Haim Einat

The antidepressant activity of inositol in the forced swim test involves 5-HT2 receptors

The effect of inositol as an antidepressant was previously demonstrated in both animal models of depression-like behavior and in clinical trials. Unlike most antidepressant drugs, inositol does not have a clear target in the synapse and was not demonstrated to alter monoamine levels in the brain. The present study attempted to draw a psychopharmacological profile of inositols behavioral effects by exploring the interactions between the drug and specific receptor agonists and antagonists in the forced swim test. Rats received inositol treatment (or control) in combination with the serotonergic metabolism inhibitor PCPA or with the noradrenergic neurotoxin DSP-4. Results indicated that PCPA but not DSP-4 abolished the ability of inositol to cause a reduction in immobility time in the forced swim test. In mice, the specific 5-HT(2A)/5-HT(2C) antagonist ritanserin, but not the 5-HT(1A)/5-HT(1B)/beta adrenergic antagonist pindolol, abolished inositols effect in the forced swim test. The 5-HT(2A)/5-HT(2C) agonist DOI and the 5-HT(1A) agonist 8-OH-DPAT did not have any significant effects on inositols activity. The present data indicates that the antidepressant effect of inositol may involve 5-HT(2) receptors. It is thus possible that the effects of reuptake antidepressant drugs and the effects of inositol may have a common final pathway.

Preliminary evaluation of oral anticonvulsant treatment in the quinpirole model of bipolar disorder

Summary. A potential model for bipolar disorder, quinpirole-induced biphasic locomotion, was used for a preliminary evaluation of behavioral effects of oral anticonvulsant treatment. Quinpirole, a D2/D3 agonist, induces a biphasic locomotor response starting with inhibition and followed by excitation, resembling the oscillating nature of bipolar disorder. The present study developed a paradigm for oral administration of anticonvulsants that resulted in therapeutic blood levels and tested the effects of treatment on the quinpirole-induced response.Eleven days treatment with valproate (12 g/liter water), phenytoin (6 g/kg food), and carbamazepine (8 g/kg food) resulted in therapeutic blood levels and in a borderline significant reduction in quinpirole-induced hyperactivity without effects on the hypoactive phase. Valproate effects became more significant at the height of the hyperactivity response. Eleven days treatment with topiramate (30 mg/kg) resulted in a significant attenuation of quinpirole-induced hyperactivity, qualitatively similar to the effects of the other anticonvulsants.The results suggest that mood-stabilizing anticonvulsant drugs including topiramate may attenuate quinpirole-induced hyperactivity.

The effects of inositol treatment in animal models of psychiatric disorders

Clinical trials indicate that inositol may be effective in the treatment of patients with depression, panic disorder and obsessive compulsive disorder (OCD), but not in the treatment of patients with schizophrenia, Alzheimers disease, ADHD or autism. This spectrum of clinical action parallels that of serotonin selective reuptake inhibitors (SSRIs), but inositol is a precursor in the phosphatidylinositol cycle, a second messenger system distal to the receptor for 5HT-2. To study its mechanism of therapeutic action there is a need to test inositols activity in animal models of psychopathology. In rats, chronic inositol was demonstrated to increase activity levels, reduce immobility time in the forced swim test and in the reserpine-induced hypoactivity models of depression, and reduce anxiety-like behaviors in the elevated plus-maze. The reduction in anxiety-like behaviors appears to be related to baseline levels of activity. Inositol treatment was not observed to have any effect on amphetamine-induced hyperactivity, apomorphine-induced stereotypy, or on the performance of memory tasks by monkeys. Clinical controlled trials of inositol in patients with depression, panic disorder, and OCD were small, and positive psychoactive effects in animals clearly strengthen the case for further clinical trials and potential for general therapeutic use in humans.

Environmental modulation of both locomotor response and locomotor sensitization to the dopamine agonist quinpirole.

The study tested whether differences in locomotor activation during chronic treatment result in differential behavioral sensitization induced by the D2/D3 dopamine agonist quinpirole. One group of rats received repeated injections of quinpirole in their home cage and another group received this treatment in an alternate environment of similar size. In the home cage, quinpirole induced less locomotion than in the non-home environment. When tested in activity monitors at the end of chronic treatment, the home cage group showed less sensitized locomotion to quinpirole than the non-home cage rats. Thus, the extent of locomotor sensitization to quinpirole appears to be related to the amount of locomotion characteristic of the training environment. Such differential sensitization may reflect a modulation of the hierarchy of expression of quinpirole-enhanced hyperactivity via a non-associative process.

Chronic epi-inositol has an anxiolytic-like effect in the plus-maze model in rats.

Behavioural effects of myo-inositol have been demonstrated in animal models of psychiatric disorders and in clinical trials in psychiatric patients. These effects of myo-inositol were thought to be consequences of its being a substrate for the enzyme phosphatidylinositol (PI) synthase. Recently, epi-inositol, an unnatural stereoisomer of myo-inositol that is not a substrate for PI synthase, was found to also have effects similar to those of myoinositol to reverse lithium-pilocarpine seizures. The present study measured the behaviour of rats in an elevated plus-maze model of anxiety after chronic treatment of 11 daily i.p. injections of epi-inositol, myo-inositol, or control solution. Epi-inositol reduced levels of anxiety-like behaviour in rats compared with controls, and its effect was stronger than that of myo-inositol. The increased relative effect of epi-inositol could be due to slower metabolism or to a different mechanism of action.

