Unilateral Versus bilateral electroconvulsive shock in albino rats: comparison of behavioral symptomatology and neocortical reactivity changes.

Electrophysiological studies have shown asymmetric brain reactivity in schizophrenia, supporting the hypothesis of left hemisphere hyperarousal in this disease. It may be assumed, therefore, that neuroleptic treatment restores hemispheric balance in schizophrenic patients by selectively suppressing the hyperactive left hemisphere. This hypothesis was tested in the present study, which compared bilaterally recorded visual evoked potentials (VEP) in 9 nonmedicated patients and 29 schizophrenics treated with various neuroleptic drugs, as well as in 34 normal controls. In medicated patients later VEP components showed enhancement over the right hemisphere as a function of the overall dose (chlorpromazine equivalent) of neuroleptics. Reversed asymmetry was seen in drug-free patients. In view of this result, some amendments of the concept of left hemisphere hyperactivity in schizophrenia are proposed.

Ziskind-Somerfeld Research Award 1993. Biochemical, behavioral, and clinical studies of the role of inositol in lithium treatment and depression.

Lithium (Li) reduces brain inositol levels by inhibiting the enzyme inositol monophosphatase. The enzyme inositol-1-phosphatase was measured in human red blood cells of controls, Li-free bipolar patients, and Li-treated bipolar patients and was found to be reduced by 80% in Li-treated bipolars, thus supporting the concept that chronic Li at therapeutic concentrations inhibits this enzyme. Two behaviors in rats caused by Li, reduction of rearing, and Li-pilocarpine seizures, are reversed by intracerebroventricular replenishment of inositol. The reversal is stereospecific to the naturally occurring myo-inositol; whereas the stereoisomer L-chiro-inositol is ineffective. The reversal is dose-dependent, requiring a dose consistent with known quantities of brain inositol depletion; and is time-dependent, as inositol must be given 1-8 h before stimulation. High-dose peripheral inositol also reverses the limbic seizures induced by Li-pilocarpine, and using gas chromatography was shown to increase brain inositol levels that had been reduced by Li treatment. Low-dose inositol could be shown to reverse a peripheral Li-induced side effect, polyuria/polydipsia, in rats and in patients treated with Li. A higher dose of inositol markedly reduced Hamilton Depression Ratings in 9 of 11 unipolar major depressive disorder patients previously unresponsive to tricyclics, in an open design, but had no effect on chronic schizophrenics in a controlled double-blind randomized crossover trial. A new inositol monophosphatase inhibitor, a fungal product originally discovered as a complement inhibitor, was found to act like Li and lower the seizure threshold for subconvulsant doses of pilocarpine. These data suggest that inositol monophosphatase inhibition is a key mechanism of Li's therapeutic action and that design of new inositol monophosphatase inhibitors may be a practical strategy to create new compounds with Li-like therapeutic effects.

Sexual function and affect in parkinsonian men treated with L-dopa.

Using psychiatric interviews, sexual and affect rating scales, hormonal studies, and neurologic assessment, the authors assessed the effect of L-dopa treatment on men with Parkinson's disease. Patients demonstrated variable affect changes. Approximately one-half of the patients reported an increased sexual interest that was not related to improvement in locomotor function. Hormonal factors appeared to be involved. The findings suggest that male parkinsonian patients who possess an intact hypothalamic-pituitary-gonadal axis experience increased sexual function related to L-dopa treatment.

Double-blind, controlled trial of inositol treatment of depression.

OBJECTIVE: CSF levels of inositol have been reported to be lower than normal in depressed subjects. The authors administered inositol to depressed patients in a double-blind, controlled trial. METHOD: Under double-blind conditions, 12 g/day of inositol (N = 13) or placebo (N = 15) was administered to depressed patients for 4 weeks. RESULTS: The overall improvement in scores on the Hamilton Depression Rating Scale was significantly greater for inositol than for placebo at week 4. No changes were noted in hematology or in kidney or liver function. CONCLUSIONS: This may be the first use of the precursor strategy for a second messenger rather than a neurotransmitter in treating depression. Although inositol had a significant antidepressant effect in this study, replication is crucial.

Behavioral reversal of lithium effects by four inositol isomers correlates perfectly with biochemical effects on the PI cycle: depletion by chronic lithium of brain inositol is specific to hypothalamus, and inositol levels may be abnormal in postmortem brain from bipolar patients.

