RESUMO
In previous studies we described that perinatal protein deprivation facilitates the development and expression of behavioral sensitization to cocaine. In this research, we explored whether the increased reactivity observed in deprived (D) versus control (C) rats is also evident during drug-free withdrawal periods. Considering that activation of the extracellular signal-regulated protein kinase (ERK) is suggested to be involved in cocaine-induced behavioral sensitization, we study the effects of perinatal protein deprivation on phosphorylated ERK2 (pERK2) protein levels in the NAc (core and shell) during different drug-free withdrawal periods. To induce behavioral sensitization, C- and D-rats received a daily injection of cocaine (5-10 mg/kg, i.p.) for 7 days and locomotor activity was performed on days 1 and 7. Cocaine-sensitized animals were left drug-free and pERK2 was assessed on withdrawal days (WD) 1, 4, 7 and 21. In the NAc core, cocaine induced ERK signaling pathway activation in a dose-dependent manner, and only D-rats showed a significant increase in pERK2 protein levels with the lowest dose of cocaine (5 mg/kg). Moreover, sensitized C-rats with 10 mg/kg showed an increase in pERK2 levels from WD7 while D-rats showed this activation on WD4, which remained increased on WD7 and 21. In contrast, in the NAc shell, only sensitized D-rats with cocaine 10 mg/kg showed ERK2 activation on WD21. These results suggest that perinatal protein deprivation facilitates the molecular processes involved in neuronal plasticity occurring during withdrawal.
Assuntos
Cocaína/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Desnutrição/metabolismo , Núcleo Accumbens/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Ratos , Ratos WistarRESUMO
The development of sensitization to the locomotor effects of morphine and cross-sensitization between morphine and cocaine were evaluated in adult rats submitted to a protein malnutrition schedule from the 14th day of gestation up to 30 days of age (D-rats), and compared with well-nourished animals (C-rats). Dose-response curves to morphine-induced locomotor activity (5, 7.5, 10 or 15 mg/kg, i.p., every other day for 5 days) revealed a shift to the left in D-rats compared to C-rats. This implies that D-rats showed behavioral sensitization to the lower dose of morphine used (5 mg/kg), which was ineffective in C-rats. Furthermore, when a cocaine challenge (10 mg/kg, i.p) was given 48 h after the last morphine administration, only D-rats exhibited cross-sensitization in morphine-pretreated animals (7.5 and 10 mg/kg). In order to correlate the differential response observed with the functioning of the mesocorticolimbic dopaminergic system, extracellular dopamine (DA) levels were measured in the nucleus accumbens (core and shell) and the dorsal caudate-putamen. A challenge with cocaine in morphine pre-exposed animals produced an increase in DA release, but only in the nucleus accumbens "core" of D-rats. Similar DA levels were found in the nucleus accumbens "shell" and in the dorsal caudate-putamen of both groups. Finally, these results demonstrate that D-rats had a lower threshold for developing both a progressive behavioral sensitization to morphine and a cross-sensitization to cocaine. In accordance with these behavioral findings, a higher responsiveness of the nucleus accumbens core, expressed by increased DA levels, both basal and after cocaine challenge, was observed in D-rats.
