RESUMO
Recent evidence suggests that mu opioid receptors (MOR) are key regulators of hippocampal structure and function. For example, exogenous MOR agonists morphine and heroin negatively impact hippocampal function and decrease adult hippocampal neurogenesis. Here we explored the role of MOR in the birth and survival of hippocampal progenitor cells by examining adult neurogenesis in mice that lack MOR. Adult male mice lacking exon 1 of MOR were injected with the S phase marker bromodeoxyuridine (BrdU) and killed either 2 hours or 4 weeks later to evaluate proliferating and surviving BrdU-immunoreactive (IR) cells, respectively, in the adult hippocampal granule cell layer. Wild-type (WT), heterozygote, and homozygote mice did not differ in the number of BrdU-IR cells at a proliferation time point. However, 4 weeks after BrdU injection, heterozygote and homozygote mice had 57% and 54% more surviving BrdU-IR cells in the hippocampal granule cell layer as compared with WT mice. A decrease in apoptosis in the heterozygote and homozygote mice did not account for the difference in number of surviving BrdU-IR cells since there were no alterations in number of pyknotic, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive, or activated caspase 3-IR cells compared with WT. In concordance with the increased numbers of granule cells maturing into neurons, heterozygote and homozygote mice had larger hippocampal granule cell layers and increased numbers of granule cells. These findings indicate that MOR may play a role in regulating progenitor cell survival and more generally encourage further exploration of how MOR activation can influence hippocampal structure and function.
Assuntos
Hipocampo/citologia , Hipocampo/fisiologia , Neurônios/fisiologia , Receptores Opioides mu/genética , Receptores Opioides mu/fisiologia , Animais , Antimetabólitos/farmacologia , Apoptose , Bromodesoxiuridina/farmacologia , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Tamanho Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Grânulos Citoplasmáticos/fisiologia , Proteínas de Ligação a DNA , Éxons/genética , Genótipo , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso , Proteínas Nucleares , FenótipoRESUMO
Thalamocortical neurons innervating the barrel cortex in neonatal rodents transiently store serotonin (5-HT) in synaptic vesicles by expressing the plasma membrane serotonin transporter (5-HTT) and the vesicular monoamine transporter (VMAT2). 5-HTT knock-out (ko) mice reveal a nearly complete absence of 5-HT in the cerebral cortex by immunohistochemistry, and of barrels, both at P7 and adulthood. Quantitative electron microscopy reveals that 5-HTT ko affects neither the density of synapses nor the length of synaptic contacts in layer IV. VMAT2 ko mice, completely lacking activity-dependent vesicular release of monoamines including 5-HT, also show a complete lack of 5-HT in the cortex but display largely normal barrel fields, despite sometimes markedly reduced postnatal growth. Transient 5-HTT expression is thus required for barrel pattern formation, whereas activity-dependent vesicular 5-HT release is not.
Assuntos
Monoaminas Biogênicas/metabolismo , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Neurônios Aferentes/metabolismo , Neuropeptídeos , Transportadores de Ânions Orgânicos , Córtex Somatossensorial/metabolismo , Vesículas Sinápticas/metabolismo , Tálamo/metabolismo , Envelhecimento/metabolismo , Animais , Proteínas de Transporte/análise , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Espaço Extracelular/metabolismo , Fenclonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de GABA , Imuno-Histoquímica , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Proteínas de Membrana/análise , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios Aferentes/ultraestrutura , Serotonina/análise , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina , Córtex Somatossensorial/citologia , Córtex Somatossensorial/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/ultraestrutura , Tálamo/citologia , Proteínas Vesiculares de Transporte de Aminas Biogênicas , Proteínas Vesiculares de Transporte de Monoamina , Vibrissas/inervação , Vibrissas/fisiologiaRESUMO
Dopamine transporter (DAT) knockout (KO) mice show numerous behavioral alterations, including hyperlocomotion, cognitive deficits, impulsivity and impairment of prepulse inhibition of the startle reflex (PPI), phenotypes that may be relevant to frontostriatal disorders such as schizophrenia. Dendritic spine changes of pyramidal neurons in the dorsolateral prefrontal cortex (DLPFC) are among the most replicated of findings in postmortem studies of schizophrenia. The mechanisms that account for dendritic changes in the DLPFC in schizophrenia are unclear. Here, we report basal spine density of pyramidal neurons in the medial prefrontal cortex (mPFC), the motor cortex, the CA1 region of the hippocampus, and the basolateral amygdala in DAT KO mice. Pyramidal neurons were visualized using DAT KO mice crossbred with a Thy1-GFP transgenic mouse line. We observed a significant decrease in spine density of pyramidal neurons in the mPFC and the CA1 region of the hippocampus in DAT KO mice compared to that in WT mice. On the other hand, no difference was observed in spine density of pyramidal neurons in the motor cortex or the basolateral amygdala between DAT genotypes. These results suggest that decreased spine density could cause hypofunction of the mPFC and the hippocampus, and contribute to the behavioral abnormalities observed in DAT KO mice, including cognitive deficits. This might suggest that aberrant dopaminergic signaling may trigger dystrophic changes in dendrites of hippocampal and prefrontocortical pyramidal neurons in schizophrenia.
