Exogenous GM1 ganglioside increases accumbal BDNF levels in rats.

Gangliosides are compounds that are abundant throughout the CNS, participating actively in neuroplasticity. We previously described that exogenous GM1 ganglioside pretreatment enhances the rewarding properties of cocaine, evidenced by a lower number of sessions and/or dosage necessary to induce conditioned place preference (CPP). Since GM1 pretreatment did not modify cocaine's pharmacokinetic parameters, we suspected that the increased rewarding effect found might be mediated by BDNF, a neurotrophic factor closely related to cocaine addiction. This study was performed to investigate the possibility that GM1 may induce changes in BDNF levels in the nucleus accumbens (NAc), a core structure in the brain's reward circuitry, of rats submitted to three conditioning sessions with cocaine (10 mg/kg, i.p.). The results demonstrate that GM1 administration, which showed no rewarding effect by itself in the CPP, induced a significant increase of BDNF protein levels in the NAc, which may account for the increased rewarding effect of cocaine shown in the CPP paradigm.

GM1 ganglioside enhances the rewarding properties of cocaine in rats.

GM1 pretreatment enhanced the rewarding properties of cocaine as assessed in the conditioned place preference paradigm. This effect was shown by the lower dosage of cocaine necessary to induce conditioning compared with rats receiving cocaine alone, as well as by the fewer number of sessions necessary to induce place preference. GM1 pretreatment did not modify the plasma level of cocaine, but it induced a significant increase in the brain cocaine level compared with animals receiving cocaine alone. In order to evaluate the possibility that GM1 pretreatment may alter the pharmacokinetic parameters of cocaine, the brain and plasma esterase activities, the plasma bound/free cocaine ratio and the brain blood barrier permeability to i.v. Evans Blue administration were assessed. None of these parameters was modified by the GM1 administration. In addition, GM1 (100microM) did not alter the dopamine transporter inhibition induced by cocaine (10(-7)-10(-5)M), as determined by the uptake of [(3-)H]-dopamine in the microsacs of nucleus accumbens. In conclusion, GM1 pretreatment, which did not have any effect per se, increased the rewarding effect of cocaine, a phenomenon correlated with a significant increase in the brain cocaine levels. The different pharmacokinetic parameters evaluated, as well as the inhibitory effect of cocaine on the dopamine transporter, were not modified by GM1, but it modifies the brain cocaine disposition. Thus, the mechanisms by which GM1 enhanced the rewarding effects of cocaine merit further study.

Altered serotonergic function of dorsal raphe nucleus in perinatally protein-deprived rats: effects of fluoxetine administration.

We have previously described that perinatally undernourished rats showed increased locus coeruleus activity, a phenomenon reversed by repeated desipramine or fluoxetine administration. Since there is reciprocal modulation between the locus coeruleus and the dorsal raphe nucleus, and because these structures are associated with the pathophysiology of different states of anxiety, we evaluated the activity of serotonergic dorsal raphe neurons from early malnourished animals compared with controls, using in vivo extracellular single-unit recordings. The number of spontaneously active cells/track was significantly higher in protein-deprived animals, although the firing rate and the sensitivity of 5-HT(1A) receptors did not differ from those of controls. Five days of fluoxetine administration (5 mg/kg/day i.p.) was able to reverse the increased number of active serotonergic cells without affecting their firing rate. Furthermore, subsensitivity of 5-HT(1A) autoreceptors developed in the same way after repeated fluoxetine administration in both control and protein-deprived animals. These results suggest that the increased noradrenergic transmission observed in protein-deprived animals may induce an activation of serotonergic neurons in the dorsal raphe nucleus, and that this effect is normalized following fluoxetine treatment, which normalizes locus coeruleus activity.

Pharmacological reactivity to cocaine in adult rats undernourished at perinatal age: behavioral and neurochemical correlates.

The influence of neuronal alterations induced by early undernutrition on the stimulant effect of cocaine was assessed in adult rats submitted to a protein deprivation schedule at perinatal age. To evaluate the sensitization phenomenon induced by repeated cocaine administration, different groups of control (C) and deprived (D) rats received a daily injection of cocaine (5, 10 or 15 mg/kg, i.p.) for 16 days. Behavioral parameters were assessed every two days in an open-field. Dose-response curves obtained with different doses of cocaine used revealed a shift to the left in the locomotor activity curves of D rats compared to controls. Thus, D animals showed a clear behavioral sensitization to the lower dose of cocaine, whereas this phenomenon was only observed in C rats for the higher dose used. To correlate this differential development of sensitization with neurochemical parameters, we assessed extracellular dopamine (DA) levels in nucleus accumbens (core and shell) and in the dorsal caudate-putamen, using a microdialysis technique. A challenge with cocaine in cocaine pre-exposed animals produced a different increase in DA output only in nucleus accumbens "core" of D animals. Comparable DA levels were observed in nucleus accumbens shell and in dorsal caudate-putamen of both groups. These results demonstrate that D rats had a lower threshold developing a progressive behavioral sensitization following repeated cocaine administration, as well as higher responsiveness of the nucleus accumbens (core) expressed by increased DA release.

