RESUMEN
Both ionotropic and metabotropic glutamate receptors (mGluRs) are involved in the behavioral effects of pyschostimulants; however, the specific contributions of individual mGluR subtypes remain unknown. Here we show that mice lacking the mGluR5 gene do not self-administer cocaine, and show no increased locomotor activity following cocaine treatment, despite showing cocaine-induced increases in nucleus accumbens (NAcc) dopamine (DA) levels similar to wild-type (WT) mice. These results demonstrate a significant contribution of mGlu5 receptors to the behavioral effects of cocaine, and suggest that they may be involved in cocaine addiction.
Asunto(s)
Cocaína/farmacología , Actividad Motora/efectos de los fármacos , Receptores de Glutamato Metabotrópico/fisiología , Refuerzo en Psicología , Animales , Cocaína/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados/genética , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/deficiencia , Receptores de Glutamato Metabotrópico/genética , Valores de Referencia , AutoadministraciónRESUMEN
The [14C]2-deoxyglucose method was applied to measure the effects of the synthetic cannabinoid agonist WIN 55212-2 intravenous administration on glucose utilization in the rat brain. Two doses of the drug, that have been reported previously to increase extracellular dopamine concentrations in the shell of the nucleus accumbens, were used (0.15-0.30 mg/kg). At the lower dose, WIN 55212-2 increased energy metabolism selectively in the accumbens shell. Conversely, the higher dose of the drug reduced glucose utilization in the hippocampal formation and ventromedial thalamic nucleus without affecting energy metabolism in the accumbens shell. These results may be useful to further understanding the addictive potentials of cannabinoid drugs.
Asunto(s)
Encéfalo/metabolismo , Desoxiglucosa/farmacocinética , Morfolinas/farmacología , Naftalenos/farmacología , Animales , Benzoxazinas , Encéfalo/efectos de los fármacos , Cannabinoides/administración & dosificación , Cannabinoides/farmacología , Radioisótopos de Carbono/farmacocinética , Metabolismo Energético/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inyecciones Intravenosas , Masculino , Morfolinas/administración & dosificación , Naftalenos/administración & dosificación , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-Dawley , Núcleos Talámicos/efectos de los fármacos , Núcleos Talámicos/metabolismoRESUMEN
Vulnerability to develop drug abuse could be related to differential sensitivity to some central effects of such drugs. Several results point to mesoaccumbens dopamine release elicited by psychostimulants as the rate-limiting factor of their reinforcing, hence addictive, effects and to locomotor stimulation as an indirect index of such a response. In this paper, we report parallel differences in sensitivity to amphetamine-induced locomotor stimulation and mesoaccumbens dopamine release in two inbred strains of mice characterized by differential susceptibility to develop drug self-administration. Thus, mice of the C57BL/6 strain responded with a simultaneous increase of locomotor activity and mesoaccumbens dopamine release measured by intracerebral microdialysis to amphetamine challenge. On the contrary, mice of the DBA/2 strain did not present either response. No strain differences in mesoaccumbens dopamine outflow or 3,4-dihydroxyphenylacetic acid concentration were found in basal conditions or following saline challenges. However, mice of the C57BL/6 strain were characterized by higher levels of accumbal homovanillic acid in basal conditions, in line with the results obtained in rats rendered more sensitive to the locomotor effects of psychostimulants by repeated administration. Finally, in both strains amphetamine decreased accumbal levels of the two metabolites. These results suggest that genotype modulates the locomotor effects of amphetamine through sensitivity of the mesoaccumbens system to amphetamine-stimulated dopamine release. Moreover, they provide a basis to test the hypothesis of mesoaccumbens dopamine involvement in individual susceptibility to the addictive effects of drugs by quantitative trait loci analysis in recombinant inbred strains.