Assuntos
Espinhas Dendríticas/patologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Células Piramidais/patologia , Tonsila do Cerebelo/patologia , Animais , Região CA1 Hipocampal/patologia , Espinhas Dendríticas/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Feminino , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Córtex Motor/patologia , Especificidade de Órgãos , Células Piramidais/metabolismo , Esquizofrenia/genética , Esquizofrenia/patologiaRESUMO
Current evidence indicates that virtually all neuropsychiatric disorders, like many other common medical disorders, are genetically complex, with combined influences from multiple interacting genes, as well as from the environment. However, additive or epistatic gene interactions have proved quite difficult to detect and evaluate in human studies. Mouse phenotypes, including behaviors and drug responses, can provide relevant models for human disorders. Studies of gene-gene interactions in mice could thus help efforts to understand the molecular genetic bases of complex human disorders. The serotonin transporter (SERT, 5-HTT, SLC6A4) provides a relevant model for studying such interactions for several reasons: human variants in SERT have been associated with several neuropsychiatric and other medical disorders and quantitative traits; SERT blockers are effective treatments for a number of neuropsychiatric disorders; there is a good initial understanding of the phenotypic features of heterozygous and homozygous SERT knockout mice; and there is an expanding understanding of the interactions between variations in SERT expression and variations in the expression of a number of other genes of interest for neuropsychiatry and neuropharmacology. This paper provides examples of experimentally-obtained interactions between quantitative variations in SERT gene expression and variations in the expression of five other mouse genes: DAT, NET, MAOA, 5-HT(1B) and BDNF. In humans, all six of these genes possess polymorphisms that have been independently investigated as candidates for neuropsychiatric and other disorders in a total of > 500 reports. In the experimental studies in mice reviewed here, gene-gene interactions resulted in either synergistic, antagonistic (including 'rescue' or 'complementation') or more complex, quantitative alterations. These were identified in comparisons of the behavioral, physiological and neurochemical phenotypes of wildtype mice vs. mice with single allele or single gene targeted disruptions and mice with partial or complete disruptions of multiple genes. Several of the descriptive phenotypes could be best understood on the basis of intermediate, quantitative alterations such as brain serotonin differences. We discuss the ways in which these interactions could provide models for studies of gene-gene interactions in complex human neuropsychiatric and other disorders to which SERT may contribute, including developmental disorders, obesity, polysubstance abuse and others.
