Pathophysiological Bases of Comorbidity: Traumatic Brain Injury and Post-Traumatic Stress Disorder.

The high rates of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) diagnoses encountered in recent years by the United States Veterans Affairs Healthcare System have increased public awareness and research investigation into these conditions. In this review, we analyze the neural mechanisms underlying the TBI/PTSD comorbidity. TBI and PTSD present with common neuropsychiatric symptoms including anxiety, irritability, insomnia, personality changes, and memory problems, and this overlap complicates diagnostic differentiation. Interestingly, both TBI and PTSD can be produced by overlapping pathophysiological changes that disrupt neural connections termed the "connectome." The neural disruptions shared by PTSD and TBI and the comorbid condition include asymmetrical white matter tract abnormalities and gray matter changes in the basolateral amygdala, hippocampus, and prefrontal cortex. These neural circuitry dysfunctions result in behavioral changes that include executive function and memory impairments, fear retention, fear extinction deficiencies, and other disturbances. Pathophysiological etiologies can be identified using experimental models of TBI, such as fluid percussion or blast injuries, and for PTSD, using models of fear conditioning, retention, and extinction. In both TBI and PTSD, there are discernible signs of neuroinflammation, excitotoxicity, and oxidative damage. These disturbances produce neuronal death and degeneration, axonal injury, and dendritic spine dysregulation and changes in neuronal morphology. In laboratory studies, various forms of pharmacological or psychological treatments are capable of reversing these detrimental processes and promoting axonal repair, dendritic remodeling, and neurocircuitry reorganization, resulting in behavioral and cognitive functional enhancements. Based on these mechanisms, novel neurorestorative therapeutics using anti-inflammatory, antioxidant, and anticonvulsant agents may promote better outcomes for comorbid TBI and PTSD.

Dopamine D1 receptor agonist treatment attenuates extinction of morphine conditioned place preference while increasing dendritic complexity in the nucleus accumbens core.

The dopamine D1 receptor (D1R) has a role in opioid reward and conditioned place preference (CPP), but its role in CPP extinction is undetermined. We examined the effect of D1R agonist SKF81297 on the extinction of opioid CPP and associated dendritic morphology in the nucleus accumbens (NAc), a region involved with reward integration and its extinction. During the acquisition of morphine CPP, mice received morphine and saline on alternate days; injections were given immediately before each of eight daily conditioning sessions. Mice subsequently underwent six days of extinction training designed to diminish the previously learned association. Mice were treated with either 0.5mg/kg SKF81297, 0.8mg/kg SKF81297, or saline immediately after each extinction session. There was a dose-dependent effect, with the highest dose of SKF81297 attenuating extinction, as mice treated with this dose had significantly higher CPP scores than controls. Analysis of medium spiny neuron morphology revealed that in the NAc core, but not in the shell, dendritic arbors were significantly more complex in the morphine conditioned, SKF81297-treated mice compared to controls. In separate experiments using mice conditioned with only saline, SKF81297 administration after extinction sessions had no effect on CPP and produced differing effects on dendritic morphology. At the doses used in our experiments, SKF81297 appears to maintain previously learned opioid conditioned behavior, even in the face of new information. The D1R agonist's differential, rather than unidirectional, effects on dendritic morphology in the NAc core suggests that it may be involved in encoding reward information depending on previously learned behavior.

Acquisition of morphine conditioned place preference increases the dendritic complexity of nucleus accumbens core neurons.