Asunto(s)
Anfetamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Microdiálisis , Núcleo Accumbens/efectos de los fármacos , Especificidad de la EspecieRESUMEN
The effects of selective D1 or D2 dopamine receptor agonists and the indirect dopamine agonist cocaine on hippocampal acetylcholine release in mice of the C57BL/6 and DBA/2 inbred strains were investigated using intracerebral microdialysis. The D1 SKF 38393 (10, 20, 30 mg/kg, i.p.), the D2 agonist LY 171555 (0.5, 1, 2 mg/kg, i.p.) and cocaine (5, 10, 15 mg/kg, i.p.) all increased, dose-dependently, acetylcholine release in the hippocampus of C57BL/6 mice. Both the D1 agonist and cocaine did not produce any significant effect in DBA/2 mice. In the latter strain, however, LY 171555 produced a decrease in acetylcholine release that was evident after 60 min from injection of the doses of 0.5 and 1 mg/kg, but not at the dose of 2 mg/kg. The effects observed in C57BL/6 mice as well as those produced by low doses of LY 171555 in the DBA/2 strain were consistent with previous results obtained in rats. The present results indicate major strain-dependent differences in the effects of dopamine agonists on hippocampal acetylcholine release in mice. Moreover, they suggest a complex genotype-related neural organization of dopamine-acetylcholine interactions in the mesolimbic system. Finally, the strain differences in the effects of the dopamine agonists on hippocampal acetylcholine release parallel previously reported strain differences in the effects of these substances on memory consolidation.
Asunto(s)
Acetilcolina/metabolismo , Agonistas de Dopamina/farmacología , Hipocampo/metabolismo , Ratones Endogámicos C57BL/metabolismo , Ratones Endogámicos DBA/metabolismo , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Cocaína/farmacología , Hipocampo/efectos de los fármacos , Ratones , MicrodiálisisRESUMEN
The activity of cholinergic interneurons in the striatum appears to be modulated by a variety of different systems including dopamine, opiate, and glutamate. The purpose of this study was to characterize the effects of drugs known to act on these three systems (i.e., cocaine, morphine, and MK-801) on striatal ACh overflow with microdialysis procedures, and to determine if alterations in ACh function induced by these agents are related to changes in locomotor activity. Cocaine was found to increase striatal ACh following intraperitoneal injections of 20 and 40 mg/kg, but not 10 mg/kg. The increases in locomotor activity induced by cocaine appeared to be dose dependent, while the effects on striatal ACh were not. Injections of 0.1 mg/kg MK-801 (a non-competitive NMDA receptor antagonist) produced dramatic increases in locomotor activity while decreasing striatal ACh overflow. A lower dose (0.03 mg/kg) of MK-801 failed to alter locomotor activity or striatal ACh. Morphine produced an apparent dose-dependent elevation in striatal ACh while only the lowest dose (5 mg/kg) increased locomotor activity. There appears to be no relationship between alterations in striatal ACh and locomotor output following systemic administration of these psychoactive agents.
Asunto(s)
Acetilcolina/metabolismo , Cocaína/farmacología , Maleato de Dizocilpina/farmacología , Morfina/farmacología , Actividad Motora/efectos de los fármacos , Neostriado/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Electroquímica , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Masculino , Microdiálisis , Neostriado/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Different types of clinically effective antidepressants prevent the behavioral effects of experimental stress, and some of these treatments affect mesolimbic dopamine (DA) functioning. Animal studies have demonstrated that repeated psychostimulant administration and repeated or chronic stressful experiences also affect mesolimbic DA functioning. These results could suggest homologies among stress, psychostimulants and antidepressants. The present experiments show that either repeated stress (120 min restraint daily for 10 consecutive days) or subchronic treatment with the antidepressant minaprine (5 mg/kg daily for 10 consecutive days) significantly reduced the inhibitory effect of 120 min of restraint on climbing, a behavioral response dependent on mesolimbic DA functioning. However, the antidepressant did not induce the altered sensitivity of presynaptic DA receptors promoted by repeated stress. Chronic stressful experience (13 days of food restriction) and repeated amphetamine (2.5 mg/kg daily for 10 consecutive days) were as effective as subchronic minaprine in reducing immobility in the Porsolt's swimming test. However, whilst both stress and amphetamine enhanced struggling, minaprine promoted swimming. Finally, chronically stressed mice and mice pretreated with amphetamine showed enhanced sensitivity to amphetamine-induced locomotion, whilst this effect was absent in animals pretreated with the antidepressant. These results indicate that although chronic and repeated stress as well as amphetamine have some antidepressant-like behavioral effects, their mode of action could be different from that of clinically active substances.