Assuntos
Proteínas de Transporte/genética , Modelos Animais de Doenças , Meio Ambiente , Regulação da Expressão Gênica/genética , Glicoproteínas de Membrana/genética , Transtornos Mentais/genética , Proteínas do Tecido Nervoso/genética , Animais , Comportamento Animal/fisiologia , Fator Neurotrófico Derivado do Encéfalo/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina , Humanos , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Knockout , Camundongos Mutantes , Camundongos Transgênicos , Monoaminoxidase/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Locos de Características Quantitativas/genética , Receptor 5-HT1B de Serotonina/genética , Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina , Simportadores/genéticaRESUMO
Homozygous mu-opioid receptor (MOR) knockout (KO) mice developed on a chimeric C57B6/129SV background lack morphine-induced antinociception, locomotion and reward. Therefore it appears that MOR largely mediates these morphine actions. However, one factor that could affect the extent of knockout deficits in morphine-induced behavior is the genetic background against which the gene deletion is expressed. To examine the effect of genetic background chimeric C57B6/129SV MOR knockout mice from the 15th generation of those developed in our laboratory were backcrossed for 10 successive generations with C57BL/6 mice, a strain which is more sensitive to many of the properties of morphine, to produce congenic MOR (con-MOR) KO mice. Heterozygote conMOR KO mice display attenuated morphine locomotion and reduced morphine analgesia compared to wild-type mice. Homozygote con-MOR KO mice display baseline hyperalgesia, no morphine place preference, no morphine analgesia and no morphine locomotion. These results are not qualitatively different from those observed in the MOR KO strain with a chimeric C57B6/129SV background, and suggest that although the strain has separate influences on these functions, it does not substantially interact with deletion of the mu opiate receptor gene.
Assuntos
Animais Congênicos/fisiologia , Camundongos Endogâmicos C57BL/fisiologia , Camundongos Knockout/fisiologia , Receptores Opioides mu/genética , Analgesia , Analgésicos Opioides/farmacologia , Animais , Animais Congênicos/genética , Quimera , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Condicionamento Psicológico/fisiologia , Camundongos , Camundongos Endogâmicos C57BL/genética , Camundongos Knockout/genética , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Percepção Espacial/efeitos dos fármacos , Percepção Espacial/fisiologia , Especificidade da EspécieRESUMO
Homozygous transgenic knockout mice without mu-opioid receptors lack morphine-induced antinociception, locomotion, tolerance, physical dependence, and reward. mu receptors thus appear to play central roles in these morphine actions. Different levels of mu receptor expression are found in different humans and in different animal strains. In vitro studies indicate that some morphine responses persist after inactivation of as many as 90% of the initial mu receptor complement, while others are attenuated after inactivating many fewer receptors. Varying levels of mu receptor reserve could thus exist in different mu-expressing neuronal populations in vivo. Heterozygous mu receptor knockout mice express half of wild-type mu receptor levels. Tests of morphine actions in these mice reveal evidence for differing mu receptor reserves in brain circuits that mediate distinct opiate effects. Heterozygotes display attenuated locomotion, reduced morphine self-administration, intact tolerance, rightward shifts in morphine lethality dose/effect relationships, and variable effects on place preference compared to wild-type mice. They demonstrate full physical dependence, as measured by naloxone-precipitated abstinence following five days of morphine administration. Neuroadaptive changes in sites other than mu receptors could be involved in some of these results. Nevertheless, these data document substantial influences that individual differences in levels of mu receptor expression could exert on distinct opiate drug effects. They support the idea that functional mu receptor reserve differs among the diverse neuronal populations that mediate distinct properties of opiate drugs.
Assuntos
Comportamento Animal/fisiologia , Química Encefálica/genética , Camundongos Knockout/metabolismo , Morfina/farmacologia , Entorpecentes/farmacologia , Receptores Opioides mu/deficiência , Receptores Opioides mu/genética , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Relação Dose-Resposta a Droga , Feminino , Dose Letal Mediana , Masculino , Camundongos , Camundongos Knockout/genética , Dependência de Morfina/fisiopatologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nociceptores/efeitos dos fármacos , Nociceptores/metabolismo , Medição da Dor/efeitos dos fármacos , Receptores Opioides mu/efeitos dos fármacos , Recompensa , AutoadministraçãoRESUMO
A series of experiments examined the effects of 8 weeks of social isolation on spontaneous locomotor activity, prepulse inhibition (PPI) of the acoustic startle response, latent inhibition (LI) in a conditioned suppression paradigm, and basal and d-amphetamine stimulated dopamine (DA) release in the ventral striatum, as measured by in vivo microdialysis. Both isolation-reared animals (those isolated from the weaning age) and isolation-housed animals (those isolated as adults) were hyperactive when placed in a novel environment. Social isolation also led to deficits in PPI of the acoustic startle response that were specific to isolation-reared animals. Isolation rearing was without effect on the expression of LI but did lead to an enhanced response to systemic d-amphetamine in terms of striatal DA release. The data are discussed with respect to the involvement of ventral striatal DA mechanisms in the expression of PPI and LI, differences in the impact of social isolation in young and adult animals, and the utility of social isolation model as a nonlesion, nonpharmacologic means of perturbing ventral striatal DA function.
