RESUMEN
Opiate addiction is now a major public health problem. Perinatal insults and exposure to opiates such as morphine in utero are well known to affect development of the hypothalamic-pituitary-adrenal axis of the offspring adversely and are associated with a higher risk of developing neurobehavioral problems. Oxycodone is now one of the most frequently abused pain killers during pregnancy; however, limited data are available regarding whether and how perinatal oxycodone exposure (POE) alters neurobehavioral outcomes of the offspring. We demonstrated that exposure to 0.5 mg/kg/day oxycodone in utero was associated with hyperactivity in adult rats in an open field. No significant effects of POE were detected on isolation-induced ultrasonic vocalizations in the early postnatal period or on learning and memory in the water maze in adult offspring. Our findings are consistent with hyperactivity problems identified in children exposed to opiates in utero.
RESUMEN
Prenatal ethanol exposure can result in social deficits in humans and animals, including altered social interaction and poor communication. Rats exposed to ethanol prenatally show reduced play fighting, and a combination of prenatal ethanol exposure and neonatal whisker clipping further reduces play fighting compared with ethanol exposure alone. In this study, we explored whether expression of hedonic ultrasonic vocalizations (USVs) correlated with the number of playful attacks by ethanol-exposed rats, rats subjected to postnatal sensory deprivation by whisker clipping or both compared to control animals. In normally developing rats, hedonic USVs precede such interactions and correlate with the number of play interactions exhibited in dyads. Pregnant Long-Evans rats were fed an ethanol-containing liquid diet or a control diet. After birth, male and female pups from each litter were randomly assigned to the whisker-clipped or non-whisker-clipped condition. Animals underwent a social interaction test with a normally developing play partner during early or late-adolescence. USVs were recorded during play. Prenatal ethanol exposure reduced both play and hedonic USVs in early adolescence compared to control rats and persistently reduced social play. Interestingly, ethanol exposure, whisker clipping and the combination abolished the significant correlation between hedonic USVs and social play detected in control rats in early adolescence. This relationship remained disrupted in late adolescence only in rats subjected to both prenatal ethanol and whisker clipping. Thus, both insults more persistently disrupted the relationship between social communication and social play.
RESUMEN
Fetal alcohol spectrum disorder (FASD) is estimated to occur in 1 % of all live births. The developing cerebellum is vulnerable to the toxic effects of alcohol. People with FASD have cerebellar hypoplasia and developmental deficits associated with cerebellar injury. Choline is an essential nutrient, but many diets in the USA are choline deficient. In rats, choline given with or following alcohol exposure reduces many alcohol-induced neurobehavioral deficits but not those associated with cerebellar function. Our objective was to determine if choline supplementation prior to alcohol exposure would ameliorate the impact of ethanol on a cerebellar-associated behavioral test in mice. Pregnant C57Bl6/J mice were maintained on a choline-deficient diet from embryonic day 4.5. On postnatal day 1 (P1), pups were assigned to one of eight treatment groups: choline (C) or saline (S) pre-treatment from P1 to P5, ethanol (6 g/kg) or Intralipid(®) on P5, C and or S post-treatment from P6 to P20. On P30, balance and coordination were tested using the dowel crossing test. Overall, there was a significant effect of treatment and females crossed longer distances than males. Ethanol exposure significantly reduced the total distance crossed. Choline pre-treatment increased the distance crossed by males, and both pre- and post-treatment with choline significantly increased total distance crossed for females and males. There was no effect of choline on Intralipid®-exposed animals. This is the first study to show that choline ameliorates ethanol-induced effects on balance and coordination when given before ethanol exposure. Choline fortification of common foodstuffs may reduce the effects of alcohol.
