Encephalitis and catatonia treated with ECT.

OBJECTIVE: To describe 2 cases of encephalitis with neuropsychiatric symptoms including catatonia, compounded by neuroleptic use for delirious agitation culminating in malignant catatonia responsive to electroconvulsive therapy (ECT). BACKGROUND: Neuropsychiatric symptoms including catatonia can be manifestations of limbic encephalitis and encephalitides of unidentified etiology, including encephalitis lethargica. Catatonic features are often difficult to appraise in this context. This can easily lead to the use of neuroleptics, which may precipitate worsening of catatonia. METHOD: Medical, neurologic, and psychiatric histories, physical examination findings, results of laboratory, imaging and neurophysiologic investigations, and treatment response with medications and ECT were recorded. RESULTS: Both patients showed significant improvement with ECT. CONCLUSIONS: Malignant catatonia can complicate encephalitis lethargica and idiopathic limbic encephalitis, which already carry high mortality rates. When neuroleptics are used for agitation in cases of encephalitis, physicians must be wary of precipitating malignant catatonia and neuroleptics should be discontinued when such a danger emerges. Although lorazepam is helpful in treating catatonia, it may not suffice, as in the cases presented. ECT deserves serious consideration early in the course of malignant catatonia and for catatonia nested in encephalopathy secondary to encephalitis, unresolved with lorazepam.

Microinjection of the L-type calcium channel antagonist diltiazem into the ventral nucleus accumbens shell facilitates cocaine-induced conditioned place preferences.

BACKGROUND: Calcium (Ca2+) influx within the nucleus accumbens shell (NASh) can influence brain reward processes. We found previously that rats self-administer NMDA receptor antagonists (which block Ca2+ influx through NMDA receptors) into the NASh. We also found that manipulations which increase expression of Ca2+-permeable AMPA receptors within this region make cocaine aversive. Here we examined if Ca2+ influx via L-type Ca2+ channels within the NASh would influence cocaine reward. METHODS: Rats received bilateral microinjections of the L-type Ca2+ channel antagonist diltiazem into the ventral NASh prior to place conditioning with systemic cocaine. RESULTS: Microinjections of diltiazem (10 nmol/hemisphere) into the ventral NASh facilitated the ability of a sub-threshold dose of cocaine (5.0 mg/kg) to establish place preferences, but did not affect place conditioning on their own (5.0-40 nmol/hemisphere). Microinjections into more dorsal regions had no effects. CONCLUSIONS: Blockade of Ca2+ influx through L-type channels Ca2+ within the ventral NASh increases cocaine reward.

Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats.

We showed previously that cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) of rats regulates immobility in the forced swim test (FST), an assay used to study depression. Because CREB regulates expression of dynorphin (which acts at kappa-opioid receptors) in NAc neurons, these findings raised the possibility that kappa-receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the kappa-antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at kappa-receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar kappa-antagonists: 5'-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment, and 5'-acetamidinoethylnaltrindole (ANTI), which was potent and effective after systemic treatment. The behavioral effects of the kappa-antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the kappa-agonist [5alpha,7alpha,8beta]-N-methyl-N-[7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec8-yl]-benzenacetamide (U-69593) dose dependently increased immobility in the FST, consistent with prodepressant-like effects. The effects of the kappa-ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective kappa-antagonist (ANTI) did not affect the rewarding impact of lateral hypothalamic brain stimulation at a dose with strong antidepressant-like effects. These findings are consistent with the hypothesis that CREB-mediated induction of dynorphin in the NAc "triggers" immobility behavior in the FST. Furthermore, they raise the possibility that kappa-antagonists may have efficacy as antidepressants, but lack stimulant or reward-related effects.

Antidepressant-like effects of cytidine in the forced swim test in rats.

BACKGROUND: Altered brain phospholipid metabolism may be involved in the pathophysiology of cocaine dependence and mood disorders. Evidence suggests that citicoline, a rate-limiting metabolite for phospholipid synthesis, reduces cocaine craving in human addicts. Because antidepressants can reduce cocaine craving, we explored in rats the possibility that citicoline has antidepressant effects. We also tested the primary metabolites of citicoline, cytidine and choline. METHODS: We examined if citicoline or metabolites alter immobility in the forced swim test. We used two scoring methods: latency to become immobile, a simple method that identifies antidepressants, and behavioral sampling, a complex method that differentiates antidepressants according to pharmacological mechanisms. RESULTS: Over a range of doses, citicoline did not affect behavior in the forced swim test. At molar equivalent doses, cytidine dramatically decreased immobility, whereas choline tended to increase immobility. The effects of cytidine resemble those of desipramine, a standard tricyclic antidepressant. None of the treatments affected locomotor activity, and cytidine did not establish conditioned place preferences. CONCLUSIONS: Citicoline does not have effects in the forced swim test, but its primary metabolites have opposing effects: cytidine has antidepressant-like actions, whereas choline has prodepressant-like actions. At antidepressant doses, cytidine lacks stimulant and rewarding properties. This is the first report of potential antidepressant effects of cytidine.

Altered responsiveness to cocaine in rats exposed to methylphenidate during development.

Evidence in laboratory animals indicates that exposure to stimulants produces sensitization to their rewarding effects, a process that in humans would be expected to increase the risk of substance abuse. However, therapeutic administration of stimulants such as methylphenidate (MPH) in children with attention deficit hyperactivity disorder reportedly reduces the risk of substance abuse. Here we show in rats that exposure to MPH during pre-adolescence causes behavioral and neurobiological adaptations that endure into adulthood, and that are consistent with increased sensitivity to the aversive effects of cocaine.