Locus coeruleus activity in perinatally protein-deprived rats: effects of fluoxetine administration.

We have previously described an increased locus coeruleus activity in perinatally protein-deprived rats. Since locus coeruleus dysfunction has been involved in different types of anxiety disorders and considering the modulating action of serotonergic transmission on locus coeruleus activity, we assessed the effect of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on locus coeruleus activity as measured by the firing rate and the number of spontaneously active cells/track. Repeated fluoxetine administration reduced locus coeruleus activity in both control and protein-deprived rats, although the reduction was greater in protein-deprived rats. Dose-response curves for the inhibitory effect of clonidine showed subsensitivity of alpha2-adrenergic autoreceptors in protein-deprived rats, a phenomenon reversed by fluoxetine treatment. Dose-response curves for the inhibitory effect of 2,5-dimethoxy-4-iodoamphetamine (DOI) were similar in both groups of rats. Following fluoxetine administration, subsensitivity to this effect developed in control but not in protein-deprived rats. Extracellular noradrenaline level in the prefrontal cortex, as measured by microdialysis procedure, was higher in protein-deprived rats compared to controls, and this difference was reduced after fluoxetine administration. A challenge with yohimbine increased the extracellular noradrenaline level in control but not in protein-deprived rats, suggesting subsensitivity of alpha2-adrenergic autoreceptors in early protein malnourished animals. These results stress the complexity of plastic changes induced by early protein malnutrition and sustain the hypothesis that perinatally protein-deprived rats may represent a useful animal model for screening antipanic agents.

Perinatal undernutrition impairs spatial learning in recovered adult rats

Se estudió la capacidad de aprendizaje de ratas deprivadas de proteínas durante la etapa perinatal (ratas D) comparándolas con ratas controles (ratas-C) en el test de navegación espacial de Morris. Las ratas-D mostraron mayores latencias de escape para localizar una plataforma sumergida en ausencia de pistas proximales durante el período de adquisición de la prueba. Una experiencia de pre-entrenamiento a las condiciones de nado no mejoró este déficit. Al evaluar la retención de la información espacial a 1, 3, 10 y 30 días posteriores al entrenamiento, no se observaron diferencias significativas entre los grupos. Tampoco se encontró diferencia en el aprendizaje con plataforma visible, resultado que nos permite descartar alteraciones en la capacidad motora del animal deprivado. En conclusión, los resultados sugieren que la hiponutrición perinatal induce un déficit en la capacidad del animal adulto recuperado para resolver eficientemente el test de navegación espacial, aún después de un prolongado período de recuperación nutricional

Perinatal undernutrition impairs spatial learning in recovered adult rats

Se estudió la capacidad de aprendizaje de ratas deprivadas de proteínas durante la etapa perinatal (ratas D) comparándolas con ratas controles (ratas-C) en el test de navegación espacial de Morris. Las ratas-D mostraron mayores latencias de escape para localizar una plataforma sumergida en ausencia de pistas proximales durante el período de adquisición de la prueba. Una experiencia de pre-entrenamiento a las condiciones de nado no mejoró este déficit. Al evaluar la retención de la información espacial a 1, 3, 10 y 30 días posteriores al entrenamiento, no se observaron diferencias significativas entre los grupos. Tampoco se encontró diferencia en el aprendizaje con plataforma visible, resultado que nos permite descartar alteraciones en la capacidad motora del animal deprivado. En conclusión, los resultados sugieren que la hiponutrición perinatal induce un déficit en la capacidad del animal adulto recuperado para resolver eficientemente el test de navegación espacial, aún después de un prolongado período de recuperación nutricional (AU)

Perinatal undernutrition alters different pharmacological effects of ethanol in adult recovered rats

Distintos efectos del etanol fueron estudiados en ratas adultas sometidas a un esquema de deprivación proteica en edad perinatal. La respuesta hipotérmica e hipnótica del etanol fue mayor en los animales experimentales que en los controles, mientras que el efecto anticonflicto del etanol fue menor en los animales deprivados. No se encontraron diferencias en el "clearance" plasmático del etanol entre los animales controles y experimentales. Estos resultados demuestran que el efecto deletéreo de la hiponutrición temprana persiste en el animal adulto recuperado nutricialmente e induce una reactividad alterada a distintos tratamientos farmacológicos

Perinatal undernutrition alters different pharmacological effects of ethanol in adult recovered rats

Distintos efectos del etanol fueron estudiados en ratas adultas sometidas a un esquema de deprivación proteica en edad perinatal. La respuesta hipotérmica e hipnótica del etanol fue mayor en los animales experimentales que en los controles, mientras que el efecto anticonflicto del etanol fue menor en los animales deprivados. No se encontraron diferencias en el "clearance" plasmático del etanol entre los animales controles y experimentales. Estos resultados demuestran que el efecto deletéreo de la hiponutrición temprana persiste en el animal adulto recuperado nutricialmente e induce una reactividad alterada a distintos tratamientos farmacológicos (AU)