Contexts associated with opioid reward trigger craving and relapse in opioid addiction. Effects of reward-context associative learning on nucleus accumbens (NAc) dendritic morphology were studied using morphine conditioned place preference (CPP). Morphine-conditioned mice received saline and morphine 10 mg/kg subcutaneous (s.c.) on alternate days. Saline-conditioned mice received saline s.c. each day. Morphine-conditioned and saline-conditioned groups received injections immediately before each of eight daily conditioning sessions. Morphine homecage controls had no CPP training, but received saline and morphine in the homecage concomitantly with the morphine-conditioned group. Morphine conditioning produced greater place preference than saline conditioning. Mice were sacrificed 1 day after CPP expression. Dendritic changes were studied using Golgi-Cox staining and digital tracing of NAc core and shell neurons. In the NAc core, morphine homecage administration increased spine density, while morphine conditioning increased dendritic complexity, as defined by increased dendritic count, length and intersections. Place preference positively correlated with dendritic length and intersections in the NAc core. The core may mediate reward consolidation and determine how context-related signals from the shell lead to motor behavior. The combination of drug and conditioning in the morphine-conditioned group produced unique morphological effects different from the effects of drug or conditioning procedures by themselves. An additional study found no differences in neuron morphology between saline-conditioned mice, trained as described earlier, and mice that were not conditioned, but received saline in the homecage. The unique effect of morphine reward learning on NAc core dendrites reflects a brain substrate that could be targeted for therapeutic intervention in addiction.

Extinction of opiate reward reduces dendritic arborization and c-Fos expression in the nucleus accumbens core.

Recurrent opiate use combined with environmental cues, in which the drug was administered, provokes cue-induced drug craving and conditioned drug reward. Drug abuse craving is frequently linked with stimuli from a prior drug-taking environment via classical conditioning and associative learning. We modeled the conditioned morphine reward process by using acquisition and extinction of conditioned place preference (CPP) in C57BL/6 mice. Mice were trained to associate a morphine injection with a drug context using a classical conditioning paradigm. In morphine conditioning (0, 0.25, 0.5, 1, 5, or 10 mg/kg) experimental mice acquired a morphine CPP dose response with 10mg/kg as most effective. During morphine CPP extinction experiments, mice were divided into three test groups: morphine CPP followed by extinction training, morphine CPP followed by sham extinction, and saline controls. Extinction of morphine CPP developed within one extinction experiment (4 days) that lasted over two more trials (another 8 days). However, the morphine CPP/sham extinction group retained a place preference that endured through all three extinction trials. Brains were harvested following CPP extinction and processed using Golgi-Cox impregnation. Changes in dendritic morphology and spine quantity were examined in the nucleus accumbens (NAc) Core and Shell neurons. In the NAcCore only, morphine CPP/extinguished mice produced less dendritic arborization, and a decrease in neuronal activity marker c-Fos compared to the morphine CPP/sham extinction group. Extinction of morphine CPP is associated with decreased structural complexity of dendrites in the NAcCore and may represent a substrate for learning induced structural plasticity relevant to addiction.

Repeated valproate treatment facilitates fear extinction under specific stimulus conditions.

Single dose treatment with histone deacetylase inhibitor (HDACi) agents has been shown to enhance extinction learning in rodent models under certain conditions. The present novel studies were designed to examine the effects of repeated HDACi treatment, with valproate or sodium butyrate, on the extinction of conditioned fear. In Experiments 1 and 2, short duration CS exposure (30s) in combination with vehicle administration progressively attenuated conditioned fear responses over 40 or more sessions. This effective extinction training was not augmented by HDACi treatments. In Experiment 3, we used a long duration CS exposure (120 s) to weaken extinction training. With these extinction parameters, repeated valproate treatment substantially facilitated the acquisition and retention of fear extinction. Results of this study extend previous work suggesting that HDACi's have utility in augmenting the efficiency of fear extinction, although their apparent benefits are critically dependent upon specific parameters of extinction training.

Dendritic structural plasticity in the basolateral amygdala after fear conditioning and its extinction in mice.

