Claire Monier

Effects of dietary alpha-linolenic acid deficiency on neuromuscular and cognitive functions in mice

Mice were fed a diet deficient in alpha-linolenic acid [18:3 (n-3)] or a control diet and the effect of this deficiency was assessed by behavioral and pharmacological measurements. Three weeks before mating female mice were fed a diet containing either peanut oil poor in alpha-linolenic acid (n-3)- or peanut+rapeseed oil rich in alpha-linolenic acid (n-3)+ = controls. Pups, aged 47 to 61 days, fed the same diet as their dams, were used for behavioral experiments. Muscular function and neuromuscular coordination assessed by the traction test, the elevated rotarod test and swimming endurance were unchanged by the (n-3)- deficiency. The level of anxiety assessed by the elevated plus-maze (anxiety protocol), the light-dark transition and the neophobia tests did not differ between (n-3)- and control (n-3)+ mice. Defensive behavior was not changed by the diet. The pentobarbital-induced loss of the righting reflex had the same duration in males, females, and controls as in (n-3) deficient mice; the latency to pentobarbital-induced loss of the righting reflex was significantly shorter in females than in males but did not differ according to the diet. Mice fed the (n-3)- deficient diet showed less efficient learning in the elevated plus-maze (learning protocol) and poorer understanding of the situation (or less motivation to escape) in the low rotarod test than mice fed the control (n-3)+ diet.

Effect of dietary α-linolenic acid deficiency on habituation

Abstract Three weeks before mating, two groups of SWISS OF 1 mice were fed a diet that was similar but contained either peanut oil poor in alpha-linolenic acid [18: 3 (n-3)] (n − 3 deficient = deficient mice = (n-3)−) or peanut + rapeseed oil rich in alpha-linolenic acid (n − 3 nondeficient = controls = (n − 3)+). Pups, fed the same diet as their dams, aged 45 to 62 days were used for brain lipid analysis and for behavioral experiments, aimed at determining whether there is a relation between the dietary intake of alpha-linolenate and a simple form of learning: habituation. The behavior of mice was compared using four models: exploration recorded in a photocell actimeter, activity in an open-field, duration of immobility in the forced swimming test and number of escape attempts from a small closed space. Habituation was measured by testing the mice in the same situation after some time had elapsed since the first test. Exploration in the photocell actimeter was significantly reduced between day 1 and 4 in nondeficient mice, but, not in deficient mice. The number of square crossings in the open-field was significantly reduced on the second test neither in the control nor in the deficient mice. In the forced swimming test, the habituation (increase in duration of immobility) was significantly greater (255%) in nondeficient than in deficient mice (163%) In the escape attempt experiment, the habituation showed a trend to be greater in controls than in deficient mice (p = 0.061) and was significantly greater in females than in males (p = 0.028) These results suggest that a simple form of learning, habituation, occurs more slowly in mice fed a diet deficient in alpha-linolenic acid.

Influence of a dietary α-linolenic acid deficiency on learning in the Morris water maze and on the effects of morphine

Female OF1 mice were fed on a diet deficient in alpha-linolenic acid or on a control diet 3 weeks before mating and throughout pregnancy and lactation. Pups fed on the same diet as their mothers were used for experiments. The effects of dietary alpha-linolenic acid deficiency were studied in a model of learning, the Morris water maze, and on the following effects of morphine: increase in locomotor activity, modifications of rectal temperature and analgesia. In the place and in the cue versions of the Morris water maze, learning occurred at the same speed in the two diet groups; however, in the place version of the test, the level of the performance was significantly lower in the deficient mice. The probe trial and the extinction procedure did not show any difference between the two diet groups. The morphine-induced increase in locomotor activity occurred significantly earlier and was greater in the deficient diet group. Morphine induced an early hypothermia followed by a late hyperthermia; the hypothermia was significantly greater and the hyperthermia significantly smaller in the deficient mice. The pain thresholds and the morphine-induced analgesia were unmodified by the dietary deficiency. The plasma levels of morphine were similar in the two diet groups.

