Olgierd Pucilowski

Chronic mild stress-induced anhedonia : greater effect in a genetic rat model of depression

The effects of acute and chronic stressors on saccharin intake and preference in the hypercholinergic Flinders Sensitive Line (FSL) rat, a putative genetic animal model of depression, were studied and compared to the control Flinders Resistant Line (FRL) rats. Overall, the FRL rats drank significantly less saccharin and water than the FSL rats when compared over a wide range of saccharin concentrations (0.01-5%) under baseline conditions. A 0.02% saccharin concentration was used in subsequent experiments. We observed a significant suppression of saccharin intake/preference at 1 h following a single 5-min exposure to cold swim stress only in FSL rats. There was a tendency to increase saccharin intake in both lines at 1 h following a scrambled foot shock stress. These effects of acute stressors disappeared upon retesting for saccharin consumption/preference 23 h after the stress. Chronic 4-week exposure to unpredictable mild stressors significantly (p < 0.01) decreased saccharin consumption in the FSL rats, but not in the FRL rats. The FSL rats also exhibited a significantly greater decrease in saccharin preference (-24% vs. prestress baseline, as compared to -7% in FRL controls, p < 0.05). In conclusion, FSL rats appear more prone than the FRL rats to chronic, as well as immediate acute, stress-induced anhedonic effects. This outcome further supports the notion that the FSL rat is a useful model of a genetic predisposition to depressive-like reactions.

Administration of antidepressants, diazepam and psychomotor stimulants further confirms the utility of Flinders Sensitive Line rats as an animal model of depression

Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression because they resemble depressed humans in that they have elevated REM sleep, reduced activity, and increased immobility and anhedonia after exposure to stressors. The present paper reviews experiments on the drug treatment of FSL and control Flinders Resistant Line (FRL) rats related to their utility as an animal model of depression, and presents new information. FSL rats exhibited exaggerated immobility in the forced swim test which is counteracted by the tricyclic antidepressants imipramine and desipramine and the serotonin reuptake blocker sertraline; the low immobility exhibited by the FRL rats is generally unaffected by these compounds. In contrast to these “therapeutic” effects of well recognized antidepressants, lithium and bright light treatment did not alter the exaggerated immobility of FSL rats. Novel data indicated that neither FSL nor FRL rats exhibited alterations in swim test immobility following chronic administration of the psychomotor stimulant amphetamine (2 mg/kg) and the anticholinergic scopolamine (2 mg/kg), which typically reduce immobility after acute administration. However, it was found that the calcium channel blockers verapamil (5 and 15 mg/kg) and nicardipine (10 mg/kg) did reduce the exaggerated immobility in FSL rats following chronic administration, suggesting that these compounds need to be evaluated further in humans. Previous studies have indicated no differences between FSL and FRL rats evaluated in the elevated plus maze, either at baseline or after the administration of diazepam, suggesting that the FSL rat may not differ from controls in anxiety-related behavior. Another recently published study showed that the FSL rat also did not differ from normal Sprague-Dawley rats in startle tests, indicating that the FSL rats do not exhibit behaviors shown in animal models of schizophrenia. These findings confirm the utility of FSL rats as an animal model of depression because the FSL rats do not appear to exhibit behaviors analogous to anxiety or schizophrenia and because they respond “therapeutically” to antidepressants and not psychomotor stimulants.

Effects of Chronic Mild Stress on Serum Complement Activity, Saccharin Preference, and Corticosterone Levels in Flinders Lines of Rats

Complement proteins and fragments participate in the induction and modulation of specific and nonspecific immune reactions. We have examined the effect of 4 weeks of chronic mild stress (CMS) on complement sheep red blood cell hemolytic activity measured in CH50 units in two selectively bred lines of rats, the Flinders resistant line (FRL) and the Flinders sensitive line (FSL), that differ in cholinergic sensitivity and behavioral characteristics. Additionally, CMS-induced hedonic deficit (decreased preference for 0.02% saccharin over water) and serum corticosterone levels were compared in FRL and FSL rats. CMS caused a significantly (p < 0.01) greater decline in CH50 responses in FSL (-15%) than in FRL (-7%) rats. This was accompanied by a significant (p < 0.01) suppression of saccharin preference over a 24 h period in both FRL and FSL rats. Both lines showed a similar, more than 2-fold (p < 0.01) increase in corticosterone levels following CMS. These results further confirm that CMS induces a depressive-like state in rats as well as the validity of the FSL rat as a genetic model of depression. They also indicate that the effect of stress on the immune system can be monitored by measuring the complement CH50 response.

Aggressive behaviour and the central serotonergic systems.

A brief critical review of serotonin involvement in two classes of aggressive behaviour, i.e. affective and predatory aggression, is presented. Special emphasis is put on the differentiation between the role played in aggression by the two ascending serotonergic systems, the mesolimbic and the mesostriatal. It is concluded that only serotonergic neurons from the dorsal raphe nucleus forming the mesostriatal system play an inhibitory role in both classes of aggression. The mesolimbic system does not seem to be directly involved in an aggression modulation. The data suggesting that the dorsal raphe may mediate its inhibitory influence through the medial amygdala is presented and discussed. Finally some attention is given to the problem of serotonin metabolism variability (biorhythm) and its implications in behavioural studies.

Immobility-reducing effects of antidepressants in a genetic animal model of depression

Chronic treatment with the tricyclic antidepressants imipramine (15 mg/kg) and desmethylimipramine (5 mg/kg) significantly reduced the exaggerated immobility normally exhibited by the Flinders Sensitive Line (FSL) rats in the Forced Swim Test. The control group, Flinders Resistant Line (FRL) rats were only slightly affected. In contrast, chronic treatment with the anticholinesterase diisopropyl fluorophosphate at doses known to down regulate muscarinic receptors did not alter swim test immobility in either FSL or FRL rats. Our findings support the validity of the FSL rats as an animal model of depression and suggest that serotonergic and/or noradrenergic, but not cholinergic mechanisms, may underlie the exaggerated immobility of the FSL rats.