Augmentation of lithium's behavioral effect by inositol uptake inhibitors

Summary. Lithium inhibits the enzyme inositol monophosphatase and thus obstructs the enzymatic degradation of inositol triphosphate (IP3) to inositol in the phosphate-phosphoinositide (PIP) cycle. This inhibition may result in reduced availability of the second messengers IP3 and DAG that are derivates of the PIP cycle, and this action is currently a leading hypothesis regarding lithiums therapeutic and prophylactic effect in affective disorders. Inositol is also available to the cell by uptake from the intercellular matrix, and therefore it is possible that compounds that block the uptake may have lithium-like effects. To test this hypothesis, the present study evaluates the effects of two inositol uptake inhibitors, the carbohydrate L-fucose and the cyclodepsipeptide nordidemnin, in a behavioral model of pilocarpine-induced seizures known to be enhanced by lithium. We tested the possibility that L-fucose produces lithium-like effects, or that L-fucose or nordidemnin augment lithiums behavioral effects.Results indicate that acute ICV treatment with L-fucose did not by itself have a lithium-like effect in the behavioral model, but significantly augmented lithiums effect when combined with lithium treatment. Nordidemnin treatment showed similar effects.The results suggest that when inositol monophosphatase is inhibited by lithium, further restriction of cellular inositol availability may result in an augmentation of lithiums behavioral effects. It is possible that such manipulations may be applicable in the treatment of patients with affective disorders, especially patients who are poor responders to lithium monotherapy.

The anxiolytic effect of chronic inositol depends on the baseline level of anxiety

Summary. Inositol, a precursor for membrane phosphoinositides involved in signal transduction, has been found to be clinically effective in a number of psychiatric disorders and to reverse behavioural effects of lithium. To gain insight into the mechanism of action of inositol, it is critical to establish its efficacy in animal models. Following the initial report by Cohen et al. (1997b) that inositol was anxiolytic in the elevated plus maze model of anxiety, the effect of chronic intraperitoneal and chronic dietary inositol administration in rats was tested in four experiments. There was a significant increase in closed arm and total arm entries following chronic injection of inositol, but no effect of inositol when it was given chronically in rat chow.Because the first 2 experiments suggested that the mode of drug administration affected the control levels of anxiety (open arm entries and time in open arms) in control groups, the effect of chronic dietary inositol was tested in rats that were exposed to a mild and a more severe form of stress. Chronic saline injections elevated anxiety in the plus maze, which was only marginally affected by chronic dietary inositol. Following 3 weeks administration of 5% dietary inositol rats were pre-exposed to a cat. There was a clear in-crease in number of entries into open arms, suggesting an anxiolytic effect of inositol.

Animal Models of Bipolar Disorder: From a Single Episode to Progressive Cycling Models

Animal models of psychopathology are divided into three major groups: heuristic models that assume a common underlying mechanism between a superficially different animal behavior and a particular human pathology; theory-based evidential models, which place emphasis on a common feature (etiological or behavioral) of both the model and the pathology; representative models involving generalization of a well-validated behavior to model the pathology (Overmier and Patterson, 1988; Ursin and Murison, 1986). The choice of a particular model for research will depend ultimately on the extent to which the etiology of the disorder is known, the specificity and efficacy of the pharmacological treatments available, and the facility with which the pathological behaviors can be mimicked in laboratory animals.

Endogenous cardiac steroids in animal models of mania

Bipolar disorder (BD) is a complex psychiatric disorder characterized by mania and depression. Alterations in brain Na+, K+‐ATPase and cardiac steroids (CSs) have been detected in BD, raising the hypothesis of their involvement in this pathology. The present study investigated the behavioral and biochemical consequences of a reduction in endogenous brain CS activity in animal models of mania.

Epi-inositol: A potential antidepressant

Inositol is a simple polyol precursor in a second messenger system important in the brain. A double‐blind controlled trial of 12 g daily of inositol in 28 patients with depression for 4 weeks found significant benefit for inositol compared to placebo on the Hamilton Depression Scale. Because many antidepressants are effective in panic disorder, 21 patients with this disorder completed a double‐blind, placebo‐controlled crossover treatment trial of inositol 12 g per day. Frequency and severity of panic attacks and severity of agoraphobia declined significantly with inositol treatment compared to placebo. Because serotonin reuptake inhibitors benefit obsessive‐compulsive disorder (OCD) and inositol is reported to reverse desensitization of serotonin receptors, 13 patients with OCD completed a double‐blind, controlled crossover trial of 18 g inositol or placebo for 6 weeks each. Inositol significantly reduced scores of OCD symptoms compared with placebo. Epi‐inositol, an artificial stereoisomer of myoinositol, was found to have effects similar to those of myoinositol in reversing lithium–pilocarpine seizures and in reversing lithium‐induced rises in cytidine monophosphorylphosphatidate in cultured cells as does myoinositol. We measured the behavior of rats in an elevated plus‐maze model of anxiety after chronic treatment of 11 daily ip injections of epi‐inositol, myoinositol, or control solution. Epi‐inositol reduced anxiety levels of rats compared with controls, and its effect was stronger than that of myoinositol. Epi‐inositol could be a more effective psychoactive drug than its natural analog. Drug Dev. Res. 50:309–315, 2000.