Social isolation disrupts hippocampal neurogenesis in young non-human primates.

Social relationships are crucial for the development and maintenance of normal behavior in non-human primates. Animals that are raised in isolation develop abnormal patterns of behavior that persist even when they are later reunited with their parents. In rodents, social isolation is a stressful event and is associated with a decrease in hippocampal neurogenesis but considerably less is known about the effects of social isolation in non-human primates during the transition from adolescence to adulthood. To investigate how social isolation affects young marmosets, these were isolated from other members of the colony for 1 or 3 weeks and evaluated for alterations in their behavior and hippocampal cell proliferation. We found that anxiety-related behaviors like scent-marking and locomotor activity increased after social isolation when compared to baseline levels. In agreement, grooming-an indicative of attenuation of tension-was reduced among isolated marmosets. These results were consistent with increased cortisol levels after 1 and 3 weeks of isolation. After social isolation (1 or 3 weeks), reduced proliferation of neural cells in the subgranular zone of dentate granule cell layer was identified and a smaller proportion of BrdU-positive cells underwent neuronal fate (doublecortin labeling). Our data is consistent with the notion that social deprivation during the transition from adolescence to adulthood leads to stress and produces anxiety-like behaviors that in turn might affect neurogenesis and contribute to the deleterious consequences of prolonged stressful conditions.

Assessment of seizure susceptibility in pilocarpine epileptic and nonepileptic Wistar rats and of seizure reinduction with pentylenetetrazole and electroshock models.

PURPOSE: Pentylenetetrazole (PTZ) and maximal electroshock (MES) models are often used to induce seizures in nonepileptic control animals or naive animals. Despite being widely used to screen antiepileptic drugs (AEDs), both models have so far failed to detect potentially useful AEDs for treating drug-resistant epilepsies. Here we investigated whether the acute induction of MES and PTZ seizures in epileptic rats might yield a distinct screening profile for AEDs. METHODS: Status epilepticus (SE) was induced in adult male Wistar rats by intraperitoneal pilocarpine injection (Pilo, 320 mg/kg, i.p.). One month later, controls or naive animals (Cont) that did not develop SE postpilocarpine (N-Epi) and pilocarpine-epileptic rats (Epi) received one of the following: phenobarbital (PB, 40 mg/kg), phenytoin (PHT, 50 mg/kg), or valproic acid (VPA, 400 mg/kg). Thirty min later the animals were challenged with either subcutaneous MES or PTZ (50 mg/kg, s.c.). RESULTS: VPA, PB, and PHT were able to prevent MES in all groups tested (Cont, N-Epi, and Epi groups), whereas for the PTZ model, only the Cont group (naive animals) had seizure control with the same AEDs. In addition, Epi and N-Epi groups when challenged with PTZ exhibited a higher incidence of severe seizures (scores IV-IX) and SE (p < 0.05, Fisher's exact test). CONCLUSIONS: Our findings suggest that the induction of acute seizures with PTZ, but not with MES, in animals pretreated with pilocarpine (regardless of SE induction) might constitute an effective and valuable method to screen AEDs and to study mechanisms involved in pharmacoresistant temporal lobe epilepsy (TLE).

Behavioral characterization of pentylenetetrazol-induced seizures in the marmoset.

This study was designed to characterize seizures induced with pentylenetetrazol (PTZ) in marmosets. Thirteen adult marmosets (Callithrix sp.) received 20, 30, or 40 mg/kg of PTZ intraperitoneally. PTZ caused all animals to switch their natural behavioral repertoire to early convulsive behavior. Seizure scores were low at lower PTZ doses, whereas the highest dose of PTZ led to seizure scores IV and V (according to Racine's scale) in 69% of animals. To further characterize the model we performed a preliminary evaluation of the efficacy of three antiepileptic drugs: phenobarbital, phenytoin, and carbamazepine. Phenobarbital prevented PTZ-induced seizures in 100% of trials. As expected, phenytoin and carbamazepine were not effective against PTZ-induced seizures. The present study describes the PTZ model of seizures in marmosets with a drug-response profile similar to that of the rodent model, thus bringing to a well-known model (PTZ in rodents) the complexity of a nonhuman primate brain.

Influence of chronic cocaine treatment and sleep deprivation on sexual behavior and neurogenesis of the male rat.

The present study investigated the influence of chronic cocaine treatment on genital reflexes associated with paradoxical sleep deprivation (PSD), and possible alterations in hippocampus neurogenesis of the male rat. At 21 days of age, the rats were distributed into two groups and injected with saline or cocaine (7 mg/kg, three times a week for 12 weeks). At age 90 days, they were submitted to a four-day period of PSD (PSD groups) or maintained in home-cages (control groups), challenged with saline or cocaine administration, and placed in observation cages to assess genital reflexes. Two additional groups were used to quantify neurogenesis. PSD rats treated chronically with cocaine and challenged with saline did not differ from their respective control groups. The association of PSD with cocaine potentiated penile erection (PE) when compared to PSD-saline (saline challenged) rats, and these effects were similar to those observed in long-term cocaine treated rats. The bromodeoxyuridine (BrdU) assay indicated a reduction in BrdU-positive cells in the adult hippocampus after chronic cocaine treatment. These findings show that long-term cocaine treatment from brain development through adulthood had a marked effect on sexual responses and neuronal proliferation.

Behavioral and histopathological analysis of domoic Acid administration in marmosets.

PURPOSE: To induce status epilepticus (SE) followed by the subsequent onset of spontaneous recurrent seizures, thus characterizing a new model of temporal lobe epilepsy in a nonhuman primate. METHODS: Male and female marmosets (Callithrix jacchus) (n = 18), ages between 2 and 8 years, were injected with domoic acid (0.5-4 mg/kg, i.p.) or saline, and behaviorally assessed with regard to the presence of acutely induced seizures and for < or = 6 months for spontaneous seizures. Injection of doses ranging from 3.5 to 4 mg/kg either did not induce SE or resulted in fatal SE. Even a 5-min SE duration (SE blockade resulting from diazepam injection) proved lethal to marmosets within 1 h of domoate administration, regardless of intensive care and monitoring of the animals. Animals injected with doses ranging from 0.5 to 3 mg/kg that developed only a few minor convulsive signs were allowed a 6-month survival period for the assessment of spontaneous epileptic events. At the end of the experiment, 6-month period, or acute intoxication associated with SE induction, animals were deeply anesthetized and had their brains subjected to histologic processing for Nissl and delta-FosB. RESULTS: For the animals injected with domoate that did not develop SE (i.e., those that survived), we could not detect any behavioral signs of spontaneous epileptic seizures in the 6-month observation period, and only minor indications of neuropathologic changes (i.e., neuronal death) over Nissl-stained sections, as well as some small changes in the staining for delta-FosB in a few of the animals. CONCLUSIONS: Systemic administration of domoic acid to marmosets is not effective for the generation of a model of chronic temporal lobe epilepsy. Administration of domoic acid at doses that do not lead to SE also did not lead to the development of temporal lobe epilepsy or clear-cut behavioral changes over a 6-month period.