The effects of inositol treatment in animal models of psychiatric disorders

Journal of Affective Disorders 62 (2001) 113–121www.elsevier.com/ locate / jad

The effects of inositol treatment in animal models of psychiatricdisorders

*Haim Einat, R.H. Belmaker

Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel

Abstract

Clinical trials indicate that inositol may be effective in the treatment of patients with depression, panic disorder andobsessive compulsive disorder (OCD), but not in the treatment of patients with schizophrenia, Alzheimer’s disease, ADHDor autism. This spectrum of clinical action parallels that of serotonin selective reuptake inhibitors (SSRIs), but inositol is aprecursor in the phosphatidylinositol cycle, a second messenger system distal to the receptor for 5HT-2. To study itsmechanism of therapeutic action there is a need to test inositol’s 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 thereserpine-induced hypoactivity models of depression, and reduce anxiety-like behaviors in the elevated plus-maze. Thereduction in anxiety-like behaviors appears to be related to baseline levels of activity. Inositol treatment was not observed tohave any effect on amphetamine-induced hyperactivity, apomorphine-induced stereotypy, or on the performance of memorytasks by monkeys. Clinical controlled trials of inositol in patients with depression, panic disorder, and OCD were small, andpositive psychoactive effects in animals clearly strengthen the case for further clinical trials and potential for generaltherapeutic use in humans. 2001 Elsevier Science B.V. All rights reserved.

Keywords: Inositol; Animal models; Depression; Anxiety; Second messengers

1. Introduction disorders (Rodgers, 1997; Willner, 1991b), it is clearthat their use is still the best option to screen

The development of novel drugs for the treatment potential novel drug treatments in psychiatry.of psychiatric disorder and the understanding of their Inositol is an endogenous polyol that has emergedmechanism of action is dependent on our ability to during the last few years as a new possible treatmenttest pharmaceutical compounds in appropriate animal in psychiatry (Levine, 1997). Inositol is the pre-models of these diseases (Abramson and Seligman, cursor of the PI cycle in the cell and as such is1977; Willner, 1991a). Beyond the thoroughly dis- necessary for the production of two second messen-cussed problematics of animal models for psychiatric gers: Inositol triphosphate (IP ) and DAG. Unlike3 3

most psychotropic drugs, inositol is probably notacting directly in the synapse but in second mes-*Corresponding author. Tel.: 1 972-7-6401-602; fax: 1 972-7-senger systems distal to receptors.6401-621.

E-mail address: [email protected] (R.H. Belmaker). Inositol does not readily enter the brain and only

0165-0327/01/$ – see front matter 2001 Elsevier Science B.V. All rights reserved.PI I : S0165-0327( 00 )00355-4

114 H. Einat, R.H. Belmaker / Journal of Affective Disorders 62 (2001) 113 –121

about 3% of plasma inositol crosses the blood brain activity levels in normal rats; reserpine inducedbarrier (Spector, 1998). Yet, exogenously adminis- hypoactivity; the Porsolt forced swimming test.tered oral inositol was demonstrated to increase CSFinositol levels in chronic schizophrenic patients 1.1.1. Activity levels studies(Levine et al., 1993c). In rats, acute intraperitoneal Two studies examined the effects of inositol oninjection of 5 g/kg resulted in increased inositol activity level in rats, the first one tested the effects oflevels in cortex, hypothalamus and hippocampus acute intraperitoneal inositol treatment (Kofman et(Patishi et al., 1996) and chronic dietary inositol (5% al., 1993) and the second examined the effects ofin food for 3 weeks) elevated inositol levels in the chronic oral inositol administration (Kofman et al.,cortex and hippocampus (Kofman et al., 1998). 1998).

