Biomedical subjects
Publications and source records attributed to F Borsini.
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.
GABA content was reduced in the nucleus accumbens, cortex and brainstem of rats after 5 but not after 45, 120 min or 24 hr, from the termination of the pretest session. This reduction was not observed in rats performing on rotarod. Intraperitoneal AOAA (25 mg/kg; 24, 5 and 1 hr before the test), reduced at the same extent immobility time regardless whether the animals had been exposed to a pretest session. In pretested animals, reduction in immobility time produced by AOAA (25 mg/kg X 3 times) was similar to that observed following 50 mg/kg, 5 hr before testing. This reduction was not antagonized by GABA antagonists bicuculline (2 mg/kg) or picrotoxin (2 mg/kg), given intraperitoneally 30 and 20 min before the test respectively. Intraperitoneal sodium valproate (200 or 400 mg/kg; 24, 5 and 1 hr before the test) and isoniazide (200 mg/kg) or 4-deoxypyridoxine (400 mg/kg), administered 1 or 1.5 hr before the test, were ineffective. AOAA (25 mg/kg X 3 times) gave a similar increase in GABA levels to 50 mg/kg only once in the brainstem, nucleus accumbens and hypothalamus and a greater increase in the other brain areas. After 5 hr from single dosing, 25 mg/kg AOAA increased GABA levels less than 50 mg/kg AOAA in the brainstem, nucleus accumbens, frontal cortex and striatum, and increased it to same extent in the other areas. Sodium valproate (400 mg/kg X 3 times) increased GABA levels in all brain areas, except hippocampus, although to a lesser extent than AOAA.
Subcutaneous chronic desipramine (DMI, 5 mg/kg once daily for 18 consecutive days) prevented subcutaneous THIP (20 mg/kg) reduction in body temperature but did not affect THIP behavioral depressant effect (open-field behavior). Repeated DMI treatment did not affect subcutaneous baclofen (2.5-10 mg/kg) reduction in body temperature and behavioral depression (open-field behavior).
The D-2 agonist LY 171555 (0.05, 0.1, 0.2 mg kg-1 s.c.) but not the D-1 agonist SK&F 38393 (5, 10, 20 mg kg-1 s.c.) reduced reserpine-induced hypothermia (RIH) in mice. This effect was antagonized by the D-2 antagonist (-)-sulpiride (50 mg kg-1 i.p.) but not by the D-1 antagonist SCH 23390 (0.1 mg kg-1 s.c.). SK&F 38393 (20 and 1 mg kg-1 s.c.) did not alter the effect of LY 171555 (0.1 and 0.2 mg kg-1) on RIH, but administration of both LY 171555 (0.2 mg kg-1 s.c.) and SK&F 38393 (1 mg kg-1 s.c.) antagonized the reserpine-induced sedation.
Muscimol as well as catecholaminergic drugs reduce immobility time in the forced swimming test. In view of the fact that GABAergic drugs may facilitate some brain catecholaminergic functions, we investigated as to whether or not muscimol would reduce immobility time through activation of catecholaminergic mechanisms. The effect of muscimol (2 mg/Kg i.p.) on reduction of immobility time was prevented by intraperitoneal alpha-methyl-para-tyrosine (250 mg/Kg i.p.), which reduces brain catecholamine content, haloperidol (0.5 mg/Kg) and sulpiride (100 and 50 mg/Kg), antidopaminergic drugs, and meta-chlorphenyl-piperazine (0.6 and 1.25 mg/Kg), a serotonergic agonist, but not by clonidine (0.1 mg/Kg), an alpha2-adrenoceptor agonist, d, 1-propranolol (5 mg/Kg), an antagonist of beta-adrenergic receptors, or subcutaneous prazosin (3 mg/Kg), an alpha1-adrenolytic drug. Our findings indicate that a) muscimol reduces immobility time by stimulating dopaminergic neurons and b) activation of the serotonergic system antagonizes muscimol effect.
1. The time course and regional distribution of 'spontaneous' cutaneous lesions in rats desensitized to capsaicin as newborns was correlated to behavioural observations and regional distribution of substance P-like immunoreactivity (SP-LI) and tachykinin-like immunoreactivity (TK-LI) in various skin areas. 2. 'Spontaneous' skin lesions in the form of wounds, scabs and areas of alopecia were observed in 80-90% of rats desensitized to capsaicin. No major sex-related differences were observed with regard to incidence and distribution of the lesions with the possible exception of a lesser tendency to bilateral lesions in female rats. 3. 'Spontaneous' skin lesions were almost restricted to the head: the areas most frequently affected were snouts, periocular and retroauricular regions and ventral area of the neck. 4. No major differences were observed between capsaicin- or vehicle-treated animals in spontaneous or novelty-induced grooming as well as in open-field gross behaviour. Likewise, no differences were observed in the mouse-killing behaviour. 5. Both SP-LI and TK-LI in various skin areas were significantly reduced by systemic capsaicin pretreatment. The rank order of various skin areas for SP-LI or TK-LI levels was: snouts greater than thigh greater than neck greater than abdomen approximately equal to retroauricular region. 6. Intradermal injection of Arg-neurokinin B, a potent and water soluble derivative of neurokinin B, produced a similar plasma extravasation (Evans blue leakage technique) in the skin of vehicle- or capsaicin-pretreated rats. 7. In capsaicin-desensitized rats fur regrowth (measured at abdominal level, 28 days after shaving) was significantly less than in vehicle-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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.
