High cocaine dosage decreases neurogenesis in the hippocampus and impairs working memory.

Drug addiction is a chronic brain disorder, characterized by the loss of the ability to control drug consumption. The neurobiology of addiction is traditionally thought to involve the mesocorticolimbic system of the brain. However, the hippocampus has received renewed interest for its potential role in addiction. Part of this attention is because of the fact that drugs of abuse are potent negative regulators of neurogenesis in the adult hippocampus and may as a result impair learning and memory. We investigated the effects of different dosages of contingent cocaine on cell proliferation and neurogenesis in the dentate gyrus of the hippocampus and on working memory during abstinence, using the water T-maze test, in adult rats. We found that cocaine, in addition to the changes it produces in the reward system, if taken in high doses, can attenuate the production and development of new neurons in the hippocampus, and reduce working memory.

Glycogen synthase kinase-3beta heterozygote knockout mice as a model of findings in postmortem schizophrenia brain or as a model of behaviors mimicking lithium action: negative results.

In mice glycogen synthase kinase (GSK)-3beta heterozygote knockout status was reported to cause reduced immobility in the Porsolt forced swim test and reduced amphetamine-induced hyperactivity, behaviors that mimic the effects of lithium. GSK-3beta protein and mRNA level and activity have been reported to be reduced in the postmortem brain of schizophrenia patients and this could suggest the involvement of GSK-3beta in the etiology of schizophrenia. However, apomorphine-induced stereotyping was reported to be unchanged in GSK-3beta heterozygote (HZ) knockout (KO) mice. As such behaviors are not always robust, study in another laboratory seemed indicated. Motor activity and coordination were assessed in the rotarod test. Behavior was studied in the following tests: pilocarpine-induced seizures model for lithium action, Porsolt forced swim test, tail suspension test, elevated plus-maze, large open field, startle response and prepulse inhibition of acoustic startle response, amphetamine-induced hyperactivity, and apomorphine-induced stereotypic climbing. We could not confirm the report that GSK-3beta HZ KO mice exhibit reduced immobility in the Porsolt forced swim or reduced amphetamine-induced hyperactivity in a manner mimicking the behavioral effects of lithium. We did not find increased apomorphine-induced stereotypic climbing or disruption of prepulse inhibition, suggesting that human postmortem findings regarding GSK-3beta in schizophrenia are not mediated by changes in dopamine receptors and are not the cause of prepulse inhibition deficits in schizophrenia. These data do not support the role of GSK-3beta in schizophrenia or in the mechanism of therapeutic action of lithium. Although differences in the genetic background of the GSK-3beta HZ KOs used in the present study compared with that of the previous study could be responsible, such results could suggest that the previously reported effects of GSK-3beta knockout on behavior are not robust.

Homozygote inositol transporter knockout mice show a lithium-like phenotype.

OBJECTIVE: Lithium inhibits inositol monophosphatase and also reduces inositol transporter function. To determine if one or more of these mechanisms might underlie the behavioral effects of lithium, we studied inositol transporter knockout mice. We previously reported that heterozygous knockout mice with reduction of 15-37% in brain inositol had no abnormalities of pilocarpine sensitivity or antidepressant-like behavior in the Porsolt forced swim test. We now report on studies of homozygous inositol transporter knockout mice. METHODS: Homozygote knockout mice were rescued by 2% inositol supplementation to the drinking water of the dam mice through pregnancy and lactation. Genotyping was carried out by polymerase chain reaction followed by agarose electrophoresis. Brain free myo-inositol levels were determined gas-chromatographically. Motor activity and coordination were assessed by the rotarod test. Behavior of the mice was studied in lithium-pilocarpine seizure models for lithium action and in the Porsolt forced swim test model for depression. RESULTS: In homozygote knockout mice, free inositol levels were reduced by 55% in the frontal cortex and by 60% in the hippocampus. There were no differences in weight or motor coordination by the rotarod test. They behaved similarly to lithium-treated animals in the model of pilocarpine seizures and in the Porsolt forced swimming test model of depression. CONCLUSIONS: Reduction of brain inositol more than 15-37% may be required to elicit lithium-like neurobehavioral effects.

Discrimination and avoidance learning in adult mice following developmental exposure to diisopropylfluorophosphate.