The inositol depletion hypothesis of lithium (Li) action has been criticized, because depletion of inositol after chronic Li treatment has not been reproducible, effects of inositol to reverse Li-induced behaviors occurred also with epi-inositol, a unnatural isomer, and because inositol is ubiquitous in brain and hard to relate to the pathogenesis of affective disorder. Therefore, we review our studies showing that lithium depletion of brain inositol occurs chronically in the hypothalamus, a region not previously examined; that behavioral effects of four different inositol isomers including epi-inositol correlate perfectly with their biochemical effects; and that inositol in postmortem human brain is reduced by 25% in frontal cortex of bipolars and suicides as compared with controls. Because inositol in postmortem brain is reduced and not increased in bipolar patients, the relationship between inositol, lithium, and affective disorder is complex.

Regular and lasting neocortical spiking produced by systemic administration of a steroid derivative in the rat.

The hypothesis was tested that sedation and stereotyped behaviour, developing in rats after the administration of the steroid derivative with gamma-aminobutyric acid (GABA) antagonistic properties, R 5135, are of an epileptiform nature. Electroencephalographic (EEG) and visual evoked potentials (VEP) were recorded and behaviour was observed over not less than 5-7 hr after subconvulsive doses of R 5135. Doses of 2-4 mg/kg of the compound produced quasi-rhythmic spikes resembling experimental focal epileptic discharges in all rats. This epileptiform activity was accompanied by behavioural sedation and somnolence, followed by a build-up of stereotyped behaviour and sporadic episodes of epileptiform motor activity, developing 1-2 hr after injection. The secondary components (SNW) of the visual evoked potentials were suppressed by R 5135 and the primary potential (N1) facilitated, virtually reducing the visual evoked potential to the form of an evoked spike. Pretreatment with the anticonvulsant GABAergic drugs gamma-acetylenic GABA (GAG) (100 mg/kg), sodium valproate (VPA) (400 mg/kg) and diazepam (5 mg/kg) suppressed the motor components of seizure activity, producing severe ataxia, but not the electrographic manifestation of seizure activity. Neither gamma-acetylenic GABA nor valproate significantly altered the latency to onset of spiking, although all three drugs did significantly reduce the frequency of discharges. Diazepam was the only anticonvulsant tested which completely suppressed spike activity in 3 of 5 rats. Moreover, R 5135 was found to antagonize diazepam, but not valproate induced suppression of secondary components of the visual evoked potential, suggesting that diazepam and R 5135 may compete for the same receptor.

Myo-inositol attenuates the enhancement of the serotonin syndrome by lithium.

Lithium elicits opposite effects on two behavioural syndromes in rats: enhancement of the 5-HT1A-linked serotonin syndrome and attenuation of the 5-HT2-linked wet dog shakes. The ability of intracerebroventricular (ICV) myo-inositol or forskolin to reverse the enhancement of the serotonin syndrome by lithium was tested in rats that were fed chronic dietary lithium or control diet and injected with the serotonin agonist 5-MeODMT (5-methoxy-N, N-dimethyltryptamine). Lithium enhanced the total serotonin syndrome score and particularly flat posture and tremor. Inositol, but not forskolin, mitigated the effects of lithium. Inositol was also injected in the lateral ventricle of rats pretreated with chronic dietary lithium or regular rat chow for 3 weeks and injected with carbidopa and L-5-hydroxytryptophan (5-HTP). Lithium attenuated wet dog shakes, but inositol had no significant effect on lithium-treated or control rats. These findings suggest that the enhancement of the serotonin syndrome by lithium may be related to lithium-induced inositol depletion.

Chronic dietary inositol enhances locomotor activity and brain inositol levels in rats.

myo-Inositol has been found to be clinically effective in depression, obsessive compulsive disorder (OCD) and panic disorder when given chronically per os. The present study examined the effects of chronic dietary inositol in rats on locomotor behaviour. Regional brain levels of inositol were analyzed by gas chromatography. Chronic dietary inositol significantly enhanced locomotion and rearing in rats and elevated inositol levels by 36% in the cortex and 27% in hippocampus. No differences in inositol levels were found in the striatum or cerebellum. The stimulatory effects of inositol may be related to its effects as an atypical antidepressant in depressed patients.

Restoration of brain myo-inositol levels in rats increases latency to lithium-pilocarpine seizures.

Lithium pretreatment in rats potentiates the epileptogenic effects of pilocarpine and other cholinergic agonists. In order to determine if this effect of lithium could be reversed by myo-inositol, rats were pretreated with intracerebroventricular (ICV) injections of myoinositol, artificial CSF or L-chiro-inositol. Lithium chloride, 3 meq/kg was administered intraperitoneally 20-24 h prior to the subcutaneous injection of pilocarpine, 20 or 30 mg/kg. In both experiments, myo-inositol significantly prolonged the latency to the appearance of clonic seizures and lowered the pilocarpine seizure score. myo-Inositol prevented the development of clonic seizures in 50% of the rats receiving pilocarpine, 20 mg/kg. The levels of cortical myo-inositol in rats injected with myo-inositol were approximately double those of the CSF and L-chiro-inositol groups.