Assuntos
Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Locomoção/efeitos dos fármacos , Desnutrição/fisiopatologia , Morfina/farmacologia , Entorpecentes/farmacologia , Envelhecimento , Animais , Núcleo Caudado/efeitos dos fármacos , Núcleo Caudado/fisiopatologia , Cocaína/administração & dosagem , Cocaína/sangue , Dopamina/metabolismo , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/sangue , Relação Dose-Resposta a Droga , Feminino , Locomoção/fisiologia , Masculino , Morfina/administração & dosagem , Morfina/sangue , Entorpecentes/administração & dosagem , Entorpecentes/sangue , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Putamen/efeitos dos fármacos , Putamen/fisiopatologia , Ratos , Ratos WistarRESUMO
In the current research, we assessed the influence of a protein malnutrition schedule from the 14th day of gestation up to 40 days of age (D-rats) on the rewarding properties of morphine in adult rats by means of the conditioned place preference paradigm. Well-nourished animals (C-rats) administered with different doses of morphine (0.75, 1.5, 3, 6, 12 or 24 mg/kg i.p.) exhibited a conditioning place preference with doses of 3 and 6 mg/kg, whereas in D-rats such a conditioning effect was observed with doses of 1.5 and 3 mg/kg. No adverse effects were observed in either C- or D-rats for the higher doses of morphine. In addition, when animals of both groups were pretreated twice a day for 3 days with increasing doses of morphine (5, 10 and 20 mg/kg s.c.), only D-rats elicited sensitization to the conditioning effect with the lowest dose of morphine (0.75 mg/kg i.p.). Furthermore, sensitized D-rats showed a selective and significant increase in FosB expression in the nucleus accumbens (core and shell), basolateral amygdala and medial prefrontal cortex, brain areas that are functionally related to the rewarding neural circuit. These results demonstrate that a deficient nutritional status during the perinatal period results in adult subjects having neural alterations, leading to an increased responsiveness to morphine and/or enhanced reinforcement effects, which correlates with an overexpression of FosB in selective brain areas related to the rewarding network.
Assuntos
Encéfalo/efeitos dos fármacos , Transtornos da Nutrição Fetal/fisiopatologia , Dependência de Morfina/fisiopatologia , Morfina/farmacologia , Deficiência de Proteína/fisiopatologia , Recompensa , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiopatologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/metabolismo , Sistema Límbico/fisiopatologia , Dependência de Morfina/metabolismo , Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiopatologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Gravidez , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
The rewarding properties of cocaine were assessed in adult rats submitted to a protein malnutrition schedule from the 14th day of gestation up to 40 days of age (deprived rats), as compared with well-nourished animals (control rats) using the conditioned place preference paradigm. Dose-response curves to cocaine (3, 5, 10, 15, 30, 45 or 60 mg/kg i.p.) revealed in deprived rats a conditioning effect with doses of 5 and 10mg/kg; doses of 15 and 30 mg/kg did not show any conditioning place preference and doses of 45 and 60 mg/kg revealed a significant aversive effect. In control rats, cocaine elicited place preference with doses of 10, 15 and 30 mg/kg, whereas 45 and 60 mg/kg did not show either conditioning or aversive effects. Furthermore, sensitization to the conditioning effect of cocaine was obtained in deprived animals with a low dosage of cocaine, that was ineffective in controls (5 mg/kg/day for 10 days). Related to the higher rewarding effects, sensitized deprived rats showed a selective and significant increase in FosB expression in nucleus accumbens (core and shell) and basolateral amygdala, brain areas related to the rewarding neuronal circuits. These results suggest that a deficient nutritional status during early life may induce in adult subjects an increased responsiveness to behavioral effects of cocaine and/or enhanced its reinforcement properties.
Assuntos
Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Desnutrição Proteico-Calórica/fisiopatologia , Recompensa , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Imuno-Histoquímica , Masculino , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , RatosRESUMO
The spontaneous activity of locus coeruleus (LC) noradrenergic neurons was assessed by single unit recording in adult recovered rats undernourished at perinatal age as compared with wellnourished animals. Locus coeruleus activity, measured by the firing rate of noradrenergic neurons and the number of spontaneously active cells/track was significantly higher in deprived rats than in controls. In addition, dose-response curves for the inhibitory LC activity of clonidine showed a shift to the right in deprived animals indicating a subsensitivity of alpha2-adrenergic autoreceptors. This fact suggests an alteration in the negative feedback mechanism mediated by somatodentritic alpha2 autoreceptors that modulate the activity of LC neurons, and may account for the behavioral alterations attributed to early undernutrition. Repeated desipramine (DMI) administration to deprived rats reduced LC activity to values comparable to controls, which were not affected after a similar treatment. These data extend to previous reports on long-lasting or permanent plastic changes in the CNS induced by early undernutrition, which may be reverted by pharmacological manipulations. In addition, these results support the hypothesis that alterations induced by early undernutrition are in the same direction as and resemble those described for patients with panic disorders. Furthermore, together with behavioral alterations and selective anxiolytic effect of DMI and other drugs with antipanic effects described in early malnourished rats, the present data support the proposal that perinatally deprived rats may be a useful model for screening drugs with potential antipanic activity.