Asunto(s)
Anfetamina/farmacología , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Piridazinas/farmacología , Estrés Psicológico/psicología , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos , Cloruro de Sodio/farmacología , Factores de TiempoRESUMEN
Post-training administration of the inhibitor of cholinesterase enzymes, physostigmine, dose-dependently (0.025-0.4 mg/kg) improved retention of an inhibitory avoidance response in C57BL/6 (C57) as well as in DBA/2 (DBA) mice, the latter being more responsive than C57 mice. The effects on retention performance induced by physostigmine in C57 and DBA mice appeared to be due to an effect on memory consolidation. In fact, they were observed when drugs were given at short, but not long, periods of time after training, which is when the memory trace is susceptible to modulation. Moreover, these effects are not to be ascribed to a rewarding or non-specific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during the training were not affected by the post-training drug administration. Post-training administration of cocaine (1-5 mg/kg) dose-dependently improved retention of an inhibitory avoidance response in C57 mice, while impairing it in the DBA strain, thus confirming previous results (Puglisi-Allegra et al. 1994b). Pretreatment with cocaine at ineffective doses as well as at an effective one potentiated the effects of an ineffective as well as of an effective dose of physostigmine in C57 mice, while it antagonized the effects of the inhibitor of cholinesterase enzymes on memory consolidation in DBA mice. The present results indicate that the indirect DA receptor agonist cocaine affects physostigmine action on memory consolidation in an opposite manner in the two inbred strains, pointing to genotype-dependent interaction between cholinergic and dopaminergic activity in memory consolidation.
Asunto(s)
Reacción de Prevención/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Cocaína/farmacología , Memoria/efectos de los fármacos , Narcóticos/farmacología , Fisostigmina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Electrochoque , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratas , Especificidad de la EspecieRESUMEN
It has been proposed by some that the D1 receptor effects are mediated through striatal actions while others have suggested that they are determined indirectly through the frontal cortex. The experiments reported here represent a further attempt to resolve this controversy. It was found that focal applications of the inactive and active enantiomers of SKF-38393 (a D1 dopamine receptor agonist) to the rat striatum via reverse dialysis increased extracellular acetylcholine (ACh) in a stereoselective manner. Infusions of SKF-38393 into the frontal cortex, on the other hand, were ineffective in altering striatal ACh. Furthermore, partial hemisections caudal to the frontal cortex did not alter the ability of systemically administrated SKF-38393 to increase striatal ACh. Taken together, these results suggest that at least some of the effects of D1 receptor agonists on striatal cholinergic function are mediated through actions in the striatum and not the frontal cortex.
Asunto(s)
2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Acetilcolina/metabolismo , Cuerpo Estriado/efectos de los fármacos , Lóbulo Frontal/efectos de los fármacos , Receptores de Dopamina D1/fisiología , Animales , Cuerpo Estriado/metabolismo , Lóbulo Frontal/metabolismo , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , EstereoisomerismoRESUMEN
The effects of repeated restraint stress exposures (daily 60 min, for 6 days) on extracellular dopamine in the nucleus accumbens, during and after the stress experience, have been investigated in rats by in vivo microdialysis. On the first day, restraint increased dopamine release during the first 40 min followed by a return to basal levels (50-60 min later). As soon as restraint ceased and the rats were set free, there was another increase in dopamine release lasting 40 min. On the second and third day, restraint produced only a slight increase in dopamine release, while no significant changes were evident from the fourth to the sixth day. By contrast, from the second to the sixth day the increase in dopamine release observed once rats were freed, was unchanged in comparison to the first day. The present results show that the activation of the mesolimbic dopaminergic system induced by aversive stimuli adapts to repeated experiences differently from that produced by pleasurable events, suggesting that aversive and rewarding experiences involve different neural systems.
Asunto(s)
Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Estrés Fisiológico/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Catéteres de Permanencia , Cromatografía Líquida de Alta Presión , Diálisis , Haloperidol/farmacología , Ácido Homovanílico/metabolismo , Masculino , Núcleo Accumbens/fisiología , Ratas , Ratas Endogámicas , Restricción Física , Factores de TiempoRESUMEN
Galanin-like immunoreactive terminals hyperinnervate the basal forebrain cholinergic neurons in Alzheimer's disease. To investigate the hypothesis that galanin acts directly on basal forebrain cell bodies, in vivo microdialysis studies were conducted in awake rats which analyzed the actions of galanin on acetylcholine release. Microinjection of galanin into the cholinergic cell body region of the medial septum-diagonal band (MS-DBB) inhibited acetylcholine release in the ventral hippocampus. These results are consistent with an interpretation that galanin terminals synapsing on cholinergic cell bodies of the basal forebrain may serve to inhibit the release of acetylcholine in the terminal fields of the cholinergic neurons.