Previous research suggests that morphology and arborization of dendritic spines change as a result of fear conditioning in cortical and subcortical brain regions. This study uniquely aims to delineate these structural changes in the basolateral amygdala (BLA) after both fear conditioning and fear extinction. C57BL/6 mice acquired robust conditioned fear responses (70-80% cued freezing behavior) after six pairings with a tone cue associated with footshock in comparison to unshocked controls. During fear acquisition, freezing behavior was significantly affected by both shock exposure and trial number. For fear extinction, mice were exposed to the conditioned stimulus tone in the absence of shock administration and behavioral responses significantly varied by shock treatment. In the retention tests over 3 weeks, the percentage time spent freezing varied with the factor of extinction training. In all treatment groups, alterations in dendritic plasticity were analyzed using Golgi-Cox staining of dendrites in the BLA. Spine density differed between the fear conditioned group and both the fear extinction and control groups on third order dendrites. Spine density was significantly increased in the fear conditioned group compared to the fear extinction group and controls. Similarly in Sholl analyses, fear conditioning significantly increased BLA spine numbers and dendritic intersections while subsequent extinction training reversed these effects. In summary, fear extinction produced enduring behavioral plasticity that is associated with a reversal of alterations in BLA dendritic plasticity produced by fear conditioning. These neuroplasticity findings can inform our understanding of structural mechanisms underlying stress-related pathology can inform treatment research into these disorders.

Treatment of addiction and anxiety using extinction approaches: neural mechanisms and their treatment implications.

Clinical interventions which produce cue and contextual extinction learning can reduce craving and relapse in substance abuse and inhibit conditioned fear responses in anxiety disorders. In both types of disorders, classical conditioning links unconditioned drug or fear responses to associated contextual cues and result in enduring pathological responses to multiple stimuli. Extinction therapy countermeasures seek to reduce conditioned responses using a set of techniques in which patients are repeatedly exposed to conditioned appetitive or aversive stimuli using imaginal imagery, in vivo exposure, or written scripts. Such interventions allow patients to rehearse more adaptive responses to conditioned stimuli. The ultimate goal of these interventions, extinction of the original conditioned response, is a new learning process that results in a decrease in frequency or intensity of conditioned responses to drug or fear cues. This review explores extinction approaches in conditioned drug reward and fear responses. The behavioral, neuroanatomical and neurochemical mechanisms of conditioned reward and fear responses and their extinction are derived from our understanding of the animal literature. Extensive neuroscience research shows that even though many mechanisms differ in conditioned fear and reward, converging prefrontal cortical glutamatergic pathways underlie extinction learning. Efficacy of pharmacological and behavioral treatment approaches in addiction and anxiety disorders may be optimized by enhancing extinction and weakening the bond between the original conditioned stimuli and conditioned responses. Adjunctive pharmacotherapy approaches using agents which alter glutamate or γ-aminobutyric acid signaling or epigenetic mechanisms in prefrontal cortical pathways can enhance extinction learning. A comparative study of extinction processes and its neural mechanisms can be translated into more effective behavioral and pharmacological treatment approaches in substance abuse and anxiety.

Dietary omega-3 fatty acid supplementation for optimizing neuronal structure and function.

Direct actions of omega-3 polyunsaturated fatty acids (PUFAs) on neuronal composition, neurochemical signaling and cognitive function constitute a multidisciplinary rationale for classification of dietary lipids as "brain foods." The validity of this conclusion rests upon accumulated mechanistic evidence that omega-3 fatty acids actually regulate neurotransmission in the normal nervous system, principally by modulating membrane biophysical properties and presynaptic vesicular release of classical amino acid and amine neurotransmitters. The functional correlate of this hypothesis, that certain information processing and affective coping responses of the central nervous system are facilitated by bioavailability of omega-3 fatty acids, is tentatively supported by developmental and epidemiological evidence that dietary deficiency of omega-3 fatty acids results in diminished synaptic plasticity and impaired learning, memory and emotional coping performance later in life. The present review critically examines available evidence for the promotion in modern society of omega-3 fatty acids as adaptive neuromodulators capable of efficacy as dietary supplements and as potential prophylactic nutraceuticals for neurological and neuropsychiatric disorders.

Heightened muscle tension and diurnal hyper-vigilance following exposure to a social defeat-conditioned odor cue in rats.