A possible relevence of inositol to psychiatric For the first study, Sprague Dawley rats weredisorders was first suggested by Barkai et al. (1978) housed 4 per cage in a temperature controlled (238C)who reported that patients with affective disorders and 12 h light dark cycle colony room, with food andhad reduced CSF inositol levels. Although these water provided ad lib. All tests were done during thefindings were not replicated (Levine et al., 1996), dark phase of the light dark cycle. Rats were dividedrecent studies reported reduced inositol level in to five groups which received saline (n 5 8); glucosefrontal cortex of post mortem brains of patients with 1 g/kg (n 5 10); glucose 5 g/kg (n 5 10; inositol 1bipolar disorder and victims of suicide (Shimon et g /kg (n 5 9); and inositol 5 g /kg (n 5 10). All drugsal., 1997). Furthermore, clinical studies with inositol were diluted in distilled water and administered viademonstrated that it may have therapeutic value in intra-peritoneal injection in a volume of 2 ml /100 gthe treatment of depression (Levine, 1997; Levine et weight. Two hours after injection, rats were placed inal., 1993a, 1995a), depression accompanying post- automated activity monitors (Optivarimax, Colum-traumatic stress disorder (Kaplan et al., 1996), panic bus Instruments, USA) and their behavior monitoreddisorder (Benjamin et al., 1995), and obsessive- for horizontal and vertical activity for 20 min.compulsive disorder (OCD; Fux et al., 1996). In The vertical activity (number of rearings) of thecontrast, no therapeutic effects were found in schizo- inositol 1 g /kg group was significantly higher thanphrenic patients (Levine et al., 1993b; Levine et al., of the other groups (ANOVA: F(4,42) 5 3.18, P 5

1994), Alzheimer patients (Barak et al., 1996), 0.022; followed by Neuman–Keuls post-hoc test).individuals with Attention Deficit Hyperactivity Dis- No other significant effects were found but a similarorder (Levine et al., 1995b), or autistic patients non-significant trend was demonstrated for horizontal(Levine et al., 1997). This clinical spectrum parallels activity induced by the same inositol dose (1 g/kg).that of the anti-depressant serotonin selective uptake For the second study, 20 male rats were housed 5inhibitors (SSRI’s). per cage in similar conditions to the previous experi-

The present paper reviews a variety of studies of ments. Rats received ad lib food containing 5%the effects of inositol treatment on animal behavior. inositol or 5% glucose plus mannitol at 1:2 ratio forTwo studies tested the effects on normal behavior 3 weeks. On day 22 of treatment, rats were placed inand the others tested effects on animal models of activity monitors for 30 min. Total ambulatorypsychopathology. The goal of these studies was to activity as well as horizontal activity (rearing) levelsconfirm psychoactive effects for this compound were measured and served for later analysis.which had been studied in only a small number of Results show that inositol treatment induced in-patients, and to define at least one robust effect of creased ambulation (approximately 30% increase,inositol in an animal model that could be used for F 5 11.64, P 5 0.003) and increased rearing (ap-detailed neurochemical studies of mechanism and proximately 60% increase, F 5 16.27, P , 0.0008)dose–response relationships. compared with control animals.

1.1. Depression related studies 1.1.2. Reserpine induced hypoactivity (Einat et al.,1999)

The effects of inositol treatment were tested in Two experiments were conducted to test thethree different conditions related to depression: effects of inositol in the reserpine induced hypoac-

H. Einat, R.H. Belmaker / Journal of Affective Disorders 62 (2001) 113 –121 115

tivity model of depression. The difference between of the test session (totalling 3 min per rat). Data forthe two experiments was only in the dose of re- all measures (ambulatory behavior, vertical activity,serpine used to induce hypoactivity. and immobility score) were analyzed utilizing a

Rats (Sprague Dawley males weighing 200–250 g student’s t-test.at the beginning of experiment) were housed 4 per As shown in Table 1, inositol treatment wascage, with free access to food and water, in a effective in reducing complete immobility time intemperature controlled (228C) animal colony with 12 both experiments. A similar trend was also demon-h light dark cycle. All treatments and experimental strated in the second experiment for increased am-procedures were conducted during the light phase of bulatory behavior but did not reach statistical signifi-the cycle. cance.