Isolation impairs place preference conditioning to morphine but not aversive learning in mice

Abstract Morphine (8–100 mg/kg IP) induces place preference conditioning in mice. The effect of two different periods of isolation (15 and 30 days) was examined. Mice isolated for 15 days but not 30 days exhibited place preference conditioning to morphine (8 mg/kg). After 30 days of isolation morphine could not induce place preference conditioning with the following doses (8, 16, 64, 100 mg/kg). Social regrouping of male mice previously isolated for 30 days with naive female mice for 15 or 30 days resulted in a reappearance of the conditioned place preference to morphine (16 mg/kg). The specificity of this associative deficit was examined by testing learning in isolated compared to non-isolated mice in two distinct settings: escape learning in the Morris water maze and passive avoidance acquisition and retention. On the Morris water maze isolated mice did not differ from non-isolated mice regarding place learning, the probe trial or extinction. Isolated mice were unimpaired in passive avoidance acquisition and retention. It was concluded that the deficits in place preference conditioning were not the result of a global learning impairment in isolated mice.

Effect of isolation on pain threshold and on different effects of morphine

1. The effect of three periods of isolation (8, 15 and 30 days) were studied in mice on the pain threshold and the sensitivity to morphine. 2. The pain threshold was unchanged after 8 and 15 days of isolation but increased after 30 days of isolation. 3. The analgesic effect of morphine was unchanged after 8 and 15 days of isolation but increased after 30 days of isolation. 4. The tolerance to morphine analgesia was unchanged after 8 and 15 days of isolation but increased after 30 days of isolation (morphine-induced analgesia was reduced). 5. The physical dependence on morphine induced by precipitated withdrawal was unchanged after 8 and 15 days of isolation but decreased after 30 days of isolation. 6. It is suggested that isolation may modify the metabolism the metabolism/absorption of morphine in a different way according as the treatment is unique or chronic.

Benzodiazepines reverse the anti-immobility effect of antidepressants in the forced swimming test in mice

The present study provides evidence that, in mice subjected to the forced swimming test, the anti-immobility effect of the tricyclic antidepressants, desipramine and imipramine (16-32 mg/kg) was antagonized by the acute co-administration of a benzodiazepine, diazepam (0.25-2 mg/kg) and lorazepam (0.125 mg/kg). This effect cannot be accounted for by variations in plasma and/or brain levels of each compound since brain and plasma concentrations of desipramine and plasma levels of diazepam and desmethyldiazepam, measured immediately after the swimming test, were not significantly modified by the co-administration. Diazepam (2 mg/kg) also counteracted the reduction of time spent immobile induced by the MAO inhibitors, toloxatone (256 mg/kg) and selegiline (4 mg/kg) and the 5-HT1A receptor agonist, 8-OH-DPAT (1 mg/kg), but not by the psychostimulant, caffeine (32 mg/kg). The sedative neuroleptic, thioridazine (4 mg/kg) was also found to reverse the anti-immobility effect of desipramine whereas the non-benzodiazepine anxiolytics, alpidem (8 mg/kg) and buspirone (0.5 mg/kg) did not. These results indicate that the observed interactions were unlikely to be accounted for by a reduction of the stressful aspect of the situation whereas the participation of some motor or sedative component could not be totally ruled out.

Increase in the isolation-induced social behavioural deficit by agonists at 5-HT1A receptors

The effect of 5-HT1A agonists was studied in the isolation-induced social behavioural deficit test. The drugs 8-OH-DPAT (0.125 mg/kg), buspirone (16 mg/kg) and ipsapirone (8 mg/kg) further increased the deficit. Unlike 8-OH-DPAT, the other two drugs may act non-specifically since they reduced spontaneous motor activity at 16 mg/kg, as measured in an activity meter. In addition, 8-OH-DPAT (0.25 mg/kg), buspirone (8 mg/kg) and ipsapirone (8 mg/kg) decreased exploratory activity in the open-field test. Since the smallest active doses were very close in the behavioural deficit and in the open-field tests, it is suggested that a common phenomenon, increased emotionality or reactivity, sustained both these reductions in activity. The increase in the behavioural deficit induced by 8-OH-DPAT, was likely to have resulted from stimulation of 5-HT1A receptors, since it was impaired by pretreatment with penbutolol, a beta-adrenergic-blocking drug, also known to bind to 5-HT1 receptors. Since it was previously shown that the behavioural deficit was reduced by agonists at 5-HT1B receptors, it is proposed that the behavioural inhibition, resulting from an isolation-induced increase in reactivity is bi-directionally modulated by serotonergic drugs, where 5-HT1A agonists increase and 5-HT1B agonists decrease this inhibition.