Asunto(s)
Acetilcolina/antagonistas & inhibidores , Galanina/farmacología , Hipocampo/metabolismo , Escopolamina/farmacología , Tabique Pelúcido/fisiología , Acetilcolina/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Masculino , Microdiálisis , Microinyecciones , Ratas , Ratas Sprague-Dawley , Escopolamina/antagonistas & inhibidoresRESUMEN
The effect of the administration of the muscarinic cholinergic agonist oxotremorine on locomotor activity was investigated in DBA/2 mice subjected to chronic restraint stress of different durations (120 min daily for 10, 14 or 18 days). Oxotremorine induced a depressant effect on locomotion, which was reduced after 10 and 14 days of restraint, but not after a 18-day restraint stress. Acetylcholine (ACh) content was significantly reduced in prefrontal cortex after 10 and 14 days of stress but returned to control values after 18 days of restraint. No changes in ACh content were observed in nucleus accumbens and striatum. These results are discussed in terms of possible changes in muscarinic receptor sensitivity.
Asunto(s)
Acetilcolina/metabolismo , Actividad Motora/efectos de los fármacos , Agonistas Muscarínicos/farmacología , Oxotremorina/farmacología , Estrés Fisiológico/metabolismo , Adaptación Psicológica/efectos de los fármacos , Animales , Cromatografía Líquida de Alta Presión , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Habituación Psicofisiológica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos DBA , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Restricción Física , Factores de TiempoRESUMEN
Systemic administration of the 5-HT3 receptor antagonist ICS 205-930, but not of the benzodiazepine diazepam, was able to prevent the stimulation of dopamine release in the nucleus accumbens and prefrontal cortex induced by restraint stress. These findings suggest that stress is not simply co-extensive with anxiety and that 5-HT3 receptors could regulate the dopaminergic response to stress.
Asunto(s)
Corteza Cerebral/metabolismo , Diazepam/farmacología , Dopamina/metabolismo , Indoles/farmacología , Núcleo Accumbens/metabolismo , Núcleos Septales/metabolismo , Antagonistas de la Serotonina/farmacología , Estrés Fisiológico/metabolismo , Animales , Masculino , Ratas , Ratas Endogámicas , TropisetrónRESUMEN
The aim of the study was to determine whether cocaine causes a different pattern of functional changes in the rat as compared to the mouse. The [(14)C]2-deoxyglucose method, for measuring local cerebral metabolic rates for glucose, was carried out in Sprague-Dawley rats and in two strains of mice, C57BL/6 and DBA/2, following a single intravenous administration of cocaine. Cocaine, according to previous reports, increased glucose utilization in the nucleus accumbens of the rat, while the drug decreased metabolic rates in most of brain areas of both strains of mice. The post-hoc analysis, however, suggests that the pattern of metabolic changes differ in the two strains. In particular, the effect on the shell of the nucleus accumbens was present in the C57, but not in the DBA mice. As the C57 mice are more likely than DBA to initiate cocaine self-administration, the effect on the nucleus accumbens support the role of the mesolimbic pathway in mediating the motivational properties of psychostimulants.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cocaína/farmacología , Glucosa/metabolismo , Vasoconstrictores/farmacología , Animales , Antimetabolitos/farmacocinética , Radioisótopos de Carbono , Desoxiglucosa/farmacocinética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratas , Ratas Sprague-Dawley , Especificidad de la EspecieRESUMEN
Using brain microdialysis, acetylcholine (Ach) levels were assessed in the nucleus amygdaloideus lateralis of electrically kindled rats using a cholinesterase inhibitor in the perfusion fluid to prevent Ach breakdown. During kindling development, when the animals displayed afterdischarges lasting more than 30 s but no seizures, a significant increase in Ach levels (+66%) was observed after electrical stimulation. Ach levels were also elevated after a stage 5 kindled seizure (+48%), with no additional increment compared to rats experiencing only afterdischarges. Chronic diazepam administration prevented kindling development and the increment in Ach overflow; however, diazepam itself (following acute administration) tended to decrease Ach levels in the amygdala. These findings are convergent with pharmacological data suggesting that changes in the cholinergic function may be important especially during amygdaloid kindling development.