A treatment group (n 5 10 for each experiment)received 14 daily inositol injections (1.2 g /kg di- 1.2. Forced swim test (Einat et al., 1999)luted in deionized water to injection volume of 12ml /kg). A control group (n 5 10 for each experi- Two experiments were conducted to test thement) received equivalent injections of glucose: effects of chronic treatment with intraperitonealmannitol in a 1:2 ratio. During the last 3 days of (experiment 1) or oral (experiment 2) inositol oneach experiment all rats were also given daily rats’ performance in the Porsolt forced swim test, ansubcutaneous (SC) reserpine injections. The dose of established model of depression (Porsolt et al., 1978;reserpine was 0.5 mg/kg for the first experiment and Borsini and Meli, 1988).0.25 mg/kg for the second experiment. Reserpine Experiment 1 was designed to test a number ofwas diluted in deionized water, with a minimal doses of inositol. Accordingly, 3 groups of ratsamount of citric acid added, to injection volume of 2 received 2 weeks of daily intraperitoneal inositolml /kg. injections at different doses: 0.3 g /kg (n 5 9); 0.6

Thirty minutes after the last reserpine injection, g /kg (n 5 10); and 1.2 g/kg (n 5 8). All doses wererats were placed in automated activity monitors diluted in deionized water to volume of 12 ml /kg.(Elvicom, Israel) and their behavior monitored for Control rats (n 5 10) received injections of 1.2 g/kg,ambulatory and vertical activity for 30 min. Since 1:2 glucose: mannitol solution.the activity monitors are not sensitive enough to For experiment 2, rats were fed for 14 days withdetect locally oriented activity (and therefore dif- inositol (10% in powdered rat chow, n 5 20) or 1:2ferentiate between complete immobility and small glucose: mannitol (10% in powdered rat chow, n 5

movements), manual scoring of behavior was also 20). The powdered food replaced the regular foodperformed and an experimenter scored complete chow in this experiment and was provided ad lib.immobility periods of rats for 1 min for each 10 min Since normal daily food consumption of rats is

Table 1Effects of inositol treatment on reserpine-included hypoactivity model of depression. Significant effects are observed for the measure of‘immobility time’ at both reserpine doses

Experiment Behavior Treatment Mean 1 std P value

Experiment 1: Immobility inositol 170.9 1 7.3 0.0240.5 mg/kg time (s) control 177.6 1 3.5reserpine Ambulation inositol 248.7 1 189.5 N.S.

counts control 342.7 1 651.8

Experiment 2: Immobility inositol 38 1 25.8 0.00030.25 mg/kg time (s) control 98 1 33.9reserpine Ambulation inositol 981.5 1 364.9 N.S.

counts control 771.6 1 229.9Vertical inositol 31.8 1 23 N.S.counts control 31.1 1 28.5


approximately 10% of body weight, it can be esti- t-test for experiment 2. Significance level was set atmated that the oral daily inositol dose in this P , 0.05.experiment | 2.5–3 g. Table 2 shows the results of the forced swim test

Swim exposure for both experiments was con- experiments. These results demonstrate that chronicducted during days 13 and 14. inositol treatment with intraperitoneal 1.2 g /kg dose,

The Porsolt swim test includes two exposures to a but not with lower doses, significantly reducedwater tank, spaced 1 day apart (Borsini and Meli, immobility time compared with control animals1988; Porsolt et al., 1978; Sanchez and Meier, 1997). (ANOVA: F(4) 5 3.07586, P 5 0.026; post-hoc tests:For these experiments the tank sizes were 22 cm in inositol (1.2 g /kg) different than control, and in-diameter and 40 cm in height. The tank had a creased struggle time compared with controlsrounded lid and contained 20 cm high fresh water at (ANOVA: F(4) 5 6.23, P 5 0.0005; post-hoc test258C. During the first exposure, rats were placed into inositol (1.2 g /kg) different than control). Similarthe tank and left there for 10 min. During the second results were obtained for rats treated chronically withexposure (test session), rats were placed in the tank oral inositol (10% in powdered rat chow). Reducedand left there for 5 min during which their behavior immobility time was observed compared with controlwas videotaped. rats (t-test: t(38) 5 3.77286, P 5 0.0006) and strug-