Exposure to acetylcholinesterase inhibitors during development was shown in the past to induce sex-dependent changes in locomotion and specific cognitive and emotional tests in rodents. Adult mice that had been treated with 0.5 mg/kg diisopropylfluorphosphate (DFP), on post-natal days 14-20 were tested on active avoidance and a set-shifting task. DFP pre-treatment did not affect the active avoidance task, but impaired performance on the extra-dimensional shift task. DFP-treated females showed more general deficits in the acquisition of simple discrimination, intra-dimensional shift, extra-dimensional shift and reversal learning. These data suggest that pre-weanling exposure to cholinesterase inhibitors may have long-term consequences on attentional capabilities.

Lithium's effect in forced-swim test is blood level dependent but not dependent on weight loss.

The effects of lithium in models of depression are often inconsistent. We aimed to replicate a regimen that induces robust antidepressant effects in the forced-swim test. Mice were treated with three different doses of lithium chloride (LiCl) 0.25, 0.4 or 0.5% in food and the forced-swim test or open field test was performed on day 15. We yoked control mice to food deprivation to test whether lithium-induced food deprivation could cause the lithium effects in the forced-swim test. Treatment with LiCl doses leading to blood levels of 1.3 and 1.4 mmol/l led to highly significant reduction in immobility time in the forced-swim test, but the dose leading to a blood level of 0.8 mmol/l was not different from controls in immobility time. Mice yoked to lithium-induced food deprivation showed no difference in the forced-swim test compared with controls. In conclusion these results suggest that lithium effects in mice in the forced-swim test are dose dependent but not owing to lithium-induced weight loss.

SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior.

Two leading hypotheses to explain lithium action in bipolar disorder propose either inositol depletion or inhibition of GSK-3 as mechanisms of action. Behavioral effects of lithium are mimicked in Gsk-3beta+/- mice, but the contribution of inositol depletion to these behaviors has not been tested. According to the inositol depletion hypothesis, lithium-sensitive behavior is secondary to impaired phosphatidylinositol synthesis caused by inositol deficiency. By disrupting the sodium myo-inositol transporter1 gene, SMIT1, we show that depletion of brain myo-inositol in SMIT1+/- mice has no effect on lithium-sensitive behavior. These findings, taken together with our previous work showing that SMIT-/- mice have an even greater depletion of inositol in brain with no reduction in phosphatidylinositol levels, are difficult to reconcile with the current formulation of the inositol depletion hypothesis.

Inositol deficiency diet and lithium effects.

OBJECTIVES: A major hypothesis explaining the therapeutic effect of lithium (Li) in mania is depletion of inositol via inhibition of inositol monophosphatase. However, inositol is also present in the diet. Restriction of dietary inositol could theoretically enhance the effects of Li. METHODS: We used dietary inositol restriction in animal studies and also devised a palatable diet for humans that is 90% free of inositol. RESULTS: Dietary inositol restriction significantly augmented the inositol-reducing effect of Li in rat frontal cortex. Li reduced inositol levels by 4.7%, inositol-deficient diet by 5.1%, and Li plus inositol-deficient diet by 10.8%. However, feeding with the inositol-deficient diet did not enhance the behavioral effect of Li in the Li-pilocarpine seizure model. Fifteen patients participated in an open clinical study of the inositol-deficient diet: six rapid cycling bipolar patients responding inadequately to Li or valproate in different phases of illness; two Li-treated bipolar outpatients with residual symptomatology, and seven inpatient Li-treated bipolar patients in non-responding acute mania. The diet had a major effect in reducing the severity of affective disorder in 10 of the patients within the first 7-14 days of treatment. CONCLUSION: These results suggest that dietary inositol restriction may be useful in some bipolar patients, but controlled replication is necessary.

Lack of effect of eicosapentaenoic acid in the Porsolt forced swimming test model of depression.

BACKGROUND: Eicosapentaenoic acid (EPA) is one of the major components of fish oils. Omega-3 fatty acids, particularly EPA, have been hypothesized to play a role in the etiology, pathogenesis and treatment of mood disorders. Clinical studies have shown beneficial effects of omega-3 fatty acids in major depression, bipolar disorder and other psychiatric disorders. OBJECTIVE: The present study design evaluates the effect of EPA in the Porsolt forced swimming test. RESULTS: EPA alone did not reduce the immobility time and did not enhance the anti-immobility effect of a low dose of imipramine. Contrary to the hypothesis, EPA slightly increased the immobility time, and in some experiments tended to reduce the anti-despair effect of imipramine. CONCLUSION: The present results do not provide an animal model for the antidepressant effect of EPA as demonstrated in clinical experiments. The mechanism of EPA antidepressant action is unknown and the Porsolt forced swimming test could be non-sensitive for its antidepressant properties.