Ceftriaxone reverses ketamine-induced lasting EEG and astrocyte alterations in juvenile mice.

BACKGROUND: Ketamine, an N-methyl-d-aspartate receptor antagonist, is used as a pediatric anesthetic because of its favorable safety profile. It is also being investigated as an antidepressant. Unfortunately, ketamine causes adverse reactions including hallucinations and is associated with a high prevalence of abuse among adolescents. Although chronic ketamine use has been shown to produce cognitive impairments even years following cessation, little is known about its long-term consequences on adolescents. The beta-lactam ceftriaxone has been shown to attenuate alcohol withdrawal, and alleviate early brain injury and memory impairments following subarachnoid hemorrhage. However, its ability to reverse the effects of adolescent ketamine exposure is not known. Previous data indicate that ketamine causes a reduction in the number of Excitatory Amino Acid Transporter Type 2 (EAAT2)-containing astrocytes. Additionally, the beta lactam antibiotic ceftriaxone increased expression of EAAT2. As EAAT2 is a principal mechanism of glutamate clearance from the synapse, the current study tests the hypothesis that ceftriaxone may reverse functional consequences of ketamine exposure. METHODS: We examined the effects of chronic ketamine in juvenile mice as well as reversal by ceftriaxone using electroencephalography (EEG). Subsequently, we assessed the effects of these treatments on markers of astrocyte proliferation, using Glial Fibrillary Acidic Protein (GFAP), and function, as evidenced by EAAT2. RESULTS: Juvenile mice exposed to chronic ketamine showed lasting alterations in EEG measurements as well as markers of astrocyte number and function. These alterations were reversed by ceftriaxone. CONCLUSIONS: Data suggest that ceftriaxone may be able to ameliorate ketamine-induced long-term disturbances in adolescent brains.

Delayed emergence of behavioral and electrophysiological effects following juvenile ketamine exposure in mice.

Frequent ketamine abuse in adulthood correlates with increased risk of psychosis, as well as cognitive deficits, including disruption of higher-order executive function and memory formation. Although the primary abusers of ketamine are adolescents and young adults, few studies have evaluated its effects on juvenile cognition. Therefore, the current study analyzes the effect of adolescent ketamine exposure on cognitive development. Juvenile mice (4 weeks of age) were exposed to chronic ketamine (20 mg kg(-1), i.p. daily) for 14 days. Mice were tested immediately after exposure in the juvenile period (7 weeks of age) and again as adults (12 weeks of age). Measures included electroencephalography (EEG) in response to auditory stimulation, the social choice test, and a 6-arm radial water maze task. Outcome measures include low-frequency EEG responses, event-related potential (ERP) amplitudes, indices of social behavior and indices of spatial working memory. Juvenile exposure to ketamine was associated with electrophysiological abnormalities in adulthood, particularly in induced theta power and the P80 ERP. The social choice test revealed that ketamine-exposed mice failed to exhibit the same age-related decrease in social interaction time as controls. Ketamine-exposed mice outperformed control mice as juveniles on the radial water maze task, but did not show the same age-related improvement as adult controls. These data support the hypothesis that juvenile exposure to ketamine produces long-lasting changes in brain function that are characterized by a failure to progress along normal developmental trajectories.

Juvenile exposure to ketamine causes delayed emergence of EEG abnormalities during adulthood in mice.

BACKGROUND: Increased susceptibility to cognitive impairment or psychosis in adulthood is associated with adolescent drug abuse. Studies in adults have identified impairments in attention and memory, and changes in EEG, as common consequences of ketamine abuse. In contrast, the effects of ketamine on the juvenile brain have not been extensively tested. This is a significant omission, since abuse of ketamine is often observed within this age group. OBJECTIVES: Juvenile mice (4-6 weeks of age) were administered ketamine (20mg/kg) for 14 days. EEG was assessed in response to auditory stimulation both at one week following ketamine exposure at 7 weeks of age (juvenile) and again at 12 weeks of age (adult). EEG was analyzed for baseline activity, event-related power and event-related potentials (ERPs). RESULTS: While no effects of ketamine exposure were observed during the juvenile period, significant reductions in amplitude of the P20 ERP component and event-related gamma power were seen following ketamine when re-tested as adults. In contrast, reductions in event-related theta were seen in ketamine-exposed mice at both time points. CONCLUSIONS: Age related deficits in electrophysiological components such as P20 or event-related gamma may be due to an interruption of normal neural maturation. Reduction of NMDAR signaling during adolescence leads to delayed-onset disruption of gamma oscillations and the P20 component of the ERP. Further, delayed onset of impairment following adolescent ketamine abuse suggests that methods could be developed to detect and treat the early effects of drug exposure prior to the onset of disability.

The amphetamine-induced sensitized state as a model of schizophrenia.

Schizophrenia is a serious psychiatric disorder which impacts a broad range of cognitive, behavioural and emotional domains. In animals, exposure to an intermittent, escalating dose regimen of amphetamine induces a sensitized state that appears to share a number of behavioural and neurochemical similarities with schizophrenia. In humans repeated exposure to amphetamine, or other psychomotor stimulants, can induce sensitization as well as psychosis. The following paper evaluates the evidence for the amphetamine-induced sensitized state as an animal model of schizophrenia, focussing separately on the positive, cognitive and negative symptoms associated with this disease. Current evidence supports the use of amphetamine sensitization as a model of the positive symptoms observed in schizophrenia. Additionally, there is increasing evidence for long-lasting cognitive deficits in sensitized animals, especially in the area of attention and/or cognitive flexibility. Other areas of cognition, such as long-term memory, appear to be unaltered in sensitized animals. Finally, little evidence currently exists to either support or refute the use of amphetamine sensitization as a model of negative symptoms. It is concluded that amphetamine sensitization likely impacts behaviour by altering the functioning of mesolimbic dopamine systems and prefrontal cortical function and can serve as a model of certain domains of schizophrenia.