Patients with post-traumatic stress disorder (PTSD) exhibit exaggerated daytime muscle tension as well as nocturnal sleep disturbances. Yet, these physiological and behavioral features of the disorder are little studied in animal models of PTSD. Accordingly, the present studies were designed to assess alterations in muscle tension and diurnal hyper-vigilance resulting from exposure to a social defeat stressor paired with an olfactory stimulus, which was then used as a reminder of stressor exposure. In the first series of experiments, rats presented with an olfactory cue paired previously with a single social defeat exhibited a significant increase in muscle tension 4 weeks following defeat. In the second series of experiments, an olfactory cue paired previously with a single social defeat induced a significant increase in locomotor activity among quiescent rats 4 weeks following stressor exposure. The present results thus support the a priori hypotheses that novel physiological and behavioral hallmarks of PTSD can be documented in an animal model of the disorder and that the present overt signs of reactive hyper-vigilance can be triggered by reintroduction of an olfactory stimulus present at the time of initial trauma exposure.

Neurobehavioral consequences of stressor exposure in rodent models of epilepsy.

Both normal, non-epileptic as well as seizure-prone rodents exhibit a spectrum of anxiogenic-like behaviors in response to stressor exposure. Comparative analysis reveals that the same set of emotionality dependent measures is sensitive to both stress reactivity in normal rodents as well as stress hyperreactivity typically seen in seizure-prone rodents. A variety of unconditioned, exploratory tasks reflect global sensitivity to stressor exposure in the form of behavioral inhibition of locomotor output. Moreover, well chosen stressors can trigger de novo seizures with or without a history of seizure incidence. Seizures may be elicited in response to stressful environmental stimuli such as noxious noises, tail suspension handling, or home cage disturbance. Stress reactivity studies in rodents with a genetic predisposition to seizures have yielded important clues regarding brain substrates that mediate seizure ontogeny and modulate ictogenesis. Brains of seizure susceptible rodents reflect elevated content of the stress-related neuropeptide, corticotropin-releasing factor (CRF) in several nuclei relative to non-susceptible controls and neutralization of brain CRF attenuates seizure sensitivity. Findings outlined in this review support a diathesis-stress hypothesis in which behavioral- and neuro-pathologies of genetically seizure susceptible rodents arise in part due to multifaceted hyperreactivity to noxious environmental stimuli.

Quality of rearing guides expression of behavioral and neural seizure phenotypes in EL mice.

The present studies employed behavioral and neural markers of seizure-related plasticity to examine the relative contributions of genetic predisposition versus rearing environment in generating adult phenotypes in EL mice, a stress-induced animal model of epilepsy. Early environment was manipulated by cross-fostering pups of the EL strain to a seizure-resistant CD-1 control strain of mouse. The impact of changes in rearing quality on growth,exploratory and stress-reactivity phenotypes were examined, with a focus on the role of maternal care in shaping seizure susceptibility and neural cF os activation. Improvement in maternal care imposed by replacing biological EL dams with foster CD-1 mothers was sufficient to decrease pup mortality, to increase body weight gain (+0.1 g/day) and to delay the onset of seizure susceptibility in EL offspring beyond post-natal day 80­90. Moreover,hypoactivity in hippocampus and cortex among EL offspring cross-fostered to EL, but not CD-1 control, dams suggests that changes in rearing environment were accompanied by enduring changes in brain plasticity. Thus, neural and behavioral phenotypes of EL mice are dependent upon post-partum maternal care which if systematically enhanced can postpone seizure expression.

Improvement in motor and exploratory behavior in Rett syndrome mice with restricted ketogenic and standard diets.