Assuntos
Desipramina/farmacologia , Locus Cerúleo/fisiopatologia , Neurônios/fisiologia , Distúrbios Nutricionais/fisiopatologia , Animais , Clonidina/farmacologia , Feminino , Locus Cerúleo/efeitos dos fármacos , Modelos Animais , Neurônios/efeitos dos fármacos , Gravidez , Ratos , Ratos WistarRESUMO
Adult female rats, undernourished at perinatal age, were evaluated for anxiolytic action in the plus-maze test after acute and chronic administration of diazepam (DZP) and pentobarbital (PTB). Deprived (D) rats chronically treated with vehicle showed an increased anxiety as compared with control (C) animals. A single intraperitoneal (i.p.) administration of DZP (1 mg/kg) or PTB (7.5 mg/kg) produced similar anticonflict effect in both C and D rats. Tolerance to the anxiolytic effect of DZP and PBT developed in C rats after a 15-day administration schedule, whereas no tolerance was observed in D animals. Drug disposition was not altered after chronic treatment either in C or in D rats. Gamma-aminobutyric acid (GABA)-mediated chloride uptake in microsacs of cerebral cortex of naive D rats was decreased as compared with naive C rats. After chronic DZP administration (1 mg/kg/day i.p. for 15 days), GABA-mediated 36Cl- influx in brain cortex microsacs of C rats did not change; however, GABA efficacy was increased in microsacs of D animals. In addition, chronic DZP treatment induced GABA-benzodiazepine uncoupling in brain cortex of C rats, but not in D animals, as assessed by chloride uptake in microsacs. Chronic PTB treatment (7.5 or 30 mg/kg/day i.p. for 15 days) did not modify GABA stimulation or GABA-PTB interaction in cortical microsacs of C or D rats.
Assuntos
Animais Recém-Nascidos/fisiologia , Ansiolíticos/administração & dosagem , Diazepam/administração & dosagem , Distúrbios Nutricionais/fisiopatologia , Pentobarbital/administração & dosagem , Fenômenos Fisiológicos da Nutrição Animal , Animais , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Encéfalo/metabolismo , Cloretos/farmacocinética , Diazepam/farmacocinética , Diazepam/farmacologia , Sinergismo Farmacológico , Tolerância a Medicamentos/fisiologia , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Pentobarbital/farmacocinética , Pentobarbital/farmacologia , Ratos , Ratos Wistar , Fatores de Tempo , Ácido gama-Aminobutírico/farmacologiaRESUMO
Adult female rats, receiving a low protein diet at perinatal age and then recovered with balanced chow (D rats), were evaluated in the Open Field Drink Test (OFDT), after different acute and chronic treatments with benzodiazepines (BZD) ligands, as compared with control (C) female rats. Control and D rats showed similar reactivity to acute administration of diazepam (DZP, 1 mg/kg) and FG 7142 (2.5mg/kg), both BZD ligands with anxiolytic and anxiogenic effects, respectively. After chronic DZP treatment (3mg/kg/day i.p. for 3 weeks), C rats developed tolerance to the anxiolytic effect of DZP as well as withdrawal syndrome upon abrupt interruption of chronic treatment. On the contrary, D animals failed to develop tolerance to the anxiolytic effect of DZP, and did not show an increased anxiety upon withdrawal. The functionality of the GABAA receptor-complex, as measured by (36)Cl(-) uptake in cortical cerebral microsacs, was not altered in the DZP withdrawn rats. The lack of tolerance and withdrawal syndrome may be related to the incapacity of D rats to generate adaptive changes after chronic treatments. For instance, C rats showed a lower anxiety level in the OFDT after chronic vehicle administration, whereas D animals did not evidence such an adaptive response. Furthermore, D rats failed to respond to the anxiolytic effect of DZP after chronic vehicle treatment. These results reassert the deleterious effects of perinatal undernutrition on the capacity to develop adaptive responses to repeated drug administration or adequate stimuli.