Videotapes of the test session were scored by a gle time in the treatment group appears increasedblind observer for complete immobility time, small although the difference did not reach statisticalmovements time, and vigorous struggle time. The significance (t-test: t(38) 5 1.76297, P 5 0.086).division of activity levels to three rather than thetraditional 2 (yes or no) levels is an elaboration of 1.3. Anxiety related studiesthe method that may be more appropriate to examinethe effects of different treatments (Borsini and Meli, 1.3.1. Effects of acute and chronic inositol in the1988). Results were analyzed utilizing one-way plus-maze model of anxiety (Cohen et al., 1997a)analysis of variance (ANOVA) followed by LSD The elevated plus-maze serves to model anxiety-post-hoc tests for experiment 1, and by a student’s like behavior in rodents. It is based on a conflict

Table 2Effects of chronic intraperitoneal and chronic oral inositol on behavior in the Porsolt forced swim test. Significant effects are observed for‘immobility time’ and ‘struggle time’ measures after chronic intraperitoneal inositol, and for the ‘immobility time’ measure after chronicoral inositol

Experiment Behavior Treatment Mean6std P value

Experiment 1: Immobility control 178.2 1 32.3 0.026Chronic time (s) inositol 161 1 21.6 post hocintraperitoneal 0.3 g /kg inositol 1.2 g /kginositol inositol 168.5 1 45.2 vs. controlor control 0.6 g /kg 140.5 1 26.7

inositol1.2 g /kg

Struggle control 36 1 27.6 0.0005time (s) inositol 38 1 38.4 post hoc

0.3 g/kg inositolinositol 56.5 1 47.1 1.2 g/kg0.6 g/kg vs. controlinositol 80.3 1 47.31.2 g/kg

Experiment 2: Immobility control 147 1 49.8 0.0006Chronic oral time (s) inositol 95.1 1 36.2inositol or Struggle control 31.3 1 29 NScontrol time (s) inositol 47.5 1 29.1 (0.086)


situation between the exploratory drive of rodentsand their aversion from open spaces (e.g. Rodgersand Cole, 1994). The model is one of the mostfrequently used models in psychopharmacology andhad been validated in numerous studies (for reviewsee File, 1992). The first attempt to examine theeffects of inositol treatment in the plus-maze wasdone by Cohen et al. (1997a). In that study, theeffects of a variety of acute doses injected peripher-ally, two doses injected acutely in intracerebroven-tricular injection, and one dose injected chronicallyand intraperitoneally were examined in the elevatedplus-maze. Fig. 1. Effects of chronic inositol (1.25 g/kg daily for 14 days) in

the elevated plus-maze model of anxiety. Time spent in open armsResults of the dose–response study of acuteand number of entries to open arms. * Represents significantperipheral inositol treatment (0.03–2.5 g/kg) indi-difference, P , 0.05.

cated that a single peripheral injection of inositolmay have an anxiogenic effect compared with con-trol solution (data not shown). However, a singleICV injection of 5 mg inositol resulted in reduced that inositol significantly increased the time spent inanxiety-like behaviors in the elevated plus-maze the open arms supports a specific anxiolytic-like(data not shown). Thus, the data regarding the acute activity.effects of inositol in this model are not clear. In Support for the previous findings was foundhuman studies, inositol treatment was demonstrated recently in a study of the anxiolytic-like effect in theto have a therapeutic effect in anxiety disorders only elevated plus-maze of inositol and one of its isomers,after chronic treatment (Benjamin et al., 1995). epi-inositol (Einat et al., 1998a). Chronic intraperi-Therefore the evaluation of the effects in the model toneal inositol treatment was demonstrated again toin a chronic treatment paradigm appears to be the produce anxiolytic-like effects in the elevated plus-most appropriate. maze as shown by increase time spent and number of

