RESUMEN
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.
Asunto(s)
Receptores Nicotínicos/metabolismo , Animales , Corteza Cerebral/metabolismo , Cinética , Masculino , Membranas/metabolismo , Modelos Biológicos , Cambios Post Mortem , Ratas , Ratas EndogámicasRESUMEN
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.
Asunto(s)
Dopamina/metabolismo , Actividad Motora/efectos de los fármacos , Nicotina/farmacología , Núcleo Accumbens/efectos de los fármacos , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Dextroanfetamina/administración & dosificación , Dextroanfetamina/farmacología , Ácido Homovanílico/metabolismo , Masculino , Nicotina/administración & dosificación , Nomifensina/farmacología , Núcleo Accumbens/fisiología , Ratas , Ratas EndogámicasRESUMEN
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.
Asunto(s)
Dopamina/fisiología , Estimulantes Ganglionares/farmacología , Lobelina/farmacología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Dopamina/metabolismo , Interacciones Farmacológicas , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Dopamina/metabolismo , Sistema Límbico/metabolismo , Nicotina/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Hexametonio/farmacología , Ácido Homovanílico/metabolismo , Bombas de Infusión Implantables , Sistema Límbico/efectos de los fármacos , Masculino , Mecamilamina/farmacología , Microdiálisis , Actividad Motora/efectos de los fármacos , Nicotina/administración & dosificación , Nicotina/sangre , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Corteza Suprarrenal/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Neuronas/fisiología , Nicotina/farmacología , Serotonina/fisiología , 5,7-Dihidroxitriptamina/farmacología , Animales , Química Encefálica/efectos de los fármacos , Corticosterona/sangre , Ácido Hidroxiindolacético/metabolismo , Masculino , Neuronas/efectos de los fármacos , Ratas , Ratas Endogámicas , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismoRESUMEN
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.
Asunto(s)
Química Encefálica/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Actividad Motora/efectos de los fármacos , Nicotina/farmacología , Piperazinas/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Dopamina/análisis , Dopamina/metabolismo , Tolerancia a Medicamentos , Masculino , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/efectos de los fármacosRESUMEN
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.
Asunto(s)
Química Encefálica/efectos de los fármacos , Ibogaína/farmacología , Actividad Motora/efectos de los fármacos , Nicotina/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Dopamina/metabolismo , Ácido Hidroxiindolacético/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismoRESUMEN
The effects of nicotine administration and its withdrawal on the levels of brain hydroxyindoles and plasma corticosterone have been studied in the rat. Daily injections of nicotine (0.4 mg/kg s.c.) rapidly induced tolerance to the increase in plasma corticosterone seen in response to acute nicotine. Withdrawal of the drug from chronically treated animals caused a significant increase in plasma corticosterone. Hippocampal 5-hydroxytryptamine (5-HT) was reduced in nicotine-treated rats, significantly so in those treated for more than 20 days. The 5-hydroxyindole acetic acid (5-HIAA) concentration in the hippocampus was also reduced by nicotine although this was not a consistent observation. Hypothalamic 5-hydroxyindoles were not affected by nicotine administration itself, but, if the drug was withdrawn, the concentration of 5-HT was increased after 5 days treatment. The changes in the hypothalamus and hippocampus appeared to be relatively specific since they differed from those seen in the rest of the brain. None of the effects could be related directly to changes in the plasma corticosterone concentration.