Lack of effect of ECS on rat brain inositol monophosphatase activity and inositol levels and of i.c.v. inositol on ictal and post-ictal length.

Lithium (Li) has often been compared to ECT in therapeutic spectrum and mechanism. Inhibition of inositol monophosphatase and reduction of brain inositol are major mechanisms of Li action. Many Li effects in animals and humans are reversible by inositol. We therefore studied interactions of ECS and inositol. ECS in rats did not reduce brain inositol monophosphatase activity or brain inositol levels. Intracerebroventricular injection of 10 mg inositol, a dose that reverses Li effects, had no effect on seizure length or post-ictal length.

Differential effects of atropine, procaine and dopamine in the rat ventral tegmentum on lateral hypothalamic rewarding brain stimulation.

Microinjections of the muscarinic antagonist, atropine, of dopamine, or of the local anesthetic, procaine, in the ventral tegmentum elevated frequency thresholds for lateral hypothalamic self-stimulation. The largest and most robust effects were observed following atropine (30 or 60 micrograms) microinjections. The most sensitive sites for the atropine effect were near dopamine cells. In order to determine if the effects of atropine can be reversed by pretreatment with a cholinergic agonist, carbachol (1-3 micrograms) was microinjected 15 min prior to atropine. Carbachol pretreatment attenuated the frequency threshold elevation of atropine by 47-95%. Since atropine is a local anesthetic, the effects of procaine on self-stimulation thresholds were tested as well. Procaine (100 or 250 micrograms) in ventral tegmentum elevated frequency thresholds by much less than atropine. Therefore, while atropine attenuates reward primarily through blockade of muscarinic receptors, the local anesthetic effect of atropine may enhance the threshold elevation. Dopamine (1-10 micrograms) also elevated frequency thresholds, but when dopamine injections were repeated daily, the threshold elevations were attenuated. This attenuation contrasted with the robust effects of atropine, and may reflect the development of autoreceptor subsensitivity. Hence, both dopaminergic and muscarinic receptors in ventral tegmentum are involved in lateral hypothalamic brain stimulation reward.

Intracerebroventricular myo-inositol antagonizes lithium-induced suppression of rearing behaviour in rats.

Several biological effects of lithium have been reversed by in vitro myo-inositol. To determine if intracerebroventricular myo-inositol would reverse behavioural effects of lithium, rats were injected with 5 meq/kg lithium chloride or sodium chloride and injected intracranially with myo-inositol (10 mg) or artificial CSF 24 h and 15 min prior to measurement of activity in an automated activity monitor. Myo-inositol alone had no significant effect on behaviour, but significantly reversed suppression of rearing activity by lithium.

Cholinergic involvement in lateral hypothalamic rewarding brain stimulation.

Rats were implanted with stimulating electrodes in the lateral hypothalamus, and cannulae for chemical injections in the ventral tegmentum. Injections of atropine, a muscarinic antagonist, increased thresholds for self-stimulation in a dose-dependent fashion, without slowing bar pressing rates. Thresholds increased less for a self-stimulation site contralateral to the atropine injection. In a conditioned place preference test, the rats preferred compartments in which they received carbachol, a cholinergic agonist. Muscarinic receptors in ventral tegmentum therefore seem critical for medial forebrain bundle (MFB) reward. The possible cholinergic cells of origin are discussed.

Inositol treatment raises CSF inositol levels.

Inositol is a key precursor for synthesis of phosphatidylinositol in a major second messenger signalling system. It is biologically active in syndromes such as respiratory distress syndrome but has been thought to be excluded from CNS by the blood-brain barrier. Oral inositol treatment of 8 patients is shown to significantly increase CSF inositol by almost 70%, suggesting possible CNS therapeutic applications of this compound and possible CNS side-effects of systemic therapy.

Lithium attenuates hypokinesia induced by immobilization stress in rats.

1. Hypokinesia following immobilization stress in rats is attenuated by anti-depressant drugs used in the treatment of unipolar depression. Lithium has anti-depressant effects both clinically and in other animal models of depression, but the mechanism of its anti-depressant effect has not been elucidated. 2. To determine if lithium reverses immobilization-induced hypokinesia, the effects of lithium and immobilization stress were tested in a fully factorial 2 x 2 design. 3. Half the rats were fed chronic dietary lithium, while the other half ate regular chow. Half of each group were exposed to one hour immobilization, while the other half remained in their home cages until the test. Activity was measured for 20 min in an automated activity meter. 4. Stress significantly reduced activity, but a significant interaction between stress and lithium was found, indicating that lithium attenuated the effect of stress. 5. Lithium-induced attenuation of immobilization stress may serve as an animal model for the anti-depressant effects of lithium.