To examine the effects of chronic inositol, groups entries to the open arms of the maze (Table 3).of rats (n 5 10 per group) were treated with daily Interestingly, epi-inositol appeared to be even moreintraperitoneal injections of inositol (1.25 g/kg potent than myo-inositol in that model (data notdiluted to 10% in de-ionized water) or control shown).solution (1:2 glucose /mannitol at equal concentra- In contrast to the previous intraperitoneal findings,tion and dilution) for 14 days. Two hours after the an attempt to examine the consequences of orallast injection rats were tested in the elevated plus- inositol treatment (5% in food for 2 weeks) in themaze. As shown in Fig. 1, rats treated chronically plus-maze did not indicate any anxiolytic-like effectswith inositol spent significantly more time in the (Einat et al., unpublished observations). The observa-open arms of the maze and demonstrated a similar tion that intraperitoneal but not oral inositol hastrend in the measure of number of entries to thesearms. These measures indicate that chronic inositol Table 3treatment has anxiolytic-like properties in the ele- Effects of chronic intraperitoneal inositol treatment on behavior in

the elevated plus-maze model of anxiety. Inositol significantlyvated plus-maze model. In line with the results ofincreases ‘time spent in open arms’ and ‘number of entries to openother studies (Kofman et al., 1993; Kofman et al.,arms’1998), the inositol group also demonstrated in-Behavior Inositol Control Significance levelcreased activity compared with the control group as

observed by increased number of entries to both the Time spent in open 28.866.9 10.864.8 P 5 0.022armsopen and the closed arms of the maze (data notNumber of entries 2.560.6 1.160.4 P , 0.03shown). This finding could imply that the anxiolytic-to open armslike effect is an artifact of hyperactivity but the fact


anxiolytic-like activity appears unusual because oral- For the present experiment, rats were fed pelletsly administered inositol was reported to increase containing 5% inositol (n 5 10) or 5% 1:2 glucosebrain inositol levels and to have behavioral effects in mannitol (n 5 10) for 19 days. On day 18 all ratsintact rats (Kofman et al., 1998). However, the fact were exposed for 10 min to a domestic cat (nothat SSRIs are effective in the treatment of patients physical contact was permitted) and 24 h later eachwith anxiety disorders but do not have any anxiolytic rat was tested in the elevated plus-maze. Resultseffects in normal controls (e.g. Gelfin et al., 1998) indicate that inositol treatment reduced anxiety-likesuggested the hypothesis that inositol may be more behaviors in this paradigm as observed by a sig-active in stressed than in unstressed animals. If that nificantly higher number of rats from the inositolis the case than rats chronically treated with in- group that entered the open arms (8 /10 in the

2jections and therefore chronically stressed by that inositol group, 3 /10 in the control group, x 5 5.05.paradigm, should respond more readily to inositol P , 0.02); by increased number of entries to thetreatment than rats who received inositol in their open arms (t 5 2.48, P 5 0.024) and by a strongfood in a non-stressful manner. To test this hypoth- trend of the inositol treated rats to spend more timeesis two studies were designed that included: (a) an in the open arms than the control animals (t 5 2.0,examination of the effects of oral inositol treatment P 5 0.06).after chronic mild stress; and (b) a study of the The results of the last experiment combined witheffects of chronic oral inositol after acute stress the trend presented in the previous experiment add(Kofman et al., 2000). support to the hypothesis that inositol’s anxiolytic-

like effect is stronger when the level of anxiety is1.3.2. Testing the relationship between stress levels higher than normal.and the effects of inositol on anxiety-like behavior

The first study examined the effects of chronic 1.4. Schizophrenia related studiesmild stress and inositol treatment in the elevatedplus-maze. Rats were divided to 4 groups (n 5 10 per Amphetamine-induced hyperactivity and apomor-group) in a 2 3 2 design with oral inositol (5% in phine-induced stereotypy are both frequently used tofood for 3 weeks) treatment as one factor and chronic models for some aspects of mania (Lyon, 1991a) andmild stress (daily saline injection 20 ml /kg for the schizophrenia (Lyon, 1991b) respectively. To evalu-last 14 days of the experiment) as the second factor. ate the possible effects of inositol in these modelsResults indicated that as shown before (e.g. Lister, two preliminary experiments were conducted (Kof-1987; Pellow et al., 1985; Treit et al., 1993), stress man et al., 1993).had a significant effect on the performance of rats in The first experiment was designed to evaluate thethe elevated plus-maze. The effect of inositol on effect of acute inositol treatment on amphetamine-behavior in the plus-maze was not significant but a induced hyperactivity. Accordingly, 4 treatmentnear-significant trend was demonstrated for the inter- groups received treatment as follows: Group saline-action between inositol and stress (data not shown). saline (n 5 8), Group saline-amphetamine (n 5 9),This offers support to the hypothesis that inositol Group glucose-amphetamine (n 5 8), and Groupeffects on anxiety may be related to the level of inositol-amphetamine (n 5 9). Rats were injectedanxiety. intraperitoneal with inositol or glucose (1 g/kg