RESUMO
We have previously reported that recovered adult rats undernourished at perinatal age failed to develop tolerance to the anticonflict effect of ethanol after chronic ethanol administration (1 g/kg/day during 30 days) (4). To further study the extent of this finding, we examined the effect of a similar chronic ethanol treatment on the hypothermic and anticonvulsant effects of ethanol in perinatally deprived rats. Hypoalgesic activity was assessed in ethanol treated rats during 15 days. After chronic ethanol treatment, a similar development of tolerance to the hypothermic effect of ethanol was observed in control and deprived rats. However, tolerance to the anticonvulsant and hypoalgesic effect of ethanol was significantly reduced in deprived as compared with control animals. Thus, early undernutrition differentially affects the development of tolerance elicited by chronic ethanol administration.
Assuntos
Etanol/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Desnutrição Proteico-Calórica/fisiopatologia , Animais , Ansiolíticos/farmacologia , Temperatura Corporal/efeitos dos fármacos , Dieta com Restrição de Proteínas , Tolerância a Medicamentos , Etanol/administração & dosagem , Feminino , Medição da Dor/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar , Convulsões/fisiopatologiaRESUMO
The reactivity of 5-HT receptors following repeated immobilization sessions or after immobilization plus morphine was measured through 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) or 8-hydroxy-2-(dipropyl-amino)tetralin (8-OH-DPAT)-induced serotonergic syndrome in adult rats undernourished at perinatal age. Repeated stress enhanced the scores of forepaw treading and hindlimb abduction elicited by 5-MeODMT in control animals. In a similar way, forepaw treading induced by 8-OH-DPAT was enhanced in chronically stressed control rats. These results indicate the development of supersensitivity in 5-HT1 receptors. Conversely, this effect was not observed in undernourished animals. Morphine injections before each stress session instaured the increased reactivity to 5-HT1 sites in malnourished animals. An injection of naloxone prior to morphine before each stress session fully antagonized the increased behavioral reactivity to 5-MeODMT observed in deprived animals. A possible deficiency in the functional role of the opiate system involved in the process of adaptation to chronic stress in early undernourished rats is suggested.
Assuntos
Endorfinas/fisiologia , Distúrbios Nutricionais/metabolismo , Receptores de Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Adaptação Fisiológica , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Proteínas Alimentares/administração & dosagem , Feminino , Imobilização/efeitos adversos , Imobilização/fisiologia , Metoxidimetiltriptaminas/farmacologia , Morfina/farmacologia , Naloxona/farmacologia , Ratos , Receptores de Serotonina/efeitos dos fármacos , Estresse Fisiológico/metabolismoRESUMO
Learning ability of adult rats undernourished at perinatal age and nutritionally recovered (D-rats) was assayed in the Morris water maze test as compared with controls (C-rats). D-rats showed longer escape latencies to locate a hidden platform in absence of proximal cues during the acquisition period. Swimming pre-training experience did not improve this shortcoming. Retention scores obtained 1, 3, 10 and 30 days after training showed that spatial information was efficiently consolidated after acquisition since D-rats performed as well as C-rats on retention tests. A cue learning task revealed no significant differences between both groups. These results suggest that perinatal undernutrition induces, even after a long period of nutritional recovery, a deficit in efficient place navigation in adult rats.