Assuntos
Inibição Psicológica , Reflexo de Sobressalto/fisiologia , Isolamento Social , Estimulação Acústica , Animais , Dextroanfetamina/farmacologia , Dopamina/metabolismo , Dopamina/fisiologia , Eletrodos Implantados , Eletrochoque , Meio Ambiente , Espaço Extracelular/metabolismo , Masculino , Microdiálise , Atividade Motora/fisiologia , Núcleo Accumbens/anatomia & histologia , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiologia , RatosRESUMO
Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine, serotonin and norepinephrine, producing subjective effects in humans that are both euphoric/rewarding and also fearful, jittery and aversive. Mice with gene knockouts of each of these transporters display cocaine reward, manifest by cocaine place preferences that are at least as great as wildtype values. Norepinephrine and serotonin receptor knockouts even display enhanced cocaine reward. One explanation for these observations could be that cocaine produces aversive or anhedonic effects by serotonin or norepinephrine receptor blockade in wildtype mice that are removed in serotonin or norepinephrine receptor knockouts, increasing net cocaine reward. Adaptations to removing one transporter could also change the rewarding valence of blocking the remaining transporters. To test these ideas, drugs that block serotonin transporter (fluoxetine), norepinephrine transporter (nisoxetine) or all three transporters (cocaine) were examined in single- or multiple-transporter knockout mice. Fluoxetine and nisoxetine acquire rewarding properties in several knockouts that are not observed in wildtype mice. Adding serotonin transporter knockout to norepinephrine transporter knockouts dramatically potentiates cocaine reward. These and previous data provide evidence that serotonin and norepinephrine transporter blockade can contribute to the net rewarding valence of cocaine. They identify neuroadaptations that may help to explain the retention of cocaine reward by dopamine and serotonin transporter knockout mice. They are consistent with emerging hypotheses that actions at the three primary brain molecular targets for cocaine each provide distinct contributions to cocaine reward and cocaine aversion in wildtype mice, and that this balance changes in mice that develop without dopamine, norepinephrine or serotonin transporters.
Assuntos
Cocaína/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Fluoxetina/análogos & derivados , Fluoxetina/farmacologia , Deleção de Genes , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Proteínas do Tecido Nervoso , Neuropeptídeos , Animais , Proteínas de Transporte/genética , Condicionamento Psicológico/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Proteínas de Membrana Transportadoras/deficiência , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Proteínas da Membrana Plasmática de Transporte de Serotonina , Simportadores/deficiência , Simportadores/genética , Proteínas Vesiculares de Transporte de Aminas BiogênicasRESUMO
beta-Endorphin is a non-selective opioid peptide which binds mu-, delta- and putative epsilon (beta-endorphin-sensitive non-mu-, non-delta- and non-kappa(1)-)-opioid receptors. We have previously reported that beta-endorphin-produced G-protein activation is mediated by the stimulation of both mu- and putative epsilon-opioid receptors. The present study was designed to further characterize this putative epsilon-opioid receptor-mediated G-protein activation in the pons/medulla membrane obtained from mice lacking mu-opioid receptor, using a guanosine-5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS)-binding assay. beta-Endorphin and the mu-opioid receptor agonist [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) increased the [(35)S]GTPgammaS binding in a concentration-dependent manner (0.001-10 microM), and at 10 microM beta-endorphin and DAMGO produced approximately 250 and 120% increases of [(35)S]GTPgammaS binding in the pons/medulla membrane obtained from wild-type mice, respectively. In the pons/medulla membrane obtained from mu-opioid receptor knockout mice, beta-endorphin-stimulated [(35)S]GTPgammaS binding was only partially attenuated and a more than 100% increase by 10 microM beta-endorphin still remained, while DAMGO failed to produce any increase in [(35)S]GTPgammaS binding. The residual increase in [(35)S]GTPgammaS binding by 10 microM beta-endorphin in mu-opioid receptor knockout mice was partially but significantly attenuated by the putative epsilon-opioid receptor partial agonist beta-endorphin (1-27), but not by the delta-opioid receptor antagonist naltrindole or the kappa(1)-receptor antagonist norbinaltorphimine. Furthermore, buprenorphine significantly attenuated the residual increase in [(35)S]GTPgammaS binding by 10 microM beta-endorphin in mu-opioid receptor knockout mice. The present results indicate that beta-endorphin activates G-protein by stimulation of putative epsilon-opioid receptors in the condition lacking the mu-opioid receptor, and buprenorphine acts as an antagonist for putative epsilon-opioid receptors in this condition.