Asunto(s)
Encéfalo/metabolismo , Corticosterona/sangre , Ácido Hidroxiindolacético/metabolismo , Nicotina/farmacología , Serotonina/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Animales , Encéfalo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Hipotálamo/metabolismo , Masculino , Ratas , Factores de TiempoRESUMEN
The effects of chronic nicotine administration (0.4 mg/kg for 40 days) and its withdrawal on the adrenocortical response to acute and repeated exposure to stress have been examined and related to changes in brain 5-hydroxyindole levels. No significant effects on the response to acute stress were observed. Repeated exposure to the stressful procedure resulted in complete adaptation of the adrenocortical response and the development of a significant (P less than 0.01) positive correlation between the plasma corticosterone and hippocampal 5-HT concentrations. In nicotine-treated rats, complete adaptation did not occur and the plasma corticosterone showed a significant (P less than 0.05) negative correlation with hippocampal 5-HT. Nicotine withdrawal was not associated with any reduction in plasma corticosterone, but did abolish its relationship with hippocampal 5-HT.
Asunto(s)
Adaptación Psicológica/efectos de los fármacos , Nicotina/farmacología , Estrés Fisiológico/metabolismo , Animales , Corticosterona/sangre , Hipocampo/análisis , Masculino , Ratas , Ratas Endogámicas , Serotonina/análisisRESUMEN
The influence of tetrodotoxin (TTX) and calcium on the increase of extracellular dopamine (DA) levels in the nucleus accumbens (NAcc), evoked by the systemic administration of nicotine, cocaine and d-amphetamine, have been studied in conscious, freely moving rats using in vivo microdialysis. TTX (10(-6) M), administered via the dialysis probe, completely abolished (P < 0.01) the elevations in extracellular DA, DOPAC and HVA seen following nicotine (0.4 mg/kg SC). The removal of calcium with the inclusion of diaminoethanetetraacetic acid (EDTA 10(-4) M) in the Ringer solution was also associated with inhibition (P < 0.01) of the nicotine-induced changes in these parameters. The systemic administration of cocaine (15 mg/kg IP) and d-amphetamine (0.5 mg/kg SC) caused elevations in extracellular DA (P < 0.01) accompanied by significant decreases (P < 0.01) in HVA levels. DOPAC levels were also significantly (P < 0.01) lowered by d-amphetamine treatment. The presence of TTX and removal of calcium with addition of EDTA completely abolished the changes in NAcc DA and HVA induced by cocaine. TTX had no influence on the d-amphetamine evoked responses in NAcc DA. However, the metabolites, which were markedly reduced by the TTX, were not further decreased by the systemic administration of d-amphetamine. NAcc DA was significantly (P < 0.01) raised following d-amphetamine in the absence of calcium and presence of EDTA. However, this was significantly (P < 0.01) attenuated in comparison to that seen in the presence of calcium. The results support the conclusion that, at the dose tested, nicotine evokes increases in extracellular NAcc DA levels by calcium and impulse-dependent mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Calcio/farmacología , Dopamina/metabolismo , Espacio Extracelular/metabolismo , Nicotina/farmacología , Tetrodotoxina/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Cocaína/farmacología , Dextroanfetamina/farmacología , Espacio Extracelular/efectos de los fármacos , Ácido Homovanílico/metabolismo , Masculino , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
This paper describes the results of a postmortem study of the effects of tobacco smoking on the concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) as well as the binding of [3H]-8-hydroxy-(di-n-propylamino)-tetralin ([3H]-8-OH-DPAT) and [3H]-ketanserin in six discrete regions of human brain. Smoking was associated with significant decreases in the concentrations of 5-HIAA in the hippocampal neocortex (P less than 0.001), hippocampal formation (P less than 0.05) and the median raphe nuclei (P less than 0.05). The 5-HT level of the hippocampal formation was also significantly reduced in smokers (P less than 0.05). These changes were accompanied by significant increases in the binding of [3H]-8-OH-DPAT in the hippocampal neocortex (P less than 0.01) and hippocampal formation (P less than 0.05). [3H]-Ketanserin binding in the brain regions studied was unaffected by smoking. It is concluded that smoking is associated with a regionally selective decrease in the activity of the serotonergic system of the human hippocampus.