Asunto(s)
Depresores del Sistema Nervioso Central/toxicidad , Colina/uso terapéutico , Etanol/toxicidad , Nootrópicos/uso terapéutico , Equilibrio Postural/efectos de los fármacos , Trastornos de la Sensación , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Depresores del Sistema Nervioso Central/sangre , Etanol/sangre , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Desempeño Psicomotor/efectos de los fármacos , Trastornos de la Sensación/inducido químicamente , Trastornos de la Sensación/tratamiento farmacológico , Trastornos de la Sensación/etiologíaRESUMEN
Prenatal ethanol exposure disrupts social behavior in humans and rodents. One system particularly important for social behavior is the somatosensory system. Prenatal ethanol exposure alters the structure and function of this area. Docosahexaenoic acid (DHA), an omega 3 polyunsaturated fatty acid, is necessary for normal brain development and brains from ethanol-exposed animals are DHA deficient. Thus, we determined whether postnatal DHA supplementation ameliorated behavioral deficits induced by prenatal ethanol exposure. Timed pregnant Long-Evans rats were assigned to one of three groups: ad libitum access to an ethanol-containing liquid diet, pair fed an isocaloric isonutritive non-alcohol liquid diet, or ad libitum access to chow and water. Pups were assigned to one of two postnatal treatment groups; gavaged intragastrically once per day between postnatal day (P)11 and P20 with DHA (10 mg/kg in artificial rat milk) or artificial rat milk. A third group was left untreated. Isolation-induced ultrasonic vocalizations (iUSVs) were recorded on P14. Social behavior and play-induced USVs were tested on P28 or P42. Somatosensory performance was tested with a gap crossing test around P33 or on P42. Anxiety was tested on elevated plus maze around P35. Animals exposed to ethanol prenatally vocalized less, play fought less, and crossed a significantly shorter gap than control-treated animals. Administration of DHA ameliorated these ethanol-induced deficits such that the ethanol-exposed animals given DHA were no longer significantly different to control-treated animals. Thus, DHA administration may have therapeutic value to reverse some of ethanol's damaging effects.
Asunto(s)
Depresores del Sistema Nervioso Central/toxicidad , Ácidos Docosahexaenoicos/farmacología , Etanol/toxicidad , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Psicotrópicos/farmacología , Animales , Ansiedad/tratamiento farmacológico , Femenino , Trastornos del Espectro Alcohólico Fetal/tratamiento farmacológico , Trastornos del Espectro Alcohólico Fetal/psicología , Embarazo , Distribución Aleatoria , Ratas Long-Evans , Conducta Social , Aislamiento Social , Ultrasonido , Vocalización Animal/efectos de los fármacosRESUMEN
Prenatal exposure to ethanol results in sensory deficits and altered social interactions in animal and clinical populations. Sensory stimuli serve as important cues and shape sensory development; developmental exposure to ethanol or sensory impoverishment can impair somatosensory development, but their combined effects on behavioral outcomes are unknown. We hypothesized 1) that chronic prenatal ethanol exposure would disrupt social interaction and somatosensory performance during adolescence, 2) that a mild sensory impoverishment (neonatal unilateral whisker clipping; WC) would have a mildly impairing to sub-threshold effect on these behavioral outcomes, and 3) that the effect of ethanol would be exacerbated by WC. Long-Evans dams were fed a liquid diet containing ethanol or pair-fed with a non-ethanol diet on gestational days (G) 6-G21. Chow-fed control animals were also included. One male and female pup per litter underwent WC on postnatal day (P)1, P3, and P5. Controls were unclipped. Offspring underwent social interaction on P28 or P42, and gap-crossing (GC) on P31 or P42. Ethanol-exposed pups played less and crossed shorter gaps than control pups regardless of age or sex. WC further exacerbated ethanol-induced play fighting and GC deficits in all males but only in 28-day-old females. WC alone reduced sniffing in all males and in younger females. Thus, prenatal ethanol exposure induced deficits in social interaction and somatosensory performance during adolescence. Sensory impoverishment exacerbates ethanol's effect in 28-day-old male and female animals and in 42-day-old males, suggesting sex- and age-dependent changes in outcomes in ethanol-exposed offspring.
