 and 8 mg kg-1, i.p.) also attenuated tolerance to the locomotor depressant effect of nicotine. 3. Dizocilpine (0.3 mg kg-1, i.p.) pretreatment attenuated sensitization to the locomotor stimulant effect of nicotine (0.4 mg kg-1, s.c.) and prevented sensitization of nicotine-induced dopamine release in the nucleus accumbens. However, pretreatment with dizocilpine alone caused a modest enhancement of the behavioural response to a subsequent acute dose of nicotine. 4. D-CPPene (2.0 mg kg-1, i.p.) pretreatment prevented sensitization to the nicotine-induced dopamine release in the nucleus accumbens. There was no enhanced locomotor response that could be attributed to nicotine pretreatment when D-CPPene was co-administered with nicotine. However, pretreatment with D-CPPene alone enhanced the locomotor response to an acute dose of nicotine. 5. The results suggest the involvement of NMDA receptors in adaptations of the behavioural and neurochemical effects of nicotine that occur as a result of repeated administration of the drug.
Assuntos
Química Encefálica/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Atividade Motora/efeitos dos fármacos , Nicotina/farmacologia , Piperazinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Dopamina/análise , Dopamina/metabolismo , Tolerância a Medicamentos , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/efeitos dos fármacosRESUMO
1. In vivo brain microdialysis has been employed to investigate the effects of ibogaine on nicotine-induced changes in dopamine overflow in the nucleus accumbens (NAc) of freely moving rats. The effects of the compound on locomotor responses to nicotine and behaviour in the elevated plus-maze were also examined. 2. No changes were observed in the dopamine overflow or the locomotor activity of the animals following the administration of ibogaine (40 mg kg-1, i.p.). However, ibogaine, administered 22 h earlier, significantly (P < 0.01) attenuated the increase in dopamine overflow but not the hyperlocomotion, evoked by nicotine. 3. In the elevated plus-maze test, significant reductions in the open:total runway entries in both saline-treated controls (P < 0.05) and nicotine-treated (P < 0.01) rats were obtained when the animals were tested 22 h after pretreatment with ibogaine (40 mg kg-1, i.p.). The total activity was significantly (P < 0.01) greater in the nicotine-treated rats but this response was not affected by ibogaine pretreatment. 4. Administration of ibogaine was associated with reductions in the tissue levels of 5-hydroxyindoleacetic acid (5-HIAA) in the NAc (P < 0.01) and striatum (P < 0.05) and an increase in the level of this metabolite in the medial prefrontal cortex (mPFC) (P < 0.01) while the levels of dopamine and 5-hydroxytryptamine (5-HT) in the mPFC were reduced (P < 0.05). The DOPAC/dopamine (P < 0.05) and 5-HIAA/5-HT (P < 0.01) ratios were significantly increased in the mPFC for at least 7 days after a single treatment with ibogaine. 5. Ibogaine attenuates the nicotine-induced increases in dopamine overflow in the NAc and may, therefore, inhibit the rewarding effects of this drug. However, the long lasting anxiogenesis induced by ibogaine warrant further investigation before its use could be recommended for smokers.