Interactions of lithium and drugs that affect signal transduction on behaviour in rats.

The therapeutic mechanism of the action of lithium in the treatment of bipolar affective disorder is not known, in spite of a burgeoning number of biochemical studies linking lithium to signal transduction processes. This article reviews a decade of studies examining the behavioural manifestations of manipulating inositol, cyclic adenosine monophosphate (cAMP) and G proteins in rats. Inositol, forskolin, dibutyryl cAMP and pertussis toxin all interacted with lithium when rearing behavior was measured. Lithium potentiated the increase in locomotion induced by injections of cholera toxin into the nucleus accumbens, consistent with the hypothesis that it inactivates inhibitory G proteins. More specific interactions were found between lithium and inositol following cholinergic and serotonergic stimulation. Inositol, but not forskolin, attenuated lithium-pilocarpine seizures and the enhancement of the serotonin syndrome; however, inositol had no effect on lithium-induced attenuation of wet dog shakes following an injection of 5-hydroxytryptophan. Behavioural evidence supports biochemical findings suggesting that lithium's interactions with the phoshphatidyl inositol and cyclic AMP signal transduction systems may be relevant to its therapeutic effects in bipolar disorder. Further research on more specific behaviours may elucidate the relevant pharmacological mechanisms underlying the therapeutic effect of lithium.

Behavioral evidence for the existence of two pools of cellular inositol.

Lithium reduces brain inositol levels by inhibiting inositol monophosphatase. In a previous study it was found that administration of pilocarpine to Li-treated rats causes limbic seizure behavior which can be reversed by i.c.v. myo-inositol but not chiro-inositol, suggesting that this behavior is related to inositol depletion in the PI cycle. Hyponatremia can lower brain inositol and hypernatremia can raise brain inositol. We now report that induction of low brain inositol by hyponatremia followed by pilocarpine did not cause limbic seizures. Induction of high brain inositol using hypernatremia followed by Li-pilocarpine administration did not reverse limbic seizures. These data support the concept that inositol available for P1 synthesis and inositol for osmotic function are sequestered in different cellular pools.

Differential uptake of myo-inositol in vivo into rat brain areas.

Oral inositol has been reported to have antidepressant and antipanic properties in humans. Inositol enters the brain poorly and high doses are required. Natural uptake processes and specific transporters are involved. We here report that intraperitoneally administered inositol is taken up differently by various brain areas and that brain areas have different baseline inositol levels. These effects could be important in understanding the differential effects of lithium-induced lowering of inositol and of behavioral effects of exogenous inositol.

Epileptogenic activity in the amygdala is not affected by the amidine steroid, R 5135.

The synthetic steroid amidine 3-alpha-hydroxy-16-imino-5-beta-17aza androstan-11-one (R 5135) is known to elicit long-lasting spiking in the cortex in the presence of neocortical damage. R 5135 administered to amygdaloid-kindled and naive rats resulted in regular, high-amplitude spiking in the cortex but only occasionally elicited small-amplitude spikes in the amygdala (AMY) and hippocampus (HPC). Interictal spikes from the AMY of kindled rats were not synchronized with cortical spikes induced by the steroid. Given that R 5135 is known to be a GABAA receptor antagonist, these findings suggest that GABAA receptors in AMY and HPC may have lower affinity for 3 alpha-hydroxysteroids.

Cholinergic antagonists in ventral tegmentum elevate thresholds for lateral hypothalamic and brainstem self-stimulation.

Frequency thresholds for lateral hypothalamic self-stimulation are elevated following microinjections of atropine into ventral tegmentum (73). Many self-stimulation sites in brainstem are situated near cholinergic cell groups and axons, and ventral tegmentum receives cholinergic afferents terminals. To test the hypothesis that ventral tegmental muscarinic receptors are involved in lateral hypothalamic and brainstem self-stimulation, stimulating electrodes were placed in lateral hypothalamus and dorsal tegmentum near the midbrain-pons border, and cannulae were implanted in ventral tegmentum. Microgram injections of muscarinic antagonists, atropine or scopolamine, or a choline uptake blocker, hemicholinium-3, elevated frequency thresholds for both self-stimulation sites in a dose-dependent and time-dependent fashion. In addition, summation and collision between the two self-stimulation sites was tested using paired-pulse methods (53). Summation ranged from 31 to 87% (i.e., 24 to 47% reductions in frequency threshold were observed at long intrapair intervals), but no collision-like effects were observed at short intrapair intervals. The ventral tegmentum is a likely site for the convergence of dorsal tegmental and lateral hypothalamic self-stimulation pathways.