Asunto(s)
Acetilcolina/metabolismo , Amígdala del Cerebelo/metabolismo , Excitación Neurológica , Animales , Diazepam/farmacología , Estimulación Eléctrica , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , Convulsiones/etiología , Convulsiones/metabolismo , Convulsiones/prevención & controlRESUMEN
Two distinct pathways are thought to connect the striatum to the basal ganglia output nuclei: a direct pathway, originating from neurons bearing dopamine, D(1) receptors and an indirect pathway, originating from neurons expressing D(2) receptors. It has been recently suggested, however, that dopamine receptor sub-types may co-localize and co-operate in the striatum. We sought to verify the functional segregation of the two pathways by measuring cerebral glucose utilization following intrastriatal injection of selective D(1) (SKF 38393), D(2) (quinpirole), or non-selective indirect (amphetamine) and direct (apomorphine) dopamine agonists, in freely-moving rats. All drugs -- regardless of receptor selectivity -- reduced glucose utilization in nuclei of both the direct and indirect pathways, thus lending further support to the existence of a functional co-operation of striatal D(1) and D(2) receptors.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Agonistas de Dopamina/farmacología , Glucosa/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Anfetamina/farmacología , Animales , Apomorfina/farmacología , Ganglios Basales/efectos de los fármacos , Ganglios Basales/metabolismo , Cuerpo Estriado/metabolismo , Núcleo Entopeduncular/efectos de los fármacos , Núcleo Entopeduncular/metabolismo , Globo Pálido/efectos de los fármacos , Globo Pálido/metabolismo , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Quinpirol/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/biosíntesis , Receptores de Dopamina D2/biosíntesis , Núcleo Subtalámico/efectos de los fármacos , Núcleo Subtalámico/metabolismoRESUMEN
The present study was designed to assess the anxiety profile of the selectively bred alcohol-preferring sP and alcohol-nonpreferring sNP rats. Rats were offered either water (ethanol-naive rats) or a free choice of 10% (v/v) ethanol and water (ethanol-experienced rats) for 14 consecutive days prior to the test. Spontaneous exploration of an elevated plus maze was used as a behavioral measure of anxiety. Ethanol-naive sP rats spent less time in and made fewer entries into the open arms of the maze than ethanol-naive sNP rats. These results suggest a higher innate degree of anxiety in sP than in sNP rats. Moreover, time spent in and number of entries into the open arms of the maze were higher in ethanol-experienced than in ethanol-naive sP rats. This finding suggests that ethanol consumed voluntarily produces anxiolytic effects in sP rats. The results of the present study are discussed in terms of (a) anxiety as a genetic trait related to ethanol-preference in sP rats and (b) self-medication of anxiety as a possible factor promoting voluntary ethanol consumption in sP rats.
Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Ansiedad/genética , Consumo de Bebidas Alcohólicas/psicología , Animales , Ansiedad/psicología , Modelos Animales de Enfermedad , Ingestión de Líquidos/fisiología , Ambiente , Masculino , RatasRESUMEN
The [14C]2-deoxyglucose method allows us to investigate whether a drug affects cerebral functional activity in selected brain regions or along discrete neural pathways. Employment of the method in laboratory animals has shown that substances of abuse produce a wide variety of cerebral functional changes which depend upon a number of different variables including the kind of substance, the dose, the modality of administration, and the context. In spite of such a variability, different substances of abuse, when injected in a rat at doses, or with modalities effective in inducing self-administration, have in common the property of selectively modifying glucose utilization of the nucleus accumbens, in particular in the shell portion. It is likely that the change reflects a functional change of a neural circuitry which mediates motivational properties associated with addiction.
Asunto(s)
Mapeo Encefálico , Trastornos Relacionados con Sustancias/fisiopatología , Animales , Estimulantes del Sistema Nervioso Central , Nicotina , Agonistas Nicotínicos , RatasRESUMEN
Intracranial injections of 5 micrograms/fish (equivalent to 2 nmol/g) of the dopamine agonist Apomorphine into the paradise fish brain considerably decrease the occurrence of escape behavior with a parallel increase of time spent in swimming. All other elements of the behavioral repertoire are unaffected. The simultaneous administration of 0.5 micrograms/fish (equivalent to 0.15 nmol/g) of the dopamine antagonist Pimozide abolishes this effect. In a second experiment a dose dependent decrease in escape behavior was obtained with a parallel increase of swimming. On the bases of these pharmacological data it is concluded that the escape and the swimming reactions are truly independent units but their regulation might be closely related.