The second experiment was designed to test the diluted to 20 ml /kg) or an equivalent volume ofeffects of chronic oral inositol treatment on anxiety- saline followed 2 h later by a SC injection oflike behavior after acute stress. The paradigm used to amphetamine (0.75 mg/kg diluted to 1 ml /kg) or aninduce stress was a single exposure to a cat. A single equal volume of saline. Five minutes after the SCexposure to a predator was demonstrated to increase injection, rats were placed in activity monitorsanxiety-like behaviors in rodents and was stipulated (Optivarimax, Columbus Instruments, Columbus,to model pathologic anxiety mechanisms (Hendrei et Ohio) and their activity automatically monitored foral., 1996) as well as behaviors related to PTSD 20 min. Results indicate no observable effects of(Adamec and Shallow, 1993; Cohen et al., 1997b). inositol in this model (data not shown).


The second experiment tested the effects of acute mania-related models and on memory-related tasksinositol treatment on apomorphine-induced in monkeys.stereotypy. Rats received intraperitoneal pretreatment Clinical controlled trials of inositol in patientswith inositol (1 g /kg, 20 ml /kg), glucose (same dose with depression, panic disorder, OCD and PTSDand dilution) or saline (same volume). Two hours were small and positive psychoactive effects inlater they were injected SC with 0.5 mg/kg apomor- animals clearly strengthen the case for further clini-phine and their level of stereotypy rated by two blind cal trials and potential for general therapeutic use inobservers according to a rating scale modified from humans. A study of inositol in an animal model ofKelly and Iverson (1976). Results did not reveal any OCD would be a critical next step, although theeffects of inositol in this model (data not shown). tentativeness of present animal models of OCD could

The last two experiments tested only acute inositol make this step an unsure one. The lack of inositoltreatment and that may diminish the possibility for effects on amphetamine-induced hyperactivity, ansubstantial conclusions regarding the effects of animal model of mania, suggests that inositol may beinositol in these models. However, the effects of more anti-depressant than anti-bipolar. This is con-classical anti-psychotic drugs in these models follow sistent with its efficacy in panic disorder and OCD inacute treatment (for review see Lyon, 1991b) and humans, where anti-bipolar drugs such as lithium arethus the results may be enough to conclude that ineffective. However, the effects of lithium oninositol is not acting in any similar way to these inositol metabolism raise the speculation that inositoldrugs. might be lithium-like. This speculation is not sup-

ported by our rat model data.1.5. Memory related study (Einat et al., 1998b) The present data provide several animal behavioral

effects of inositol that are robust enough for pharma-To test the effects of inositol on memory, 4 cological analysis. It will be important to determine

Rhesus monkeys were fed with 20 g/day inositol or if inositol effects in the plus-maze and the swim test20 g 1:2 glucose:mannitol for 2 weeks in a cross are reversible with serotonin antagonists at specificover design. Spatial discrimination tests (Olton et al., receptors, for instance. Such mechanistic data could1980; Raveh et al., 1997) that permit the examina- then stimulate hypotheses that would be testable intion of a number of behavioral parameters with patients under treatment with inositol, and perhapsemphasis on working and reference memory were lead to etiological hypotheses related to the PI cycle.administered to the monkeys daily. Results indicateno effects of inositol on any of the behavioralparameters tested in this study (data not shown).

AcknowledgementsThese results are consistent with the lack of effectsof inositol in Alzheimer’s patients (Barak et al.,

The authors would like to thank Dr. Ora Kofman1996).and Dr. Hagit Cohen for their help. Supported by aStanley Foundation Center grant.

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The effects of inositol treatment in animal models of psychiatric disorders