Asunto(s)
Química Encefálica/efectos de los fármacos , Serotonina/metabolismo , Fumar/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin , Anciano , Anciano de 80 o más Años , Unión Competitiva/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Ácido Hidroxiindolacético/metabolismo , Ketanserina/farmacología , Masculino , Persona de Mediana Edad , Tetrahidronaftalenos/metabolismoRESUMEN
A majority of habitual tobacco smokers find it very difficult to quit the habit because they become addicted to the nicotine present in tobacco smoke. Nicotine, like other psychostimulant drugs of abuse, increases dopamine release in the principal terminal field of the mesolimbic system, the nucleus accumbens, and there is evidence that this mediates the 'rewarding' properties of the drug, which reinforce its self-administration. This review focuses on the working hypothesis that addiction to nicotine, and other psychostimulant drugs, depends upon their ability to evoke a sustained increase in dopamine release directly into the extracellular space which lies between the cells in the nucleus accumbens where it stimulates extra-synaptic dopamine receptors. It is suggested that increased stimulation of these receptors is associated with increased incentive learning or the attribution of increased incentive salience to the cues associated with acquisition and delivery of the drug. The hypothesis proposes that these cues can become conditioned reinforcers of drug-taking behaviour. The receptors, which mediate the effects of nicotine on mesoaccumbens dopamine neurones, are desensitised by sustained exposure to nicotine at concentrations commonly found in the plasma of habitual smokers. It is proposed that, at times when the plasma nicotine concentration is sufficiently high to cause desensitisation of the receptors, tobacco smoking is maintained by the conditioned reinforcers present in the tobacco smoke. The hypothesis predicts, therefore, that conditioned reinforcement may play a more important role in the addiction to tobacco than for most other addictive behaviours. As a result, studies with nicotine have the potential to contribute to our understanding of the neurobiology of addiction which cannot easily be explored using drugs, such as cocaine and amphetamine, which invariably increase dopamine overflow in the forebrain.
Asunto(s)
Dopamina/fisiología , Sistema Límbico/fisiopatología , Mesencéfalo/fisiopatología , Transmisión Sináptica/fisiología , Tabaquismo/fisiopatología , Animales , Condicionamiento Clásico/fisiología , Espacio Extracelular/fisiología , Humanos , Motivación , Núcleo Accumbens/fisiopatologíaRESUMEN
The effects of acute, repeated intermittent and continuous administration of nicotine on the overflow of noradrenaline in the ventral hippocampus and dopamine in the nucleus accumbens and striatum have been studied. Daily injections of nicotine (0.4 mg/kg(-1) for 5 days) enhanced noradrenaline and dopamine overflow in the ventral hippocampus and nucleus accumbens respectively (P < 0.01 and P < 0.05) but not dopamine in the striatum in response to a nicotine challenge. The responses in the ventral hippocampus and nucleus accumbens were attenuated (P < 0.01) by the constant infusion of nicotine at a dose of 1 mg kg(-1) per day; the dopamine response in the striatum required a higher dose (4 mg kg(-1) per day) before desensitisation was observed. The data suggest that the dopamine projections to the striatum are less sensitive to both stimulation and desensitisation by nicotine than the catecholamine projections to the ventral hippocampus and nucleus accumbens.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Estimulantes Ganglionares/farmacología , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Nicotina/farmacología , Norepinefrina/metabolismo , Animales , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Inhibidores de Captación de Dopamina/farmacología , Interacciones Farmacológicas , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Nomifensina/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-Dawley , Tetrodotoxina/farmacologíaRESUMEN
The effects of acute and chronic nicotine administration and its withdrawal on the rates of uptake and formation of 5-HT and the uptake of L-tryptophan, by synaptosomes prepared from discrete brain regions, have been studied in the rat. Both the acute and chronic (40 days) administration of nicotine (0.4 mg/kg s.c.) caused a decrease in the rate of formation of 5-HT by hippocampal synaptosomes (P less than 0.05) while 24 h withdrawal of the drug from chronically treated rats resulted in a partial recovery of this effect. Chronic nicotine treatment also reduced the rate of L-tryptophan uptake by hippocampal synaptosomes (P less than 0.01) an effect which appeared to be the result of a reduction in the number of L-tryptophan carrier molecules in the synaptosomal membrane. This effect, which was not reversed by withdrawal of the drug for 24 h, was not seen in synaptosomes prepared from other regions of the rat brain.