Aminooxyacetic acid (AOAA, 25 mg/kg i.p.), muscimol (2 mg/kg i.p.) and 4,5,6,7-tetrahydroisooxazol-[4,5-c]-pyridin-3-ol (THIP, 5 and 10 mg/kg s.c.), but not baclofen (10 mg/kg i.p.) administered three times (24, 5 and 1 h before the test) decreased the immobility time of rats in the behavioral 'despair' test. At these doses, AOAA, muscimol and THIP reduced motor activity. Muscimol (2 mg/kg) and THIP (5 and 10 mg/kg) exerted the antiimmobility effect even after single dosing 1 h before the test. Picrotoxin (1 and 2 mg/kg i.p.), but not bicuculline (2 mg/kg i.p.), prevented the effect of both muscimol and THIP in the behavioral 'despair' test.
Capsaicin applied on the serosal surface of the urinary bladder in urethane-anaesthetized rats produces two distinct types of motor effects: a tetrodotoxin-, hexamethonium- and lidocaine-insensitive 'tonic' contraction and a series of tetrodotoxin-, hexamethonium- and lidocaine-sensitive rhythmic contractions. Both 'tonic' and rhythmic contractions are abolished by bladder denervation indicating their neurogenic origin. The rhythmic but not the 'tonic' component of the contractile effect of capsaicin is abolished by spinal cord transection indicating activation of a supraspinal micturition reflex. The motor effects of topical capsaicin are unaffected by pretreatment with indomethacin or diphenhydramine plus cimetidine. Pretreatment with a large dose of subcutaneous (SC) capsaicin increases both volume and pressure threshold for micturition while amplitude of micturition contraction is unaffected. Moreover the spinal somatovesical reflex elicited by pinching of the perineal skin is unaffected by capsaicin-desensitization. The intracerebroventricular (ICV) administration of capsaicin reproduces the effects of SC capsaicin on the bladder response to saline filling. Rats pretreated with ICV capsaicin are as sensitive as controls in reacting to noxious heat (hot plate test) while the wiping response to instillation of capsaicin into one eye was abolished. These findings provide functional evidence for the presence in the rat urinary bladder of a capsaicin-sensitive innervation which subserves a sensory function in relaying volume/pressure information from detrusor muscle to central nervous system. Information carried through these capsaicin-sensitive fibers appears to be relevant for initiation of a supraspinal vesico-vesical micturition reflex. Functional evidence indicates that these fibers may terminate at supraspinal level.
The behavioral "despair" test is widely used to study antidepressants, mainly on the theoretical assumption that the test animal becomes desperate. In view of the above, we compared behavior of animals subjected to various experimental conditions (4, 15, 30 cm of water), in order to assess whether or not "despair" was the cause of immobility. Our results indicate that the animal's behavior in response to exposure to a dangerous situation, such as that represented by 15 or 30 cm water, depends upon previous knowledge of the environment rather than "despair." We concluded that this test is far from reproducing behavioral changes which characterize depressive illness in humans.
The antinociceptive effect of subcutaneous 4,5,6,7-tetrahydroisoxazol[5,4-c]pyridin-3-ol (THIP) or (+/-)-baclofen, measured as reaction time of rats placed on a plate heated to 55 degrees C, was assessed after a single or the last repeated (18 consecutive days) dose (5 mg kg-1 once daily) of subcutaneous desipramine. Baclofen (10 mg kg-1)-induced antinociception was reduced by acute and unaffected by chronic desipramine treatment. On the contrary, THIP (20 mg kg-1)-induced antinociception was unaffected by acute and reduced by chronic desipramine.
Daily treatment for 7 days with 5 mg/kg nomifensine, 20 mg/kg amineptine, 10 mg/kg mianserin or 20 mg/kg iprindole reduced the immobility time in the behavioural 'despair' test in rats. No stimulation of motor activity was found with any of the drugs, and iprindole and mianserin actually reduced the activity of rats in an open field. The anti-immobility effect of the various antidepressants was significantly counteracted by 0.5 mg/kg haloperidol or 100 mg/kg sulpiride. These doses of neuroleptics alone did not significantly modify the immobility time of rats not treated with the antidepressant compounds. As previously found for desipramine and amitriptyline, the data suggest that dopamine is involved in the anti-immobility effect in rats of repeated treatment with nomifensine, amineptine, mianserin and iprindole.
