The forced swimming test is reviewed. This test appears to be suitable for detecting antidepressant activity in rats but not in mice. Difference in experimental procedure may account for the different sensitivity to drugs of the two animal species.

Is the forced swimming test a suitable model for revealing antidepressant activity

The authors review the available literature on the preclinical and clinical studies involving GABAergic neurotransmission in mood disorders. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter present almost exclusively in the central nervous system (CNS), distributed across almost all brain regions, and expressed in interneurons modulating local circuits. The role of GABAergic dysfunction in mood disorders was first proposed 20 years ago. Preclinical studies have suggested that GABA levels may be decreased in animal models of depression, and clinical studies reported low plasma and CSF GABA levels in mood disorder patients. Also, antidepressants, mood stabilizers, electroconvulsive therapy, and GABA agonists have been shown to reverse the depression-like behavior in animal models and to be effective in unipolar and bipolar patients by increasing brain GABAergic activity. The hypothesis of reduced GABAergic activity in mood disorders may complement the monoaminergic and serotonergic theories, proposing that the balance between multiple neurotransmitter systems may be altered in these disorders. However, low GABAergic cortical function may probably be a feature of a subset of mood disorder patients, representing a genetic susceptibility. In this paper, we discuss the status of GABAergic hypothesis of mood disorders and suggest possible directions for future preclinical and clinical research in this area.

GABAergic dysfunction in mood disorders

5-Hydroxytryptamine-interacting drugs in animal models of anxiety disorders: More than 30 years of research

Animal models of depression: an overview.

The forced swimming test (FST) is a widely used behavioral screen in rodents that is both sensitive and selective for clinically effective antidepressant drugs. However, antidepressant drugs produce changes in the FST within 24 hr of treatment, in contrast to weeks required for the recovery from clinical depression, and high doses seem to be required to produce effects in most animal tests. This study examined behavioral effects in the FST after subacute and chronic treatment with low doses (1-5 mg/kg) of antidepressant drugs to determine whether chronic treatment produced behavioral effects at doses that were ineffective after subacute treatment. The antidepressants studied were desipramine, a selective norepinephrine uptake inhibitor, and fluoxetine, a selective serotonin uptake inhibitor. The results indicated that low doses of desipramine and fluoxetine produced different behavioral patterns in the FST, but only after chronic administration. The results strengthen the validity of the FST as a behavioral screen for antidepressant drugs with features similar to an animal model of depression.

Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression.

8-OH-DPAT (2.5–10 mg/kg) and buspirone (10 mg/kg) but not 5,7DHT (200 Μg/mouse), pCPA (75 and 150 mg/kg, three times), ritanserin (0.1 and 0.2 mg/kg), LY 53857 (1.5 and 3 mg/kg), GR 38032 F (0.1–100 Μg/kg), TFMPP (5 and 20 mg/kg) and mCPP (2.5 and 5 mg/kg) antagonized the rise in body temperature that occurs to the last mice removed from their group housing, which was termed as stress-induced hyperthermia (SIH). Ro 15-1788, at a dose which blocked the effect of diazepam on SIH, did not reverse the anxiolytic effect of buspirione. Instead, when cerebral 5-HT content was reduced to 50% by 5,7-DHT-induced lesion, the effect of buspirone on SIH was decreased. TFMPP 5 mg/kg did not shorten significantly the onset of SIH as could have been expected by an anxiogenic drug, while the dose of 20 mg/kg did not modify the pattern of SIH at all. The lower dose of TFMPP evoked a hyperthermic and the higher a hypothermic response.

Effect of serotoninergic drugs on stress-induced hyperthermia (SIH) in mice.

Animals were injected with 20 mg/kg desipramine (DMI) 1 h (acute) or 24, 5 and 1 h (subchronic) or once daily for 7 consecutive days (chronic) before the forced swimming test (FST). DMI was also injected at a dose of 40 mg/kg acutely. Animals were killed immediately after test for evaluation of brain concentrations of DMI and its demethylated metabolite desmethyldesipramine (DDMI). Acute and chronic DMI 20 mg/kg gave rise to similar brain concentrations but only chronic DMI was active on FST. Acute DMI 20 mg/kg and 40 mg/kg gave rise to different brain concentrations but similar effects on FST. DDMI concentrations were similar after the various DMI treatments. Results seem to indicate that no relationship exists between effect of DMI on FST and brain concentrations of either DMI or DDMI.

Lack of relationship between effect of desipramine on forced swimming test and brain levels of desipramine or its demethylated metabolite in rats.

A molecule, 6-methyl-6,11-dihydro-11-[(N,N-dimethylamino) acetyl]dibenzo[c,fl-[1,2,5]thiadiazepine 5,5-dioxide, (IM/P/3/4, CAS 128377-70-8), was identified in a screening program, which had the scope of finding compounds with antidepressive potential without the common sideeffects of existing antidepressive medication. IM/P/3/4 was found active a) in antagonizing apomorphine (16 mg/kg) and reserpine-induced hypothermia in mice; b) in potentiating yohimbine-induced lethality in mice; c) in reducing immobility of rats forced to swim and of mice suspended by the tail. IM/P/3/4 does not affect a) apomorphine-induced stereotypy; b) amphetamine-induced hypermotility; c) haloperidol-induced catalepsy and water-induced grooming and d) does not induce stereotypy or alter motor activity. The compound also a) reduced the beating of rat right heart atria only at a concentration of 3 x 10-4 mol/l; b) had weak anticholinergic activity; c) antagonized electroshock-induced convulsions and d) prevented indometacin-induced duodenal ulcers. IM/P/3/4 does not have good affinity for noradrenergic, serotonergic, dopaminergic, histaminergic or muscarinic receptors and does not displace imipramine, desipramine and mianserine from their binding sites. IM/P/3/4 increases 5-hydroxyindolacetic acid content and 3H-serotonin uptake in the hypothalamus. The present results suggest that IM/P/3/4 is a potential antidepressant with reduced side effects and with a mechanism of action which is different from that of other antidepressants.

A. Mancinelli

Papers

Effect of serotoninergic drugs on stress-induced hyperthermia (SIH) in mice.

Lack of relationship between effect of desipramine on forced swimming test and brain levels of desipramine or its demethylated metabolite in rats.

Potential antidepressant activity and enhancement of serotonin uptake of a new dibenzothiadiazepine derivative.

Determination of nomifensine in rat brain by high-performance liquid chromatography with fluorescence detection.