Effect of chronic antidepressant treatment on responses to apomorphine in selectively bred rat strains

The purpose of this study was to verify the dopamine-sensitizing behavioral effect of chronic antidepressant treatment in two selectively bred rat strains: the hypercholinergic Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL). Two antidepressants, desipramine HCl (DMI) and sertraline HCl, were injected IP in separate groups of FSL and FRL rats in a dose of 16.5 mumol/kg twice daily for 16 days. Twenty-four hours after withdrawal, locomotor and hypothermic responses to 0.2 mg/kg of apomorphine, SC, were examined. Attenuation of the effect of apomorphine was observed in the open field: FRLs withdrawn from sertraline were significantly less mobile than control FRLs, and the same trend was found in FSL rats. Chronic DMI resulted in similar changes in the locomotor activity. Sertraline treatment decreased apomorphine-induced hypothermia by almost half in FSLs, whereas slight hyperthermia was induced in FRL rats instead. The present results suggest that in these selectively bred strains, a serotonergic antidepressant such as sertraline may have sensitized dopaminergic autoreceptors and/or desensitized postsynaptic receptors. Apomorphine-induced hypothermia could be mediated by serotonergic neuron function that may have been altered by chronic sertraline but not DMI treatment.

Aggressive behavior inhibition by serotonin and quipazine injected into the amygdala in the rat.

The effects on aggressive behavior, open-field activity, and pain threshold of bilateral microinjections of serotonin (20 micrograms) and quipazine (20 micrograms), the direct serotonergic receptor agonist, into the cortico-medial amygdala were investigated in Wistar rats. Both drugs significantly prolonged the attack latency in isolated killer rats (predatory aggression model), and suppressed the incidence of aggressive postures/attacks in shock-induced fighting test (affective aggression). The only difference in the open-field behavior was the lower number of central square entries in drug-treated compared to saline-injected rats. None of the substances produced any significant change in jump threshold. It is concluded that stimulation of serotonin receptors within the amygdala produces inhibition of affective and muricidal behavior in isolated rats. The effect does not seem to be dependent on changes in general activity and pain sensitivity.

Inhibition of nitric oxide synthesis attenuates alcohol consumption in two strains of alcohol-preferring rats

The effect of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on voluntary alcohol consumption was examined in two different strains of alcohol-preferring rats, in a continuous-access, two-bottle-choice paradigm. Compared with the vehicle, intraperitoneal injections of L-NAME significantly and dose-dependently (10, 30, and 60 mg/kg) suppressed alcohol intake and preference in both alcohol-preferring (P) and Fawn-Hooded (FH) rats. The effect of the highest dose of L-NAME was nonspecific; it caused general decreases in consumption of alcohol, water, and food. Repeated injection of L-NAME (30 mg/kg) for 4 consecutive days significantly attenuated alcohol intake, but tolerance developed after 3 days of treatment. A single administration of a high dose of L-NAME (60 mg/kg) did not influence the blood alcohol concentrations, which suggests a possible central effect. Furthermore, a moderate dose of 30 mg/kg L-NAME, which selectively inhibited alcohol intake, did not exert a significant effect on telemetrically measured heart rate, core body temperature, and gross motor activity of alcohol naive Fawn-Hooded rats. These results suggest an involvement of nitric oxide in alcohol drinking behavior. Although the true mechanism(s) of action is not yet clear, it can be speculated that L-NAME may exert its action indirectly by modulating neurotransmitters proposed to be involved in alcohol drinking and/or by influencing other neuronal factors, such as neuronal Ca2+ channels, which have been shown to be involved in alcohol drinking behavior.

Preference for higher sucrose concentrations in cocaine abusing-dependent patients

BACKGROUND Animal studies suggest that preference for relatively high concentrations of sweet solutions and lack of control over sweet solution consumption is related to a preference for alcohol over water. There also is evidence in humans that alcoholics prefer high concentration sweet solutions. This study was designed to determine whether patients with cocaine use disorder also prefer high concentrations of sweet solutions. METHODS Sixteen patients with cocaine abuse/dependency were compared with 16 inpatient controls with an affective disorder as to their preferences for increasing concentrations of sucrose solutions. Patients were administered aqueous sucrose solutions ranging from 0.05 to 0.83 M. They were then asked to rate their degree of preference for, and the degree of sweetness of each solution. RESULTS Cocaine abusing/dependent patients significantly more often preferred the highest sucrose concentration (0.83 M). CONCLUSIONS The above information suggests that cocaine abusing/dependent patients, like alcoholics, and in contrast to inpatient controls, share a preference for high concentrations of sucrose.

Different effect of diltiazem and nifedipine on some central actions of ethanol in the rat.

The effect of two Ca2+ channel inhibitors (CCIs) on ethanol-induced hypothermia and hypnosis, on tolerance formation to both effects, and on audiogenic convulsions during ethanol withdrawal was studied in rats. Nifedipine, 2 and 5 mg/kg IP, significantly augmented the hypnotic action of ethanol without affecting hypothermia. Diltiazem failed to influence either effect of the toxin. Rectal temperature did not change in ethanol-naive rats after acute injection of diltiazem or nifedipine. Both drugs dose-dependently suppressed the development of tolerance to the hypothermic effect of ethanol without affecting the tolerance to the hypnotic action. Only nifedipine markedly suppressed the audiogenic seizure response in ethanol withdrawn animals. These data suggest that Ca2+ channels play a role in both acute and chronic effects of ethanol while pointing to certain differences in behavioral effects of various CCIs.