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Seven days of treatment with amitriptyline 10 mg kg-1 day-1, reduced the immobility time in the behavioural 'despair' test in rats. 0.5, but not 0.25 mg kg-1 haloperidol significantly counteracted the reduction of immobility caused by amitriptyline. Its anti-immobility effect was reduced by 50 and 100 mg kg-1 sulpiride, another blocker of dopamine receptors, and 5 mg kg-1 (+/-)-propranolol, a beta-adrenolytic drug. Prazosin, 3 mg kg-1, an antagonist of post-synaptic alpha-adrenoceptors, had no effect. It is suggested that dopaminergic and beta-adrenoceptors mediate the anti-immobility effect of repeated amitriptyline treatment in rats.
The effects of various doses of salbutamol, d-amphetamine and d-fenfluramine were studied on sucrose intake by freely-fed rats. All the drugs reduced sucrose consumption dose-dependently. Bilateral electrolytic lesions in the ventral noradrenergic bundle, which deplete hypothalamic noradrenaline, antagonized the effect of 1.25 mg/kg d-amphetamine on sucrose intake. A dose of 2.5 mg/kg d, 1-propranolol, a beta adrenergic blocker, prevented the effect of 10 mg/kg salbutamol but the dose of 5 mg/kg did not significantly change the effect of 0.6 or 1.25 mg/kg d-amphetamine. Captopril (35 mg/kg) reduced salbutamol's effect on water intake, but not on sucrose intake. Metergoline, 1 mg/kg, a central serotonin antagonist, but not xylamidine 2 mg/kg, a 5HT antagonist with limited access to the brain, counteracted the effect of 2.5 mg/kg d-fenfluramine on sucrose intake. These findings suggest a role for serotoninergic and adrenergic mechanisms in inhibiting ingestive behaviour maintained mainly by taste.
A 7-day treatment with 20 mg/kg/day desipramine reduced the immobility time in the behavioral "despair" test in rats. The effect of DMI was antagonized by sulpiride (100 mg/kg i.p.), metoclopramide (20 mg/kg i.p.) and clopazine (20 mg/kg i.p.) but not by haloperidol (0.5 mg/kg i.p.) or chlorpromazine (5 mg/kg i.p.). Alpha-adrenoreceptor blockers (prazosin 3 mg/kg s.c.; aceperone 10 mg/kg i.p.; azapetine 24 mg/kg s.c.; phentolamine 20 mg/kg i.p.), dl-propranolol (5 mg/kg i.p.) and clonidine (0.1 mg/kg i.p.) failed to modify the anti-immobility effect of DMI. The data suggest that a particular subtype of dopamine receptors is involved in the anti-immobility effect of a 7-day treatment with DMI in the behavioral "despair" test in rats.
First, it was confirmed that bilateral lesions in the basolateral region of the amygdala (ABL) of the rat increased the time spent eating novel as compared to familiar food in a food preference test, and that the lesions impaired learned taste aversion to a sucrose solution which had been paired with lithium chloride. Then the roles of noradrenaline and serotonin in the amygdala in these aspects of food intake were investigated. In Experiment 2, it was shown that injections of 10 and 20 nmoles of noradrenaline (NA) into the ABL increased the time spent eating familiar food in the food preference test. Higher doses of NA (50 and 100 nmoles) increased the total time spent eating without changing the preference of the rats for familiar or novel food, and produced behavioral side effects. Serotonin (5HT) injected into the ABL in doses of 10, 50 and 100 nmoles did not modify the pattern of choice of the foods. In Experiment 3, it was shown that depletion of NA in the ABL with 10 micrograms 6-hydroxydopamine did not alter the level of feeding of novel and familiar foods, but did impair taste aversion Depletion of 5HT in the ABL with 10 micrograms 5,7 dihydroxytryptamine did not alter food preferences or impair the taste aversion learning. The depletions of NA and 5HT were confirmed biochemically. These results provide further evidence for a role of the amygdala in preferences for novel as compared to familiar foods and in learning that the ingestion of a food is associated with sickness, and suggest that noradrenaline but not serotonin in the amygdala is involved in these types of control of food intake.
d-Amphetamine and d-fenfluramine caused different patterns of disruption in a learned maze performance reinforced with food. A 0.8 mg/kg dose of amphetamine increased correct and incorrect (errors) alley entrances as well as earned reinforcers consumed. Larger doses (1.6-3.2 mg/kg) decreased correct responses, increased errors, and resulted in earned reinforcers not being consumed. Metergoline pretreatment did not reverse these deficits. d-Fenfluramine (1.5 and 3.0 mg/kg) reduced correct responses dose- relatedly with a slight increase in errors after the larger dose; all earned reinforcers were consumed. Pretreatment with metergoline reversed the deficit in correct responses but not the errors. Combinations of d-amphetamine and d-fenfluramine produced greater deficits than each drug separately, with fewer correct responses and an increase in reinforcers earned but not consumed. Metergoline pretreatment before the combination did not reverse these effects but increased alley entrances scored as errors. The results indicate that the d-fenfluramine but not the d-amphetamine deficit relates to a 5-hydroxytryptamine (5-HT) mechanism. Furthermore, the enhanced effect of the combination appears to relate to drug interactions not dependent upon a 5-HT component.