Rett syndrome (RTT) is a rare X-linked autistic-spectrum neurological disorder associated with impaired energy metabolism, seizure susceptibility, progressive social behavioral regression, and motor impairment primarily in young girls. The objective of this study was to examine the influence of restricted diets, including a ketogenic diet (KD) and a standard rodent chow diet (SD), on behavior in male Mecp2(308/y) mice, a model of RTT. The KD is a high-fat, low-carbohydrate diet that has anticonvulsant efficacy in children with intractable epilepsy and may be therapeutic in children with RTT. Following an 11-day pretrial period, adult wild-type and mutant Rett mice were separated into groups that were fed either an SD in unrestricted or restricted amounts or a ketogenic diet (KetoCal) in restricted amounts for a total of 30 days. The restricted diets were administered to reduce mouse body weight by 20-23% compared to the body weight of each mouse before the initiation of the diet. All mice were subjected to a battery of behavioral tests to determine the influence of the diet on the RTT phenotype. We found that performance in tests of motor behavior and anxiety was significantly worse in male RTT mice compared to wild-type mice and that restriction of either the KD or the SD improved motor behavior and reduced anxiety. We conclude that although both restricted diets increased the tendency of Rett mice to explore a novel environment, the beneficial effects of the KD were due more to calorie restriction than to the composition of the diet. Our findings suggest that calorically restricted diets could be effective in reducing the anxiety and in improving motor behavior in girls with RTT.

Neuronal depletion of omega-3 fatty acids induces flax seed dietary self-selection in the rat.

The impact of essential dietary fatty acid deficiency on self-selection of fatty acid enriched foods is little studied in spite of widespread health promotion claims for fatty acid supplemented diets. Accordingly, the present studies investigated the consequences of consumption over four weeks of omega-3 fatty acid replete and deficient diets on dietary fatty acid self-selection and brain lipid composition in rats. Dietary omega-3 fatty acid deficiency produced correspondingly low levels (50-55% decrease) of omega-3 fatty acids in the forebrain relative to rats consuming an omega-3 fatty acid replete diet. The state of omega-3 fatty acid deficiency generated a robust preference for consumption of an omega-3 fatty acid replete diet. Moreover, omega-3 fatty acid self-selection developed slowly and was not present in rats maintained on laboratory chow diet suggesting that post-ingestive nutritional cues, rather than taste, odor or texture cues, were employed in guiding the preference for the omega-3 fatty acid enriched diet. These results provide evidence for the ability of rats with declining brain levels of omega-3 fatty acids to detect a dietary deficiency of this essential class of lipids and to identify and consume a food source capable of restoring fatty acid repletion.

Behavioral measures in animal studies: relevance to patients with epilepsy.

The relevance of behavioral endpoints in animal seizure models to clinical epilepsy is outlined and enhanced in the present review by linking specific preclinical dependent measures with a quality-of-life scale that serves as an index of the health and welfare of patients with epilepsy (Quality of Life in Epilepsy inventory). This preclinical-to-clinical translation is possible based on existing literature within at least three behavioral domains: (1) physical and motor actions, (2) affective and emotional responses to environmental challenge, and (3) social, sexual, and parental functions. Face valid commonalities in observable behaviors are emphasized with the goal of engaging basic and applied researchers in collaborative research projects to accelerate the pace of discovery in the behavioral phenotyping of epilepsy field.

Seizure susceptibility and locus ceruleus activation are reduced following environmental enrichment in an animal model of epilepsy.

Alterations in the complexity of social and physical housing environments modulate seizure susceptibility in animal models of epilepsy. The studies described here tested the hypothesis that environmental enrichment would delay seizure onset in the epileptic (El) mouse. Neural activation measured via cFos expression, accumulation of the stress neuropeptide corticotropin-releasing factor (CRF), and behavioral seizure susceptibility were quantified in El mice to better understand the mechanisms of ictogenesis. Enrichment housing of El mice from Postnatal Days 21 to 49 produced a 100% decrease in seizure susceptibility relative to El controls. cFos expression increased in the primary motor cortex, locus ceruleus, and hippocampus of El mice relative to ddY controls, an effect attenuated by enrichment housing. CRF levels were elevated by enrichment in the hippocampus of ddY mice only. This study provides evidence that enrichment housing delays the onset of seizure susceptibility in El mice while altering the neuronal and stress-related responses in seizure-associated regions of the El brain.