Asunto(s)
Encéfalo/metabolismo , Nicotina/farmacología , Serotonina/metabolismo , Animales , Encéfalo/efectos de los fármacos , Hipocampo/metabolismo , Técnicas In Vitro , Indoles/metabolismo , Masculino , Proteínas del Tejido Nervioso/metabolismo , Ratas , Ratas Endogámicas , Serotonina/biosíntesis , Sinaptosomas/metabolismo , Triptófano/metabolismoRESUMEN
Acute administration of the NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid; 2 mg/kg), abolished (P < 0.01) the sensitised mesoaccumbens dopamine response to nicotine (0.4 mg/kg) measured using in vivo microdialysis, but not the increased locomotor activity, observed in rats pretreated with nicotine prior to the test day. D-CPPene enhanced (P < 0.01) the mesoaccumbens dopamine response, but not the locomotor response, to acute nicotine given to drug-naive rats. The data suggest that sensitised mesoaccumbens dopamine responses to nicotine involve co-stimulation of NMDA receptors but that this effect is not closely related to sensitisation of the locomotor response to the drug.
Asunto(s)
Dopamina/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Locomoción/efectos de los fármacos , Nicotina/farmacología , Piperazinas/farmacología , Animales , Masculino , Microdiálisis , Ratas , Ratas Sprague-DawleyRESUMEN
This article reviews the evidence that pretreatment with nicotine causes a regionally selective sensitization of its stimulatory effects on a pathway, the mesoaccumbens dopamine (DA) system, which has been implicated in the locomotor stimulant response to nicotine and its ability to reinforce self-administration. The sensitization evoked by daily injections of nicotine is associated with a regionally selective downregulation of the control of mesoaccumbens DA neurons by inhibitory autoreceptors and depends upon co-stimulation of NMDA glutamatergic receptors. It is suggested that the sensitization is related to enhanced burst firing of mesoaccumbens neurons, which results in an enhancement of DA release into the extracellular space between the cells where it acts upon putative extrasynaptic dopamine receptors. The studies with NMDA receptor antagonists revealed a dissociation between the expression of sensitized mesoaccumbens DA and locomotor responses to nicotine. It is proposed, therefore, that the sensitized mesoaccumbens DA responses to nicotine may be implicated in psychopharmacological responses to drug concerned more closely with nicotine dependence.
Asunto(s)
Dopamina/metabolismo , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Animales , Inhibidores de Captación de Dopamina/farmacología , Humanos , Nomifensina/farmacologíaRESUMEN
Two nicotine binding sites with dissociation constants for nicotine of approximately 3 nM and 12 microM respectively have been found in homogenates of rat hippocampus, hypothalamus, parietal cortex and mesencephalon, the greatest density of high affinity binding sites being in parietal cortex (30.0 +/- 3.0 fmol (mg protein)-1), the lowest in hypothalamus (16.1 +/- 1.0 fmol (mg protein)-1). The density of the low affinity sites (approx. 20 pmol (mg protein)-1) did not show any regional variation. Neither site was present in homogenates of medulla oblongata. The accumulation of radioactivity following the subcutaneous administration of [3H]nicotine (0.4 mg kg-1) was rapid, the highest concentrations being found in the brain regions with the highest density of high affinity binding sites. Medulla oblongata did not accumulate radioactivity above the concentration found in plasma. The chronic administration of nicotine (0.4 mg kg-1 s.c. daily for 39 days) had no significant effects on [3H]nicotine binding to brain tissue or its accumulation into brain following subcutaneous administration. It is concluded that nicotine readily passes from plasma into brain tissue and is accumulated in the areas containing high affinity binding sites for the compound. It is also concluded that the biochemical and behavioural effects reported previously in response to the chronic daily administration of nicotine do not depend upon changes in its uptake or binding by brain tissue.
