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The aim of the present study was to analyze the effects of morphine injected into the second relay station of the gustatory input pathways, the parabrachial area, on preference for saccharin over water. This study was carried out using both rats whose lateral hypothalamic neurons had been lesioned by ibotenic acid and sham-lesioned rats. As already shown, an 0.3 mM solution of the sweetener, which was clearly preferred over water by the sham-lesioned animals, was neutral for the lesioned rats. The injection of 50 ng of morphine into each parabrachial area transformed this neutral response of the lesioned rats to a clear preference for the sweetener, whereas the preference of sham-lesioned rats for the same solution was converted to an aversive response. Likewise, with a more palatable solution of saccharin (2.5 mM), the injection of 50 ng of morphine decreased the preference of the nonlesioned rats but increased the preference of the lesioned animals. Using the 2.5 mM solution of saccharin, the intraparabrachial injection of higher doses of morphine (100 and 500 ng) did not greatly modify the preference for the sweetener but induced a significant decrease in total fluid intake that was still observed 11 h after the injection of the opiate. These results are discussed: the morphine-induced aversion observed in the nonlesioned rats could be explained either by a specific influence on certain opioid receptors in the parabrachial area or, more probably, by the stimulation of pathways involved in taste or visceral aversive processes and relaving in the parabrachial area. The possible role of the intrinsic cells of the lateral hypothalamus on the responses to the morphine injection is discussed within the context of each of the above hypothesis.

This experiment was carried out in order to investigate the involvement of lateral hypothalamus (LH) in electrical self-stimulation of the central amygdaloid nucleus (CeA). Adult male Sprague-Dawley rats were bilaterally implanted with a guide cannula situated above each LH and with two electrodes in the CeA. Self-stimulation was subsequently obtained separately from both right and left electrodes. The LH was then lesioned unilaterally by ibotenic acid (IBO) injection. Eight days later, the effect of this unilateral lesion on self-stimulation of the ipsilateral and contralateral CeA was tested. Then the neurons of the remaining non-lesioned LH side were lesioned with IBO and self-stimulation was tested 15 days after the second lesion. Both unilateral as well as bilateral lesions of LH produced a significant decrease in CeA self-stimulation rates but had no significant effect on the reward effectiveness. The unilateral lesions did not produce any modification of the rate-intensity function in the contralateral CeA. This lesion-induced depression in performance was reversed by treatment with phenobarbital. These results provide clear evidence that the rewarding effects of CeA electrical stimulation do not result from the activation of the LH outputs and that the apparent decrease in CeA self-stimulation may result from the LH lesion-induced increase in the frequency of epileptiform manifestations that occur following amygdaloid stimulation.

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.

The present study aimed to describe the localization, organization and density of lateral hypothalamic neurones projecting to the central amygdaloid nucleus (CeA) using WGA-apoHRP-Au as a retrograde tracer. In the lateral hypothalamus (LH) a cluster of labelled neurones was located in the middle and posterior parts of this region. This retrograde labelling is organized into perifornical and juxtacapsular subpopulations. These results provide a neuroanatomical basis for the concept that these lateral hypothalamic neurones modulate projections from CeA to pons and brainstem autonomic and gustatory centres which integrate responses related to fundamental and adaptive behaviours, and could be related to self-stimulation behaviour elicited from the CeA.

We showed recently that bilateral ibotenic acid lesions of the lateral hypothalamus (LH) produced three main behavioral disturbances in the rat, i.e., an increase in the gustatory preference and aversion thresholds for saccharin, permanent body weight and water intake deficits, and an alteration of morphine-induced modulation of taste. The two first results could suggest that the modification of the gustatory thresholds and the ingestive deficits are closely interrelated. Given this situation, we hypothesized that, conversely, a brain lesion known to induce obesity and hyperdipsia would therefore decrease the gustatory preference and aversion thresholds for saccharin. In order to test this hypothesis we analyzed the effects of the bilateral lesion of the hypothalamic paraventricular nucleus (PVH) by injection of ibotenic acid (2 μg in each side) on saccharin preference. The main results are as follows: 1) The neurotoxin selectively destroyed parvicellular neurons while the magnocellular cells were spared. 2) In comparison to the normal daily gain in body weight of the sham-lesioned animals, the lesioned rats showed an enhanced weight gain that became significant from the third day after the surgery up until the day of sacrifice, 37 days later. 3) In contrast to electrolytic lesions of the PVH, the ibotenic acid lesions of this nucleus did not induce hyperdipsia. 4) Preference and aversion thresholds for saccharin were not significantly modified by the lesion. 5) Whereas low doses of morphine suppressed the preference for saccharin in sham-lesioned rats when the concentration of the sweetener solution was at the threshold value, this suppressive effect was not observed in PVH-lesioned rats. Taken together, these results do not provide clear support for our working hypothesis, since the moderate obesity produced by the PVH lesion did not markedly modify the preference and aversion thresholds for saccharin. Two hypotheses are proposed in order to explain these data.