Paternal care paradoxically increases offspring seizure susceptibility in the El mouse model of epilepsy.

The El mouse is a model of idiopathic epilepsy in which seizures emerge on Postnatal Days (PNDs) 80-90, although time to first seizure can be modified by experiential factors including handling during development and history of past seizures. This study tested the hypothesis that a significant increase in the amount of parental investment would impact seizure susceptibility in adult El offspring. The study used a single dam control, in which the litter was reared by a female biological parent, and a biparental experimental group, in which both biological parents reared the litter. Components of parental care and pup body weights were quantified on PNDs 2-21, and adult offspring were examined using a handling-induced seizure susceptibility (HISS) test on PNDs 80-90 to assess the long-term impact of alterations in the perinatal environment. As expected, presence of both parents did increase parental/pup contact time by 350% relative to single-mother parenting and also reduced body weight, an index of perinatal stressor exposure, in already underweight El offspring. Accordingly, HISS testing of adult El offspring revealed a deleterious effect of biparental rearing, which increased seizure incidence to 30% relative to 0% for the single dam condition. These results suggest that the presence of a second care provider in addition to the dam constitutes a form of stressor exposure in El pups and, as a consequence, reduces the time to first seizure in genetically susceptible offspring.

Teratogenic effects of maternal antidepressant exposure on neural substrates of drug-seeking behavior in offspring.

If neurotransmitter balance is upset in the developing nervous system by exposure to antidepressant drugs, structural and functional hedonic phenotypes of offspring may be affected. In order to test this hypothesis, two groups of pregnant Wistar dams were exposed to vehicle or fluoxetine by implantation on gestational day 14 of osmotic minipumps delivering 0 or 10 mg/kg/day fluoxetine for 14 days. The consequences of perinatal fluoxetine exposure on offspring conflict-exploratory behavior were quantified using the elevated plus-maze on postnatal day (PND) 30. Beginning on PND 60, the reinforcing properties of acutely administered cocaine were examined using a place conditioning procedure. Beginning on PND 90, a subset of rats were implanted with jugular catheters and allowed to acquire self-administration of cocaine in an operant environment. In support of the hedonic modulation hypothesis, perinatal fluoxetine produced a significant decline in both nucleus accumbens cell count (-9%) and serotonin transporter-like immunoreactivity in the raphe nucleus (-35%) on PND 120. In the elevated plus-maze, perinatal fluoxetine exposure decreased (-21%) overall activity. In the place conditioning trial, only the fluoxetine-treated group exhibited a significant place preference for the compartment paired previously with cocaine. In a cocaine self-administration extinction trial, there was a statistically significant increase (350%) in extinction response rate among fluoxetine-exposed offspring. These findings suggest that perinatal exposure to fluoxetine perturbs adult serotonergic neurotransmission and produces a positive hedonic shift for conditioned reinforcing effects of cocaine.

Olfactory neophobia and seizure susceptibility phenotypes in an animal model of epilepsy are normalized by impairment of brain corticotropin releasing factor.

PURPOSE: The present study explored the causal relationship between stressor exposure/stress neuropeptide activation and avoidant exploratory phenotype/enhanced seizure susceptibility in an animal model of epilepsy. METHODS: The olfactory detection and investigation phenotype of seizure susceptible El (epilepsy) strain and nonsusceptible ddY control mice was first evaluated in untreated mice. In a second series of experiments, the olfactory exploration phenotype, food intake/body weight regulation, circadian locomotor activity, and seizure susceptibility were assessed over a 14-day period following central administration of the neurotoxin saporin alone or a conjugate of the stress neuropeptide, corticotropin releasing factor (CRF), and saporin (CRF-SAP) which impairs CRF system function following central administration. RESULTS: In support of the main experimental hypothesis, administration of CRF-SAP in El mice reduced handling-induced seizure susceptibility by 75% for up to 2 weeks following treatment. Similarly, El mice were slow to detect a cache of buried food pellets relative to ddY controls and this exploratory deficit was reversed 3 days following administration of CRF-SAP. Efficacy of CRF-SAP treatment was confirmed using CRF immunohistochemistry, which revealed suppression of brain CRF content in El mice treated with CRF-SAP relative to El controls. Other functional and persistent effects of CRF-SAP included increased locomotor activity and hyperphagia. CONCLUSIONS: Taken together, these results support strongly the possibility that activated brain stress neuropeptide systems are necessary for the expression of motivational and neurological perturbations in seizure susceptible El mice.

