Lydia Velley

Neurochemical lesion of the locus coeruleus of the rat does not suppress the sedative effect of clonidine

The locus coeruleus of male rats was destroyed bilaterally by injection of 6-hydroxydopamine. Rats injected with the vehicle and normal rats served as controls. Starting 20 days after the lesion, the locomotor activity of all rats was measured for 5 min every day. For the first 6 days, the lesioned rats were significantly less active than control rats; from the 7th to the 15th day, on the other hand, the locomotor activity of the two groups of rats was the same. From the 16th day onwards, the sedative effect of small doses of clonidine (2.5-100 micrograms/kg) was measured in lesioned and control animals. In spite of an almost total loss of noradrenaline in the cerebral cortex and hippocampus and a 33% loss of noradrenaline in the brain-stem of the lesioned rats, the sedative effect of clonidine was the same as in the control rats. This result suggests that the sedation produced by clonidine is not dependent on presynaptically located alpha 2-adrenoceptors.

Increase of the aversive value of taste stimuli following ibotenic acid lesion of the central amygdaloid nucleus in the rat

Male Sprague-Dawley rats received bilateral ibotenic acid lesions of the central amygdaloid nucleus (CeA) and were compared to sham-lesioned rats in their response to different concentrations of saccharin and quinine solutions. In two-bottle choice test situation, the lesioned rats exhibited a lower saccharin preference at concentrations of 2.5; 7.5 and 25 mM, while their aversion towards quinine and the highest concentration of saccharin (50 mM) was increased. In a one-bottle test, the lesioned rats showed consistent decreases in their consumption of 2.5 and 7.5 mM saccharin solutions whereas their intake of 0.9 mM solution of saccharin was equal to that of the sham-lesioned rats. The lesion of the CeA had no significant effects on the acquisition of conditioned taste aversion. There was less postoperative weight gain in lesioned rats as compared to sham-lesioned animals but the lesion had no significant effect on daily water intake. These findings suggest that the CeA plays an important role in the normal response to exteroceptive food stimuli via modulation of the aversive value of taste stimuli. The results are discussed in the context of an interaction between the CeA and the lateral hypothalamus (LH) in the modulation of palatability and feeding behavior.

Neurochemical lesion of the nucleus locus coeruleus increases neophobia in a specific exploration task but does not modify endocrine response to moderate stress

In order to test more specifically the role of the nucleus locus coeruleus (LC) in reaction to novelty, rats with bilateral 6-hydroxydopamine lesions of this nucleus, vehicle injected rats and non-operated animals were tested in the open-field and in the Hughes apparatus where motor activity is recorded in both a familiar and a non-familiar environment. In the open-field, the LC lesioned animals were significantly less active. A similar decrease of locomotor activity was observed in the Hughes test: the number of passages between the two boxes of the LC lesioned rats was significantly decreased. Likewise when the locomotor activities in the two boxes were pooled, the activity of the rats with lesions was significantly lower than the activity of the control rats, but in this case the locomotor deficit appeared only in the familiar box, the locomotor activity in the novel enclosure being the same in both LC lesioned and control animals. This result suggests that exploratory induced locomotion is not disturbed by the locus coeruleus lesion. The significant locomotor deficit showed by the LC lesioned rats in the familiar box could be due to an increased immobility induced by the stressful situation. Moreover, the deficit observed was the same whether the behavioral test began 4 days or 4 weeks after the lesion. Finally, at the end of the experiment, all rats were submitted to a moderate novel environmental stress and blood samples collected to measure the plasma levels of different stress hormones (ACTH, glucocorticoids, PRL, catecholamines).(ABSTRACT TRUNCATED AT 250 WORDS)

Intrinsic neurons are involved in lateral hypothalamic self-stimulation

The recent technique of using ibotenic acid to lesion selectively local neurons while sparing fibers of passage permitted us to answer a long-standing question: is lateral hypothalamic self-stimulation supported by fibers of passage or are the intrinsic hypothalamic neurons involved? Three groups of adult male Sprague-Dawley rats were used. In a normal group, electrodes were bilaterally implanted in the lateral hypothalamus and self-stimulation (ICSS) was obtained separately with the right and left electrodes, at various current intensities, using a nose-poke response. In the experimental group, the intrinsic neurons of the lateral hypothalamus were destroyed unilaterally by local injection of ibotenic acid (4 or 6 micrograms in 0.5 microliter); the other side served as the sham-lesion control. Ten days later ICSS electrodes were implanted bilaterally, one in the lesioned area, the other in the contralateral hypothalamus. As in the case of the normal animals, the rate of nose-poking (ICSS) was then determined separately for each electrode. In the normal rats, ICSS rates were the same with stimulation on either side and the increase in ICSS rate as a function of the increase in current intensity was the same on each side. In the experimental rats, ICSS of the lesioned side was decreased in all cases; moreover, after lesion with the 6 micrograms dose, ICSS was totally suppressed. Self-stimulation of the sham-lesioned side was not significantly different from that observed in the normal rats. In 6 rats sampled from the lesioned groups as well as in 3 additional unimplanted animals, biochemical assays compared dopamine and serotonin contents of the two striata and noradrenaline and serotonin contents of the two hippocampi. No difference was observed for these two structures between the side ipsilateral to the lesion and the contralateral side. Moreover, none of these monoamine levels differed from those seen in the unimplanted rats. These results, taken together, suggest that intrinsic lateral hypothalamic neurons are involved in ICSS.