Lesions of the dorsolateral striatum impair the acquisition of a simplified stimulus-response dependent conditional discrimination task.

The dorsal striatum has long been thought to be important for some types of learning and memory, especially stimulus-response learning. Recently, we demonstrated that selective lesions of the dorsolateral striatum, but not dorsomedial striatum in rats, retarded the acquisition of two instrumental discrimination tasks thought to require stimulus-response learning. However, since these studies investigated the effects of dorsal striatal lesions on task acquisition, which can be confounded by differences in level of reinforcement and motor impairment caused by the lesion, the interpretation of these findings was somewhat problematic. The present experiment was designed to address these issues by assessing the effects of lesions of the dorsolateral striatum on a simplified version of the conditional discrimination task, in which the importance of reinforcement and motor factors was minimized. Animals with lesions of the dorsolateral striatum showed marked impairments in learning this task, a finding that is in agreement with the notion that the dorsolateral striatum is necessary for stimulus-response learning.

Lesions of the dorsolateral or dorsomedial striatum impair performance of a previously acquired simple discrimination task.

Previous evidence has suggested a specific role for the dorsal striatum, especially the dorsolateral region of the dorsal striatum, in stimulus-response learning. In a previous study, we found an impairment in animals with dorsolateral striatal lesions on a simple discrimination task (CS+/CS-), thought to require the involvement of both stimulus-reward and stimulus-response learning. It is possible that the generally poor performance of dorsolateral lesioned animals on this experiment precluded adequate exposure to stimulus-reward pairings necessary for solving this task, and, thus, had little to do with stimulus-response learning. To test this hypothesis, the performance of animals with dorsolateral and dorsomedial striatal lesions was assessed on a previously acquired simple discrimination task. To independently assess the effects of each lesion on the performance of stimulus-reward learning, dorsolateral and dorsomedial lesioned animals were assessed on a previously acquired conditioned place preference task (CPP). In agreement with our earlier experiment, and the stimulus-response interpretation of dorsolateral striatal function, animals with dorsolateral striatal lesions were found to be impaired during post-lesion performance of the simple discrimination task, but not CPP learning. Additionally, dorsomedial lesioned animals were found to be impaired in performance of the simple discrimination task, but not on the CPP task. Possible explanations for the differences between the role of the dorsomedial striatum in acquisition and expression of the simple discrimination task are proposed.

Dorsal striatum and stimulus-response learning: lesions of the dorsolateral, but not dorsomedial, striatum impair acquisition of a simple discrimination task.

In the present experiment, the effects of neurotoxic lesions (quinolinic acid) of the dorsolateral or dorsomedial striatum were investigated on a simple instrumental discrimination task (CS+/CS-). Rats with lesions of the dorsolateral striatum were found to be impaired in the acquisition of this task, as compared to rats with either dorsomedial striatal or sham lesions. Furthermore, dorsolateral striatal lesioned animals had significantly lower levels of responding across the course of discrimination training, as assessed both by overall rate of response during CS+ presentations and number of CS+ trials without a response, despite having shown levels of responding during variable interval training that did not differ from that of sham lesioned animals. In contrast, animals with lesions of the dorsomedial striatum did not show an impairment in acquisition of the present task, but had slightly higher rates of responding during CS- presentations. It is argued that the poor acquisition and low response rates observed in animals with dorsolateral striatal lesions reflect a failure in stimulus-response learning, while the performance of animals with dorsomedial striatal lesions may have been the result of an increase in overall activity rate.

Dorsal striatum and stimulus-response learning: lesions of the dorsolateral, but not dorsomedial, striatum impair acquisition of a stimulus-response-based instrumental discrimination task, while sparing conditioned place preference learning.

While some evidence suggests that the dorsal striatum is important for stimulus-response learning, disagreement exists about the relative contribution of the dorsolateral and dorsomedial striatum to this form of learning. In the present experiment, the effects of lesions of the dorsolateral and dorsomedial striatum were investigated on two tasks that differentially require the development of stimulus-response learning. The first task utilized an operant conditional discrimination task, which is likely to rely heavily upon stimulus-response learning. The second task looked conditioned place preference learning, a task that is unlikely to require the development of stimulus-response associations. Animals with lesions of the dorsolateral striatum were impaired on the operant conditional discrimination task, but retained the ability to learn the conditioned place preference task. In contrast, animals with lesions of the dorsomedial striatum were not found to be impaired on either task used in the present experiment. These results suggest that the dorsolateral striatum is necessary for the successful acquisition of tasks that place a demand upon stimulus-response learning, while the dorsomedial striatum is not involved in this type of learning.

Plasticity in the maternal circuit: effects of experience and partum condition on brain astrocyte number in female rats.

Female rats that have received a maternal experience undergo enhanced c-fos expression in a number of brain sites when reexposed to pups. The present 2 studies examined changes in the expression of another brain protein, glial fibrillary acidic protein (GFAP), which is a major unit of the astrocytic cytoskeleton. In both experiments, primiparous and multiparous female rats were given varying amounts of postpartum contact with pups and overdosed after varying intervals, with no pups. Brains were prepared for GFAP immunohistochemical analysis. In both studies, Day 5 postpartum multiparous subjects given additional postpartum contact with pups, when compared with pup-exposed primiparous subjects, were found to have significantly higher numbers of GFAP positive cells in the medial preoptic area of the hypothalamus, an area critical for the expression of maternal behavior, but not in control sites. In Experiment 2, an opposite effect of parity was found in the medial amygdala and habenula.