Neural, endocrine and electroencephalographic hyperreactivity to human contact: a diathesis-stress model of seizure susceptibility in El mice.

The El mouse strain provides a non-induced model of idiopathic, multifactorial epilepsy in which seizures are elicited in response to stressful environmental stimuli such as tail suspension handling. In the present studies, genetically seizure susceptible El and non-susceptible ddY control mice were exposed to tail suspension, foot-shock and social stressors in order to test the hypothesis that neural and physiological responses to such stimuli would be exaggerated in the El strain. The first experiment assessed neural cell density, stress neuropeptide (corticotropin releasing factor--CRF) levels, and plasma corticosterone activation in El and ddY mice in an unhandled control condition or following exposure to tail suspension or foot-shock stressors. The second experiment assessed brain electroencephalographic activity using telemetrically monitored skull surface electrodes in El and ddY mice exposed to tail suspension or social interaction stressors. Assessment of El mouse brains revealed higher cell counts in amygdala and elevated CRF peptide content in the paraventricular thalamic nucleus relative to ddY controls. El mice exhibited significantly elevated plasma corticosterone levels 60 min following exposure to tail suspension and foot-shock stressors relative to ddY controls. Finally, El mice exhibited significantly elevated brain electroencephalographic (1-4 Hz) activity in response to tail suspension, but not social interaction, relative to ddY controls. These results indicate that potentiated neural, endocrine and physiological activation arises in the El strain following exposure to a known seizure trigger stimulus, involuntary tail suspension handling. The findings support a diathesis-stress hypothesis in which genetically seizure susceptible El mice exhibit a multifaceted hyperreactivity to noxious environmental stimuli.

Seizure prophylaxis in an animal model of epilepsy by dietary fluoxetine supplementation.

Clinical and animal model evidence suggests that selective serotonin reuptake inhibitors (SSRIs) act as anticonvulsants. The present studies tested the possibility that the El mouse model of genetically predisposed/handling-triggered epilepsy would exhibit fewer seizures following SSRI treatment via dietary fluoxetine adulteration. In particular, potential bioenergetic and neural mechanisms for anticonvulsant efficacy of fluoxetine were explored using food intake/body weight monitoring and quantification of brain serotonin transporter protein. El mice consuming a chow diet ad libitum or yoked in quantity to fluoxetine diet intake exhibited seizure incidence of 40% in response to tail-suspension handling, whereas seizures were abolished (0%) among El mice consuming a fluoxetine-adultered diet over 7 days. A 3 day period of fluoxetine administration was insufficient to exert anticonvulsant efficacy and all treatment groups exhibited the same circadian locomotor activity patterns at the time of seizure susceptibility testing. Bioenergetic factors could not account for the anticonvulsant efficacy of fluoxetine since yoked diet controls with matched food intake, body weight change and blood glucose levels exhibited the same 40% seizure incidence as ad libitum chow controls. Importantly, the 7 day period of dietary fluoxetine exposure was effective in selectively reducing cell density in the parietal cortex and increasing serotonin transporter protein content in the nucleus accumbens. Taken together, these results suggest that dietary fluoxetine supplementation abolishes handling-induced seizure susceptibility in El mice via a neural remodeling mechanism independent of energy balance.