Methionine (Met5)-enkephalin has been implicated in autonomic functions involving vagal reflexes within the nucleus of the solitary tract (NTS). We examined the light and electron microscopic relationships between neurons containing methionine (Met5)-enkephalin-like immunoreactivity (MELI) and vagal afferents and motor dendrites in the rat NTS. A polyclonal antibody raised against Met5-enkephalin and showing maximal cross-reactivity with this peptide was localized by immunoautoradiography. In the same sections, vagal afferents and motor neurons were identified by histochemical detection of anterogradely and retrogradely transported horseradish peroxidase (HRP). By light microscopy, the MELI was detected in perikarya distributed principally in the dorsomedial, intermediate and parasolitary subdivisions of the NTS. These subnuclei as well as medial and commissural divisions of the NTS also showed: (1) aggregates of silver grains thought to overlie terminals containing MELI, and (2) anterogradely transported HRP in varicose processes. Electron microscopic analysis of the dorsomedial NTS at the level of the area postrema established that MELI was detectable in perikarya, dendrites, and axon terminals. Most of the MELI was associated with large dense core vesicles (dcvs). These opioid terminals formed primarily symmetric synapses on proximal and asymmetric synapses on distal dendrites. Analysis of the dendritic targets of terminals containing MELI revealed that 13/222 were in synaptic contact with dendrites also containing MELI. The remainder of the terminals containing MELI either lacked recognized junctions or formed synapses with unlabeled dendrites. In comparison to the terminals containing MELI in the same series of sections, anterogradely labeled vagal terminals extensively formed asymmetric junctions with distal dendrites and spines. Of the observed anterogradely labeled terminals 6/84 formed synapses with dendrites containing MELI and 3/84 with dendrites containing retrogradely transported HRP. The remainder of the junctions were with dendrites lacking detectable immunoautoradiographic or HRP-labeling. The majority of the recognized synapses on labeled dendrites were at more proximal sites possibly reflecting more limited detection of both MELI and retrogradely transported HRP in smaller dendrites. However, the presence of even a few junctions at proximal sites on dendrites where synaptic transmission is known to be more effective suggests a potentially strong modulation of both opioid and vagal motor neurons by visceral afferents in the NTS. In addition to forming synapses on dendrites, both vagal afferents and terminals containing MELI showed frequent synaptic associations with unlabeled terminals, but not with each other. This finding suggests that the previously demonstrated opiate binding sites on vagal afferents is most likely attributed to other endogenous opiates.

The aim of the present study was to verify and extend a recent, isolated observation showing that, in rat, 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 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 results either from the stimulation of opioid autoreceptors or from the differential stimulation of different opioid receptor subtypes.

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. These results are discussed and in particular suggest that endorphinergic neurons located in the lateral hypothalamus are implicaed in the modulation of palatability.

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.