Isolation increases a behavioral response to the selective 5-HT1B agonist CGS 120 66B

The effect of two serotonergic drugs, CGS 120 66B acting specifically and TFMPP acting preferentially onto 5-HT1B receptors, was compared in preisolated and in pregrouped mice. Two mice put under an inverted beaker attempt to escape. The number of escape attempts of mice preisolated for 7 days was half that of pregrouped mice. In preisolated mice, TFMPP and CGS 120 66B increased the number of escape attempts up to, respectively, 200% and 300% of that of preisolated control mice. In pregrouped mice, CGS 120 66B was nearly inactive and TFMPP exerts a smaller effect. These results suggest that isolation increases the apparent responsiveness to 5-HT1B stimulants.

Benzodiazepines impair a behavioral effect induced by stimulation of 5-HT1B receptors

Seven days of isolation induce in mice a social behavioral deficit (decrease in escape attempts) reversed by TFMPP acting through activation of 5-HT1B receptors. The present experiments were performed to investigate the interaction between tranquillizing drugs and one aspect of the serotonergic functioning through the TFMPP-induced increase in escape attempts. The benzodiazepines diazepam, alprazolam, triazolam and chlordiazepoxide impaired significantly TFMPP-induced increase in escape attempts at behaviorally inactive doses. Buspirone opposed TFMPP effect, but the active doses 4 and 16 mg/kg alone decreased the number of escape attempts. ICS 205-930 in a large dose range (0.001-1 mg/kg) modified neither the number of escape attempts nor the increase induced by TFMPP. Chronic (11 days) treatment with buspirone (16 mg/kg) or ICS 205-930 (1 mg/kg) modified neither the number of escape attempts of isolated mice nor the increase induced by TFMPP. These results suggest that tranquillizing drugs of the benzodiazepines group, but not of other groups, interact with the 5-HT1B receptors; they add to the knowledge of relations between benzodiazepines and serotonin by specifying the involvement of 5-HT1B receptors.

Effect of social isolation on the metabolism of morphine and its passage through the blood-brain barrier and on consumption of sucrose solutions.

Abstract  Rationale: We have previously shown that place preference conditioning to morphine was observed in social mice at the dose of 8 mg/kg, whereas 4 weeks of isolation impairs the place preference conditioning to morphine (8–100 mg/kg). Objective: The present study, aimed at explaining this phenomenon, tested three hypotheses: firstly, a reduced sensitivity to reinforcers induced by isolation; secondly, a difference in morphine disposition in isolated and social mice; thirdly, an altered blood-brain barrier transport of morphine in isolated mice. Methods: In the sucrose experiments, mice had the choice (for 24 h) between a bottle containing tap water and a bottle containing a sucrose solution. Three sucrose concentrations were used: 0.5, 1 and 2% (weight/weight). In the morphine disposition experiments, the plasma levels of morphine and of morphine-3-glucuronide (M3G) were measured for 240 min. The brain concentrations of morphine was measured at 15 and 30 min. The passage of morphine through the blood-brain barrier was measured using a method modified from that of Takasato (1984). Results: The preference for the sucrose solutions was significantly greater in isolated than in social mice for the concentration of 2%. Isolation reduced the plasma levels of morphine and of M3G, but did not alter the brain concentration of morphine. The passage of morphine through the blood-brain barrier was altered by isolation in neither of the eight structures examined. Conclusions: We conclude that the behavioural effect of isolation observed in the conditioned place preference to morphine may depend on changes both in morphine disposition and in the sensitivity to reinforcers in isolated mice.