Assuntos
Buprenorfina/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Naltrexona/análogos & derivados , Entorpecentes/farmacologia , Receptores Opioides mu/deficiência , Receptores Opioides/metabolismo , Rombencéfalo/metabolismo , beta-Endorfina/metabolismo , Animais , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Feminino , Proteínas de Ligação ao GTP/efeitos dos fármacos , Guanosina 5'-O-(3-Tiotrifosfato) , Masculino , Bulbo/efeitos dos fármacos , Bulbo/metabolismo , Camundongos , Camundongos Knockout , Naltrexona/farmacologia , Antagonistas de Entorpecentes , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fragmentos de Peptídeos/farmacologia , Ponte/efeitos dos fármacos , Ponte/metabolismo , Ensaio Radioligante , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/genética , Rombencéfalo/efeitos dos fármacos , Radioisótopos de Enxofre , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , beta-Endorfina/antagonistas & inibidoresRESUMO
This review examines the consequences of social deprivation on brain chemistry and behavior on rats. Although social deprivation produces wide-ranging behavioral and neurochemical effects, it appears that these effects are determined by a number of factors, the most critical factor being the age or developmental stage during the period of deprivation. Roughly, the effects examined in this review may be separated into three major developmental stages and each is related to deprivation of specific types of social interaction: preweaning/neonatal, postweaning/adolescent, and adult. The effects of social deprivation during each of these stages appears to be neurochemically and behaviorally specific. However, much of the research to date has failed to examine deprivation during specific stages, often combining deprivation of different types. Nonetheless, these modifications of experience produce animals of differing phenotypes, which could be characterized as pathological in nature in many instances, and may model particular aspects of human psychopathologies or perhaps the propensity to develop those phenotypic features.
Assuntos
Comportamento Animal/fisiologia , Química Encefálica/fisiologia , Período Crítico Psicológico , Privação Materna , Isolamento Social , Fatores Etários , Animais , Animais Recém-Nascidos , RatosRESUMO
RATIONALE: Differences in mu-opiate receptor (MOR) gene expression may modulate the rewarding effects of ethanol. OBJECTIVE: The effects of MOR gene knockout (KO) were examined in wild-type (+/+), heterozygote MOR KO (+/-), and homozygote MOR KO (-/-) mice on voluntary ethanol consumption, conditioned place preference produced by ethanol, and locomotor responses to ethanol in separate groups of mice. METHODS: Voluntary ethanol consumption (2-32% v/v) was examined in a two-bottle home-cage consumption test. The conditioned place preference paradigm was a biased design. Mice received four pairings of ethanol (2.0 g/kg IP) on the initially preferred side and four pairings on the initially non-preferred side with saline. The difference in time spent on the initially non-preferred side (pre- versus post-conditioning) was the measure of drug-induced preference. After habituation to a novel locomotor test chamber mice were tested, on subsequent sessions, for ethanol induced locomotion (0.0, 0.5, 1.0, and 2.0 g/kg IP). RESULTS: Heterozygous and homozygous MOR KO mice consumed less ethanol than wild-type mice. These effects appeared to be greater in female KO mice than in male KO mice. MOR KO mice, especially females, exhibited less ethanol reward in a conditioned place preference paradigm. These effects on ethanol reward were produced by reductions in MOR expression levels as small as 50%. MOR KO mice exhibited less ethanol-stimulated locomotion than did wild-type mice, an effect that was also largest in females. CONCLUSIONS: These data fit with the reported therapeutic efficacy of MOR antagonists in the treatment of human alcoholism. Allelic variants that confer differing levels of MOR expression could provide different degrees of risk for alcoholism.