This paper summarizes some behavioral and neurochemical data relating to the delayed effect of locus coeruleus stimulation on the learning capabilities of the rat. The first observation showed that electrical stimulation of the locus coeruleus of a 15-day-old rat improved the acquisition and extinction of a food-reinforced operant task performed 4 weeks later. The neurochemical lesion of the dorsal noradrenergic bundle, 10 days before the stimulation, did not decrease the behavioral effect, whereas the neurochemical lesion of the locus coeruleus proper suppressed the improvement. Furthermore, we studied the long-term effect of the stimulation on some biochemical parameters of the coerulean system: First, the turnover of noradrenaline increased in the locus coeruleus 4 days after the stimulation, whereas it decreased 4 weeks after the treatment in the nucleus proper and in the hippocampus. Second, 4 weeks after the stimulation, the characteristics of some adrenoceptor populations were significantly changed, in particular regions of the brain. The number of α2-adrenoceptors was increased in the cortex, the hippocampus, and particularly the hypothalamus. The number of α1-adrenoceptors was increased in the cortex. Neither the number nor the affinity of β receptors was altered by the stimulation. Likewise, the number of α1-, α2-, and β-adrenoceptors in the brainstem was not changed. These results are discussed. To explain our behavioral data, we assume that the performance improvement in prestimulated rats is due, for the most part, to a reduced reaction to stressful situations. On this basis, the stress-reduction hypothesis is tentatively related to the binding data showing that the most significant increase of the α2-receptors was observed in the hypothalamus.

The reported experiments point out the effect of an imposed electrical stimulation of the lateral hypothalamus, the substantia nigra, and the locus coeruleus, in 15-day-old-rats of the Sprague-Dawley strain, on the acquisition of a food-reinforced operant conditioning performed at the 42nd day of age. The improvement observed after lateral hypothalamic stimulation confirms our previous results. The stimulation of substantia nigra has no effect. On the contrary, the animals stimulated in locus coeruleus showed the same improvement of learning as the lateral hypothalamus-stimulated animals. The identity of the implicated neural systems in both the lateral hypothalamus and locus coeruleus stimulations is discussed.

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.

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.

Single or combined neurochemical lesions of the locus coeruleus, the dorsal and the median raphe nuclei were performed on different groups of rats. Starting 10 days after the lesion, the locomotor activity of all rats was measured for 5 min every day in an open-field. For the first 21 days all lesioned rats, independently of the lesion site, were significantly less active than controls, but from the 11th to the 16th day the locomotor activity of lesioned animals increased progressively and, thus on days 15 and 16, the mean activity of all lesioned groups was not significantly different from that of the controls. From the 17th day onwards the sedative effect of small doses of clonidine (5-100 micrograms/kg) was measured. Neither single nor combined lesions modified the response to clonidine and the linear decrease of activity produced by increasing doses of clonidine was the same in all groups, lesioned or not. Biochemical assays showed a marked loss of corresponding amines as a result of the lesions in cortex, hippocampus and the brainstem. These results suggest that the alpha 2-receptors involved in clonidine-induced sedation are located neither on noradrenergic fibers coming from the locus coeruleus, nor on serotoninergic fibers originating in the median and dorsal raphe nuclei.

The aim of the present study was to analyse the involvement of neurons located in some basal forebrain areas in electrical self-stimulation elicited from the middle part of the lateral hypothalamus. The anterior hypothalamic region was unilaterally lesioned by local injection of ibotenic acid. Ten to 20 days later 4 electrodes were implanted bilaterally, two at the lesion level and two in the middle lateral hypothalamus. A small but significant self-stimulation deficit was observed in the lesioned area, while self-stimulation on the contralateral side was normal. At the middle lateral hypothalamic level, no deficit was observed when stimulation was applied either ipsilaterally or contralaterally to the anterior lesioned side. In most cases the lesion destroyed the dorsolateral part of the lateral preoptic area, the ventral pallidum-substantia innominata complex and the lateral part of the bed nucleus of the stria terminalis. Given the fact that these regions are known to project massively to the middle lateral hypothalamic area, our data suggest that descending influences originating in the damaged regions are not involved in self-stimulation elicited from the middle hypothalamus.

Resume Les experiences rapportees etudient les effects d'une stimulation electrique imposee de l'hypothalamus lateral de rats âges de 15 jours sur l'acquisition et l'inversion d'une discrimination lumiere-obscurite avec renforcement alimentaire, effectuees entre les âges de 42 et 82 jours. Lors de l'acquisition comme de l'inversion, les animaux stimules presentent des performances ameliorees par rapport a celles des rats implantes mais non stimules et des rats non implantes.

Three experiments indicated the effects of an early bilateral stimulation of the lateral hypothalamus on later learning behaviour of male rats. The animals were stimulated at 15 days of age and tested during the sixth week of life. Stimulated rats showed an improvement of performances in acquisition of a food-reinforced operant conditioning, but their performance was impaired in two avoidance tests, an inhibitory avoidance response and a two-way avoidance test. These results cannot be interpreted in terms of handling or early experience. An hypothesis of a modified synaptic competition favouring circuits which assure the regulation of approach behaviours is formulated.