Gustatory preference-aversion thresholds are increased by ibotenic acid lesion of the lateral hypothalamus in the rat

The main purpose of this study was to quantitate possible changes in the rewarding and aversive values of certain gustatory stimuli produced by bilateral ibotenic acid lesions of the lateral hypothalamus in the rat. Non-operated rats served as controls. Thirteen days after the operation, rats were placed on a water-deprivation schedule during 5 consecutive days. Rats were then given the choice of one of 5 concentrations of saccharin solution, using a two-bottle procedure. Fluid intake across concentrations generated a preference-aversion curve. The same type of procedure was used to obtain the aversion curve for increasing concentrations of quinine solution. The lesioned rats as well as the control animals showed a clear preference-aversion response to saccharin solutions and an aversive response to quinine solutions. However, the highest preference score of the lesioned rats was obtained with a saccharin concentration 3 times higher than the concentration preferred by the control rats. Moreover, unlike control rats operated animals did not show aversion to the highest concentrations of saccharin solutions. Finally in the lesioned rats the aversion threshold to quinine solutions was obtained with concentration 5 times higher than the concentration inducing aversion in the control rats. At the end of these experiments, rats used as controls were submitted, in turn, to bilateral lesion of the lateral hypothalamus. The change in the preference-aversion threshold of these rats in the saccharin choice procedure was the same as that observed with naive rats. Taken together, these results suggest that in the normal rat the palatability of certain gustatory stimuli is modulated by the intrinsic neurons of the lateral hypothalamus.

Modulation of saccharin preference by morphine and naloxone: Inversion of drug effects as a function of saccharin concentration

The aim of the present study was to verify and extend a recent, isolated observation showing that, in rats, a moderate dose of morphine may induce either an increase or a decrease in preference for saccharin, the direction of the response depending apparently on the concentration of the sweetener. Two experiments were performed successively. First, we showed that the preference threshold for saccharin (0.3 mM, two-bottle procedure) of rats placed on a schedule of restricted water access was significantly decreased following injection of 1 mg/kg of morphine. In the second experiment, three groups of naive rats were submitted to the preference test but the concentration of saccharin solution was different for each group, namely 0.3, 1 and 1.7 mM. After stabilization of the baseline responses the effect of morphine (1 mg/kg) was tested in each of the 3 groups. As observed previously morphine decreased the preference of the rats tested with the 0.3 mM solution, but markedly increased the preference of the two other groups tested with the 1 and 1.7 mM solutions respectively. The effects of low doses of naloxone (0.01, 0.1 and 1 mg/kg) were then tested on the same groups of rats with the same saccharin concentrations. The 0.01 mg/kg dose of the antagonist increased the preference for the groups of rats tested with the 0.3 and 1 mM solutions. The other two doses of naloxone decreased saccharin intake whatever the saccharin concentration used. It is suggested that these apparently paradoxical effects of morphine and naloxone could result either from the stimulation of opioid autoreceptors or from the differential stimulation of different opioid receptor subtypes.

Electrical self-stimulation in the parabrachial area is depressed after ibotenic acid lesion of the lateral hypothalamus

The involvement of lateral hypothalamic intrinsic neurons on electrical self-stimulation of the parabrachial area was analyzed. Rats were bilaterally implanted in the parabrachial area and with a guide cannula located above each lateral hypothalamus. They were subsequently tested for intracranial self-stimulation. Then, the lateral hypothalamus on one side of the brain was injected with ibotenic acid. The effect of the induced lesion was tested 8 days later on self-stimulation of the ipsilateral and contralateral parabrachial areas. The intrinsic neurons of the non-lesioned lateral hypothalamus were then destroyed with ibotenic acid. Self-stimulation was then tested 8, 12 and 30 days later. The unilateral lesion produced a significant decrease of self-stimulation using the electrode ipsilateral to the lesion, without any modification of the stimulation using the contralateral electrode. After bilateral lesion, self-stimulation was greatly reduced bilaterally. The results suggest that the main effect of the lesion was to increase the self-stimulation threshold. Given that the parabrachial area is a relay station for the gustatory inputs and that the intrinsic neurons of the lateral hypothalamus project back to the parabrachial area, the present results are tentatively interpreted as an indication that self-stimulation in this pontine area results from the activation of feedback loops between the lateral hypothalamus and the parabrachial area.