Assuntos
Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Receptores Opioides mu/genética , Receptores Opioides mu/fisiologia , Animais , Condicionamento Operante/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , RecompensaRESUMO
Adult hooded rats exposed to a repeated maternal separation procedure during the neonatal period showed a blunted expression of locomotor hyperactivity conditioned to the presentation of the daily food ration. We have demonstrated that the expression of food-conditioned anticipatory hyperactivity is sensitive to the response-enhancing effects of systemic d-amphetamine (0.5; 1.0 mg/kg) and to the response-attenuating effects of the selective dopamine D2 antagonist sulpiride (8; 20 mg/kg), the selective dopamine D1 antagonist SCH 23390 (0.01; 0.022 mg/kg) and the mixed alpha 1/alpha 2 adrenoceptor agonist clonidine (5; 15 micrograms/kg) in a dose dependent manner. Animals from the early separation groups showed a reduced enhancement of activity in response to 0.5 mg/kg d-amphetamine and a greater attenuation of activity in response to 8 mg/kg sulpiride and 5 micrograms/kg clonidine. Female separated rats also exhibited an attenuated locomotor response to the unconditioned stimulant effects of 0.5 mg/kg systemic d-amphetamine. The experiments confirm that early maternal separation attenuates the response to conditioned appetitive cues in adult rats and implicate altered dopaminergic and noradrenergic function in the changes. It is possible that early maternal separation in the rat may offer a useful preparation for investigation of the neural substrates mediating affective development and affective psychopathology.
Assuntos
Anfetamina/farmacologia , Ansiedade de Separação/psicologia , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Dopamina/farmacologia , Atividade Motora/efeitos dos fármacos , Agonistas alfa-Adrenérgicos/farmacologia , Análise de Variância , Animais , Comportamento Animal/fisiologia , Benzazepinas/farmacologia , Peso Corporal/efeitos dos fármacos , Clonidina/farmacologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Feminino , Masculino , Atividade Motora/fisiologia , Ratos , Recompensa , Fatores Sexuais , Sulpirida/farmacologiaRESUMO
Phencyclidine (PCP) and phencyclidine-like drugs (TCP, dexoxadrol, MK-801, and SKF 10,047) were evaluated for their ability to induce rotational behavior in rats with unilateral 6-OHDA lesions of the medial forebrain bundle and for their ability to alter striatal dopamine (DA) overflow with microdialysis procedures. All of the compounds tested produced rotational behavior ipsilateral to the lesion, suggesting that they were enhancing extracellular dopamine in the intact striatum. The microdialysis studies, however, did not support this contention. There appeared to be a complete dissociation between the ability of the five compounds to produce ipsilateral rotations and their ability to enhance extracellular dopamine levels in the striatum. PCP was the only compound able to elicit significant increases in striatal dopamine overflow following i.p. injections and also produce dramatic rotational behavior. MK-801 was the most potent compound in enhancing rotational output while it had no effect at all on striatal dopamine overflow. Dexoxadrol also produced significant rotational output without having any effect on extracellular levels of dopamine following i.p. injections. TCP and SKF 10,047, at doses which produced significant rotational behavior, only elevated dopamine 16% and 12%, respectively, at peak effect. It is most parsimonious to conclude that the effects of PCP-like drugs on nigro-striatal function are mediated through their ability to act as indirect NMDA receptor antagonists and not through their ability to alter striatal dopamine activity.
Assuntos
Corpo Estriado/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Alucinógenos/farmacologia , Atividade Motora/fisiologia , Fenciclidina/farmacologia , Receptores Dopaminérgicos/fisiologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Comportamento Estereotipado/fisiologia , Animais , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Masculino , Microdiálise , Ratos , Ratos Sprague-Dawley , Receptores Dopaminérgicos/efeitos dos fármacosRESUMO
Voluntary ethanol (EtOH) consumption is increased by isolation-rearing in several rat strains. The following experiments examined the effects of isolation-rearing on basal and ethanol-stimulated behavior in Fawn Hooded rats, an alcohol-preferring rat strain, compared to Wistar rats. Locomotor activity and anxiety were examined under both conditions. Basal locomotor activity was higher in isolated subjects of both strains in low light conditions, but under bright light conditions, this difference was only observed in Wistar rats. Locomotor stimulant effects of EtOH were only observed in isolation-reared rats. In the elevated plus maze, Fawn Hooded rats were more anxious than Wistar rats under low light conditions, but under bright light conditions, Wistar socials were less anxious than all of the other groups. Administration of 1.5 mg/kg EtOH produced an anxiolytic response in the elevated plus maze under bright light conditions in Fawn Hooded rats, but to a lesser degree Wistar rats, particularly Wistar isolates. In conclusion, although both strain and isolation-rearing had effects on locomotion and anxiety as well as the stimulatory and anxiolytic effects of EtOH, these effects appeared to be independent.