We investigated the effect of electrical stimulation of certain aminergic structures on the acquisition and extinction of a food-reinforced operant-conditioning task performed 4 weeks later. Thirteen-day-old male rats of the Sprague-Dawley strain were bilaterally implanted in one of the following structures: hypothalamus, nucleus locus coeruleus, dorsal raphe nucleus, or median raphe nucleus. The stimulation was applied at 15 and 16 days of age. From Day 42 or 43 onward, acquisition and extinction of an operant task were carried out. As in our previous reports, lateral hypothalamic and locus coeruleus stimulation produced a significant improvement in performance from the very beginning of the acquisition session. In these two groups of stimulated rats, the speed of extinction also increased. The stimulation of the two midbrain raphe nuclei produced about the same degree of enhancement of acquisition as of extinction, although the improvement in the performance of these stimulated rats was not as great as the facilitation observed after stimulation of the lateral hypothalamus or the locus coeruleus.

Resume La premiere experience montre une mise en place progressive du comportement d'autostimulation, entre l'ouverture des yeux et l'âge adulte, et un dimorphisme sexuel, les femelles s'autostimulant beaucoup moins que les mâles, en particulier aux âges de 30 et 45 jours. La seconde experience montre que, chez le rat mâle, l'evolution ontogenetique du comportement d'autostimulation est due, pour l'essentiel, a une baisse progressive du seuil de sollicitation des structures stimulees.

We previously showed that electrical stimulation of the nucleus locus coeruleus resulted 4 weeks later in greatly improved performance in the acquisition and extinction of a food-reinforced operant task. To ascertain whether adrenergic receptors of particular brain regions were involved in this long term behavioral modification, we studied the characteristics of alpha 1, and alpha 2 and beta-binding sites after stimulation of the locus coeruleus. In the first experiment these characteristics were studied, 4 weeks after treatment, in cortex, hippocampus, hypothalamus and the brainstem. Neither the number, nor the affinity of beta-receptors ([125I]iodocyanopindolol binding sites) was modified in any brain region. A significant increase in the number of alpha 1-receptors ([3H]prazosin binding sites) was observed in the cortex (62%). The number of alpha 2-receptors, ([3H]yohimbine binding sites), was significantly increased in cortex (99%), hippocampus (33%) and hypothalamus (113%). No significant alteration of the alpha 1, alpha 2 and beta-adrenoceptors was observed in the brainstem. To investigate the time course of these adrenoceptor changes, the characteristics of alpha 1, alpha 2 and beta-adrenoceptors were studied 2 weeks after stimulation using the same ligands and in the same brain regions. The only significant modifications observed were an increase of the alpha 2-adrenoceptors in the cortex (19.4%) and in the hypothalamus (54%). Furthermore, in both experiments, the increase in the number of alpha 1 and alpha 2-receptors was associated with a significant decrease in affinity. These results are discussed in relation to our previous behavioral and pharmacological findings.

Two experiments point out the effect of an early stimulation of the lateral hypothalamus on later behavior of rats. Stimulated at 15 days of age, animals showed an improvement in both acquisition of a food reinforced operant conditioning (two different proceedings) and extinction of this conditioning, studied during the sixth week of age. The results are discussed in terms of a high plasticity of the central nervous system at time of the stimulation.