Asunto(s)
Envejecimiento/fisiología , Etanol/toxicidad , Lateralidad Funcional/fisiología , Trastorno de la Conducta Social/inducido químicamente , Trastornos Somatosensoriales/etiología , Vibrisas/inervación , Animales , Depresores del Sistema Nervioso Central/toxicidad , Femenino , Edad Gestacional , Relaciones Interpersonales , Masculino , Aprendizaje por Laberinto/fisiología , Actividad Motora/fisiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Desempeño Psicomotor/fisiología , Ratas , Ratas Long-Evans , Factores Sexuales , Vibrisas/patologíaRESUMEN
Prenatal exposure to valproic acid (VPA) alters rodent social interactions in a dose-dependent way: exposure to a high dose of VPA (>500 mg/kg) mid-gestation decreases social interactions whereas a moderate dose of VPA (350 mg/kg) increases peer-directed social behavior. The moderate dose also decreases expression of the mRNA for serine in amygdala and orbitofrontal cortex. In this study, we examined whether d-cycloserine could ameliorate VPA-induced alterations in ultrasonic vocalizations (USVs), social interactions, and locomotor activity. Pregnant Sprague Dawley rats were given intraperintoneal injections of VPA (200mg/kg each) on gestational days 12, 12.5 and 13; controls were injected with saline. Offspring received a subcutaneous injection of saline or d-cycloserine (32 or 64 mg/kg) either acutely (1h prior to testing) or repeatedly (once per day for four days). Social interactions were assessed during late adolescence, and USVs were recorded concomitantly. Male and female rats that were exposed to VPA demonstrated more locomotor activity than control animals during habituation to the testing chamber. VPA-exposed males showed increased play fighting. d-Cycloserine normalized the VPA-induced increase in play fighting in males and also increased social motivation in females. When the pair contained a VPA-exposed rat, significantly fewer USVs were emitted and 16% of the vocalizations were of a novel waveform. These effects were not seen in pairs containing VPA-exposed animals that were treated with d-cycloserine. Overall, these findings are consistent with data from other laboratories suggesting that d-cycloserine may be a promising pharmacotherapeutic compound for improving social behavior disorders.
Asunto(s)
Cicloserina/farmacología , Conducta Social , Ácido Valproico/farmacología , Animales , Femenino , Masculino , Actividad Motora/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Sprague-Dawley , Vocalización Animal/efectos de los fármacosRESUMEN
Relapse and neurodegeneration are two of the major therapeutic targets in alcoholism. Fortuitously, the roles of glutamate/NMDA receptors (NMDARs) in withdrawal, conditioning and neurotoxicity mean that NMDAR inhibitors are potentially valuable for both targets. Preclinical studies further suggest that inhibitory modulators that specifically reduce the co-agonist effects of polyamines on NMDARs are potential non-toxic medications. Using agmatine as a lead compound, over 1000 novel compounds based loosely on this structure were synthesized using feedback from a molecular screen. A novel series of aryliminoguanidines with appropriate NMDAR activity in the molecular screen were discovered (US patent application filed 2007). The most potent and selective aryliminoguanidine, JR 220 [4- (chlorobenzylidenamino)- guanidine hydrochloride], has now been tested in a screening hierarchy for anti-relapse and neuroprotective activity, ranging from cell-based assay, through tissue culture to animal behavior. This hierarchy has been validated using drugs with known, or potential, clinical value at these targets (acamprosate (N-acetyl homotaurine), memantine and topiramate). JR220 was non-toxic and showed excellent activity in every screen with a potency 5-200x that of the FDA-approved anti-relapse agent, acamprosate. This chapter will present a review of the background and rationale for this approach and some of the findings garnered from this approach as well as patents targeting the glutamatergic system especially the NMDAR.