Asunto(s)
Encéfalo/metabolismo , Nicotina/metabolismo , Animales , Técnicas In Vitro , Cinética , Masculino , Nicotina/farmacología , Ratas , Ratas Endogámicas , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/metabolismo , Fracciones Subcelulares/metabolismoAsunto(s)
5-Hidroxitriptófano/metabolismo , Betametasona/farmacología , Hipocampo/metabolismo , Hipotálamo/metabolismo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Animales , Corticosterona/sangre , Hipocampo/efectos de los fármacos , Ácido Hidroxiindolacético/metabolismo , Hipotálamo/efectos de los fármacos , Masculino , Ratas , Serotonina/metabolismoRESUMEN
In a postmortem study of nicotinic receptors in human brain, cigarette smoking was found to be associated with increased (-)-[3H]nicotine binding to membranes prepared from gyrus rectus (Brodmann area 11) (p less than 0.001), hippocampal neocortex (Brodmann area 27), cerebellar cortex (p less than 0.01), hippocampal formation (Ammon's horn + subiculum), and the median raphe nuclei of the midbrain (p less than 0.05) but not the medulla oblongata. Analysis of the binding data suggested that the increased binding reflected an increase in the density of the receptors rather than a change in their affinity for (-)-nicotine. The effects of smoking were not influenced significantly by either the sex or age of the subject. It is concluded that smoking evokes an increase in high-affinity nicotine binding similar to that observed previously in animals treated chronically with nicotine and that the effect of smoking on these sites is probably caused by the nicotine present in the tobacco smoke.
Asunto(s)
Encéfalo/metabolismo , Receptores Nicotínicos/metabolismo , Fumar/metabolismo , Anciano , Membrana Celular/metabolismo , Corteza Cerebelosa/metabolismo , Femenino , Lóbulo Frontal/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Bulbo Raquídeo/metabolismo , Persona de Mediana Edad , Nicotina/metabolismo , Núcleos del Rafe/metabolismo , Caracteres SexualesRESUMEN
The present study examined the effects of constant nicotine infusions on dopamine overflow in the nucleus accumbens and on locomotor activity and compared them with the changes evoked by repeated daily injections (one injection per day for 5 days) of the drug. The putative anxiolytic properties of nicotine have also been examined using the elevated plus-maze test of anxiety. Repetitive daily subcutaneous injections of nicotine (0.4 mg/kg) enhanced (P < 0.01) the overflow of dopamine evoked by a challenge dose of the drug (0.4 mg/kg) and increased (P < 0.01) its stimulatory effects on locomotor activity. The constant infusion of nicotine, at doses of 1 and 4 mg/kg per day, abolished (P < 0.05) the effects of a bolus injection of nicotine on extracellular dopamine and attenuated (P < 0.01) the enhanced locomotor response evoked by daily pretreatment with nicotine boli. The mesolimbic dopamine response to a bolus injection of nicotine was not significantly attenuated by nicotine infusions when the dose was reduced to 0.25 mg/kg per day. The locomotor responses in these rats were significantly (P < 0.05) less than those seen in the animals pretreated with nicotine injections alone but were also higher (P < 0.05) than those seen in saline-treated control rats given a bolus injection of nicotine. Neither the constant infusion (4 mg/kg per day) nor the injection of nicotine (0.4 mg/kg) evoked an anxiolytic or anxiogenic effect in the elevated plus-maze test. However, the nicotine infusions did abolish the locomotor stimulant effects of the drug in this apparatus.(ABSTRACT TRUNCATED AT 250 WORDS)