Assuntos
Ansiolíticos/farmacologia , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Locomoção/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Isolamento Social/psicologia , Animais , Ansiolíticos/administração & dosagem , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Locomoção/efeitos dos fármacos , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
These experiments examined the hypothesis that isolation-rearing and strain influence hedonic mechanisms. In experiment 1, voluntary consumption of ethanol and water was monitored in the home cage of Fawn Hooded (FH) and Wistar rats. FH rats were found to consume more ethanol at low concentrations than Wistar rats, independent of rearing condition, and isolation-reared rats were found to consume more of high ethanol concentrations, independent of strain. In experiment 2, isolation-reared rats were found to consume more sucrose, independent of concentration, than socially reared rats. In experiment 3, Fawn Hooded rats were found to be more sensitive to low concentration solutions of saccharin, and to consume less of the high concentration solutions, while isolation-rearing was found to enhance consumption of high concentrations. Thus, hedonic processes are independently modulated by strain and rearing conditions, although the effects of isolation-rearing appear to be exacerbated in Fawn Hooded rats.
Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Comportamento Alimentar/psicologia , Isolamento Social/psicologia , Animais , Comportamento Alimentar/fisiologia , Masculino , Ratos , Ratos Wistar , Sacarina , SacaroseRESUMO
The monoamine neurotransmitter serotonin has long been implicated in development and maintenance of sleep patterns, yet the role of the serotonin transporter (SERT) in these processes has not been evaluated in detail. We report that genetically engineered SERT knockout mice exhibit more REM sleep (REMS) than wild type littermates (11 vs 7% of recording time under baseline conditions) and display more frequent REMS bouts that last longer. This phenotype resembles the previously reported long-term effect of repeated treatment with SERT inhibitor compounds rather than the acute REMS suppressing effect of treatment with such compounds, and is thus likely to reflect neuroadaptations to the absence of SERT, rather than an acute effect of its absence in the adult. While electroencephalographic (EEG) spectra did not differ between SERT knockout and wild type mice during non-REM sleep (NREMS) or REMS, the dynamics of the EEG during the transition from NREMS to REMS differed between the genotypes. The surge in EEG power in both the 6-9 Hz and 10-16 Hz ranges that occurs just prior to the onset of REMS (pre-REMS power surge) is of greater magnitude in SERT knockout mice than in wild type littermate controls. This observation contrasts with the reduced magnitude pre-REMS power surge observed in rats subjected to REMS deprivation relative to yoked controls. These results indicate that the pre-REMS power surge is influenced by REMS history and by monoaminergic transmission. Genetic differences in serotonin systems and developmental exposure to SERT blockers are likely to exert effects on REMS.
Assuntos
Glicoproteínas de Membrana/deficiência , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Sono REM/genética , Animais , Proteínas de Transporte/genética , Eletroencefalografia/métodos , Feminino , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos , Proteínas da Membrana Plasmática de Transporte de Serotonina , Sono REM/fisiologiaRESUMO
Although the forced swim test (FST) has long been used as a preclinical screen of antidepressant efficacy, locomotor stimulants are known to produce confounding effects using the traditional dependent measure in this test: immobility. It has recently been suggested that measurement of struggling behavior may be a better index of antidepressant activity. The present experiments examined behavior in the forced swim test in two potential animal models of depression: the Fawn hooded rat, and the isolation-reared rat. No evidence was found to support these assertions, indeed immobility was decreased in Fawn hooded compared to Wistar rats, however this appeared to be caused by increased struggling behavior in Fawn hooded socials and increased swimming in Fawn hooded isolates. Although these differential results are highly suggestive of different underlying causes of decreased immobility in Fawn hooded rats depending on rearing conditions, the data suggests that the underlying psychological functions assumed to be represented by behavior assessed in this paradigm may not be adequately discriminated.