Asunto(s)
Alcoholismo/tratamiento farmacológico , Guanidinas/farmacología , Poliaminas/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/psicología , Femenino , Trastornos del Espectro Alcohólico Fetal/tratamiento farmacológico , Guanidinas/síntesis química , Guanidinas/uso terapéutico , Terapia Molecular Dirigida , Fármacos Neuroprotectores/farmacología , Patentes como Asunto , EmbarazoRESUMEN
Rat pups, in isolation, produce ultrasonic vocalizations (USVs). These USVs have been used as a diagnostic tool for developmental toxicity. We have shown that neonatal ethanol (ETOH) exposure produces deficits in this behavior. The current study was designed to examine whether agmatine (AG), which binds to imidazoline receptors and modulates n-methyl-d-aspartate receptors (NMDAR), could reduce these deficits. In addition, this study examined critical periods for ETOH's effects on USVs by administering ETOH during either the 1st or 2nd postnatal week. Neonatal rats received intragastric intubations of either ETOH (6g/kg/day), ETOH and AG (6g/kg/day and 20mg/kg/day), AG (20mg/kg/day), or maltose on postnatal days (PND) 1-7 or 8-14. A non-intubated control was also included. Subjects were tested on PND 15. Neonatal ETOH exposure significantly increased the latency to vocalize for females and reduced the rate of USVs in both males and females exposed to ETOH on PND 1-7. Agmatine reduced these deficits, in female but not male pups. Subjects exposed to ETOH on PND 8-14 showed no evidence of abnormal USVs. These findings suggest that there may be gender differences in response to AG following neonatal ETOH exposure and also provide further support that the first neonatal week is a particularly sensitive time for the developmentally toxic effects of ETOH in rodents.
Asunto(s)
Agmatina/farmacología , Trastornos del Sistema Nervioso Inducidos por Alcohol/tratamiento farmacológico , Etanol/antagonistas & inhibidores , Trastornos Mentales/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Vocalización Animal/efectos de los fármacos , Envejecimiento/fisiología , Agmatina/uso terapéutico , Trastornos del Sistema Nervioso Inducidos por Alcohol/fisiopatología , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/fisiopatología , Depresores del Sistema Nervioso Central/antagonistas & inhibidores , Depresores del Sistema Nervioso Central/toxicidad , Modelos Animales de Enfermedad , Etanol/toxicidad , Femenino , Trastornos del Espectro Alcohólico Fetal/tratamiento farmacológico , Trastornos del Espectro Alcohólico Fetal/fisiopatología , Masculino , Conducta Materna/fisiología , Trastornos Mentales/inducido químicamente , Trastornos Mentales/fisiopatología , Embarazo , Ratas , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Caracteres Sexuales , Factores Sexuales , Conducta Social , Resultado del Tratamiento , Vocalización Animal/fisiologíaRESUMEN
Neonatal ethanol (EtOH) exposure is associated with central nervous system dysfunction and neurotoxicity in rats. Increases in polyamine levels have been implicated as one underlying mechanism for some of EtOH's effects on the developing brain. In this study we addressed whether the inhibition of polyamine biosynthesis by alpha-difluoromethylornithine (DFMO) could reduce behavioral deficits induced by early EtOH exposure. Male and female rat pups received ethanol (6 g/kg/day EtOH i.g.), or isocaloric maltose (control) from postnatal days (PND) 1-8. On PND 8, animals were injected with either saline or DFMO (500 mg/kg, s.c.) immediately following the final neonatal treatment. Subjects were tested for isolation-induced ultrasonic vocalizations (USV) on PND 16; spontaneous activity in an open field apparatus on PND 20 and 21; and balance on PND 31. Animals exposed to EtOH neonatally displayed an increased latency to the first USV and reduced frequencies of USV, hyperactivity and preference for the center of the open field and poorer balance relative to controls. DFMO minimized these deficits in latency to the first USV and balance. These data provide further support that polyamines play a role in some of the functional deficits associated with EtOH exposure during early development and that reducing polyamine activity can improve outcome.