Locomotor activity of rats after stimulation of the nucleus locus coeruleus region or after lesion of the dorsal noradrenergic bundle: Effects of clonidine, prazosin and yohimbine

We previously showed in the rat that electrical stimulation of the nucleus locus coeruleus produced, 4 weeks later, a significant increase in the number of α1 and α1 in the cerebral cortex. In a parallel pharmacological study, we tested the effects of small doses of clonidine on the locomotor activity of stimulated rats and implanted but not stimulated animals. In stimulated rats only, clonidine had a dual effect: firstly, sedation 30 min after injection, and secondly, hyperactivity which was observed 24 h after injection. In the present study, using the same behavioral paradigm, we tested the effects of small doses of clonidine on the locomotor activity of three groups of rats: stimulated in the locus coeruleus, lesioned in the dorsal noradrenergic bundle and controls. In stimulated rats injected with clonidine, delayed hyperactivity appeared 24 h after the injection, beginning at the smallest dose used (2.5 μg/kg). This hyperactivity was not due to the stimulation per se, since it did not appear in stimulated rats injected with the vehicle. In rats with dorsal noradrenergic bundle lesions, this delayed hyperactivity was observed only after a high dose (50 μg/kg) of clonidine. In a second experiment, we tested the effect of small doses of prazosin or of yohimbine on the delayed, drug-induced, hyperactivity of stimulated or lesioned rats. In stimulated rats, prazosin (an α1-adrenoceptor antagonist) suppressed the hyperactivity produced by clonidine. Yohimbine (an α2-adrenoceptor antagonist) markedly increased the locomotor activity of stimulated rats injected with vehicle. Likewise, in lesioned rats, prazosin suppressed the hyperactivity produced by a dose of 50 μg/kg of clonidine. These results are interpreted in relation to the possible role of α-adrenoceptors in the regulation of locomotor activity.

Ibotenic acid lesion of the lateral hypothalamus increases preference and aversion thresholds for saccharin and alters the morphine modulation of taste

In a previous study we showed that bilateral ibotenic acid lesions of the lateral hypothalamus in rats induced an increase in gustatory preference thresholds for saccharin solutions and which were associated with body weight and daily water intake impairments. The first aim of the present study was an attempt to dissociate the body weight and water intake deficits from the increase in gustatory thresholds. For this purpose we compared the effect of simultaneous bilateral lesions of the lateral hypothalamus with the effect of successive lesions in which each unilateral destruction was separated by a 10-day interval. Rats injected with vehicle only (either simultaneously or successively) served as controls. The two types of lesion produced very similar deficits, namely permanent body weight and water intake decreases, as well as a shift to the right in gustatory preference-aversion functions for saccharin (two-bottle procedure). The second aim of the present study was to analyse the effect of morphine (2 mg/kg SC) on saccharin preference in both lesioned and control rats. It was observed that for moderate and high concentrations of the sweetener morphine increased preference for saccharin over water but this effect was similar in both groups of rats. However, with a low concentration of the sweetener (0.3 mM) morphine clearly induced an opposite effect in the two groups of rats: the significant preference for this concentration shown by the control rats after vehicle injection was converted to a neutral response, whereas the neutral response of the lesioned animals after vehicle injection was transformed by morphine to a significant preference for saccharin over water.(ABSTRACT TRUNCATED AT 250 WORDS)

Localization of lateral hypothalamic neurons projecting to the medial part of the parabrachial area of the rat

We recently showed that electrical self-stimulation registered in the medial part of the parabrachial area, as well as the preference-aversion threshold to saccharin solutions were both significantly altered following ibotenic acid lesion of the lateral hypothalamic neurons. In order to identify the location of the neurons in the lateral hypothalamus directly projecting to the parabrachial area, we injected in the medial part of this area the retrograde tracer wheat germ agglutinin-inactive horseradish peroxidase coupled to colloidal gold. In the lateral hypothalamus a large number of labeled cells was constantly observed. This cluster of cells was located in the middle and posterior parts of the lateral hypothalamic area between the frontal plane corresponding to the posterior third of the ventromedial hypothalamic nucleus and the plane corresponding to the premammillary nuclei. In contrast, the anterior part of the lateral hypothalamus was unlabeled. Since the labeled neurons are located in the same region as those destroyed by our ibotenic acid lesions, the present results strongly suggest that these descending projections, originating in the posterior lateral hypothalamus, are implicated in reward mechanisms elicited from the parabrachial area.