Assuntos
Comportamento Animal/fisiologia , Isolamento Social , Animais , Imobilização , Masculino , Esforço Físico/fisiologia , Ratos , Ratos Endogâmicos , Ratos Wistar , Isolamento Social/psicologia , Natação/psicologia , Fatores de TempoRESUMO
This study tested the hypothesis that the hippocampus modulates dopamine-dependent function of the nucleus accumbens using behavioural and neurochemical evidence. Rats with bilateral lesions of the hippocampus induced by colchicine and kainic acid exhibited equivalent levels of spontaneous locomotor activity but a potentiation of the hyperactivity produced, dose-dependently, by D-amphetamine measured in photo-cell activity cages. The same rats subsequently received unilateral implantations of a microdialysis probe aimed at the nucleus accumbens and showed elevated levels of extracellular dopamine in response to D-amphetamine but no significant difference in basal values in comparison with sham-operated controls. The results are discussed in terms of functional interactions between the hippocampus and nucleus accumbens involving the control of mesolimbic dopamine release.
Assuntos
Dextroanfetamina/farmacologia , Dopamina/fisiologia , Hipocampo/fisiologia , Atividade Motora/fisiologia , Núcleo Accumbens/fisiologia , Transmissão Sináptica/fisiologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Nível de Alerta/efeitos dos fármacos , Nível de Alerta/fisiologia , Mapeamento Encefálico , Hipocampo/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Ratos , Transmissão Sináptica/efeitos dos fármacosRESUMO
Unilateral microinjection into rat lateral hypothalamus (LH) of the excitotoxins ibotenic acid (IBO) and N-methyl-D-aspartic acid (NMDA) produced a local zone of neuronal death but also produced a zone of demyelination. The size of this demyelination zone was related to excitotoxin dose and was smaller than the zone of neuron killing. In behavioral testing, MFB self-stimulation reward and performance were measured with a rate-frequency curve-shift method before and after IBO or NMDA lesions of the LH. Excitotoxin lesions were made anterior or posterior to the LH electrode so that the zone of neuronal death, but not demyelination, extended to the electrode tip. These lesions produced small, temporary LH stimulation reward deficits, leading to the conclusion that intrinsic LH neurons are not a major substrate of MFB stimulation reward.
Assuntos
Região Hipotalâmica Lateral/fisiologia , Neurotoxinas/farmacologia , Recompensa , Autoestimulação , Animais , Comportamento Animal/efeitos dos fármacos , Sobrevivência Celular , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/patologia , Ácido Ibotênico/farmacologia , Masculino , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Análise de RegressãoRESUMO
There is evidence that isolation rearing produces down-regulation of the dopamine D2 receptor. Therefore, isolation rearing should also modify the effects of D2 antagonists on intracranial self-stimulation (ICSS) reward. This study investigated the effect of isolation rearing on ICSS reward, and modulation of that reward by SCH23390, Raclopride and MK-801. Sprague-Dawley rats were reared alone (isolates) or in pairs from day 21 postnatal to day 75 postnatal. At this time, all rats were implanted with monopolar stimulating electrodes in the lateral hypothalamus. The ICSS rate-frequency curve-shift method was used to assess reward and operant motor function at baseline and after administration of SCH-23390 (D1 antagonist: 0.02, 0.06, 0.2 mg/kg), Raclopride (D2 antagonist: 0.01, 0.025, 0.06 mg/kg), and MK-801 (non-competitive NMDA receptor antagonist: 0.1, 0.2 mk/kg). Isolation-reared rats displayed similar measures of both basal reward and motor function when compared to socially reared controls. Isolation-reared rats were subsensitive to the reward decreasing effects of Raclopride. Socially reared rats were observed to have more variant baseline reward measures, and could be divided into distinctly different groups with different basal reward function. Isolation-rearing down-regulates D2 function but does not affect basal reward function, but some unknown factor in the social rearing environment did have a substantial effect on basal reward function.