The aim of the present study was to compare the self-stimulation deficit produced by a unilateral injection of the neurotoxin, ibotenic acid, in the lateral hypothalamus (LH) to the deficit produced by the same unilateral injection in the medial prefrontal cortex (MPC). Four groups of adult male Sprague-Dawley rats were used: in two control groups, electrodes were bilaterally implanted in the LH (5 rats) or in the MPC (6 rats) and self-stimulation (ICSS) was obtained separately with the right and left electrodes. In the two experimental groups the intrinsic neurons of the LH (8 rats) or of the MPC (10 rats) were destroyed unilaterally by local injection of ibotenic acid (4 micrograms in 0.5 microliter); the other side served as the sham-lesioned control. Ten days later ICSS electrodes were implanted bilaterally, one in the lesioned area, the other in the contralateral region. As in the case of the control rats, ICSS was determined separately for each electrode, first by a rate dependent test (nose-poke) then by a 'rate-free' test (shuttle-box). In the LH and MPC control rats, ICSS responses were the same with stimulation on either side. In the LH-lesioned rats, the ICSS rates measured with the nose-poke test were significantly decreased with stimulation on the lesioned side, whereas rates with stimulation of the non-lesioned LH were normal. Likewise, while shuttle responses with stimulation of the non-lesioned LH were normal, the OFF-time was increased and the ON-time was decreased with stimulation of the lesioned LH. In the MPC-lesioned rats, ICSS (nose-poke) was totally suppressed and the shuttle responses were disorganized since neither the ON- nor the OFF-times changed in response to increasing current intensities. Nose-poke responses with stimulation of the non-lesioned MPC were just about normal. These results show that in the two brain regions studied local neurons are involved in ICSS. The difference in the magnitude of the deficit observed suggests, that the neuronal circuits involved in MPC self-stimulation are poorly represented whereas in the LH many neuronal circuits involved in these mechanisms overlap.

We previously showed that electrical stimulation of the nucleus locus coeruleus was followed 4 weeks later by a greatly improved performance in the acquisition of a food-reinforced operant task. To ascertain whether adrenergic receptors were involved in this long-term behavioral modification, we studied the characteristics of the alpha 1, alpha 2, and beta-adrenoreceptors of the cerebral cortex 4 weeks after stimulation of the locus coeruleus. This stimulation induced a slight (14%) but significant increase in the number of alpha 1-receptor [(3H) WB 4101 binding sites] as well a rise in the number of alpha 2-receptor [(3H) clonidine binding sites]. The latter rise mainly affected high-affinity alpha 2-receptor sites (36%) and the number of low-affinity sites remained unchanged. No significant alteration in the number of beta-receptors [(3H)-dihydroalprenolol binding sites] was observed. To confirm this biochemical result, the effect of very small doses of clonidine (1, 2.5, 5 and 10 micrograms/kg) was tested on locomotor activity in the open-field. In rats stimulated 4 weeks before injection, clonidine induced a biphasic effect, comprising firstly sedation which occurred 30 min after injection, and secondly, long-term hyperactivity which began 24 h injection. For the 5 micrograms/kg dose, this rebound of activity was detectable 8 days after injection. In implanted, control rats, only the sedative effect was observed. These findings are interpreted in relation to the current theories about alpha-adrenoreceptors.

In previous studies we showed that electrical stimulation of the lateral hypothalamus of 15 day old rats significantly enhanced the learning of various tasks examined 4 weeks later. We first demonstrated that this stimulation improved the acquisition and extinction of a food-reinforced task (Velley and Cardo, 1977). In subsequent experiments, we observed the same effect on the acquisition and reversal of a light-dark discrimination whether appetitively or aversively reinforced as well as on the acquisition of a one way avoidance task (Velley et al., 1981b).

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.

The intrinsic neurons of the medial forebrain bundle were unilaterally destroyed, in rats, through local injection of ibotenic acid (4 micrograms in 0.5 microliter). Ten days later, electrodes were bilaterally implanted, one in the lesioned lateral hypothalamus, the other into the contralateral hypothalamus. Firstly, self-stimulation was studied with stimulation of each electrode separately. Later on, the effect of non-contingent electrical stimulation on evoked locomotor activity in the open-field was analysed for each electrode. While self-stimulation of the lesion area was greatly depressed in comparison with the unlesioned lateral hypothalamus, the increase in locomotor activity produced by stimulation, at the intensity applied, was the same whether the stimulated hypothalamus was lesioned or not.

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). Hormone levels were the same in the LC lesioned and normal rats in spite of the fact that a significant loss of noradrenaline (53%) was observed in the hypothalamus of the rats with lesions. This result shows that the locus coeruleus is of minor importance in the control of stress induced neuroendocrine responses.

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.

In previous studies we showed that electrical stimulation of the nucleus locus coeruleus produced, four weeks later, a significant improvement in performance in acquisition of food-reinforced operant conditioning. In the two experiments reported here, we tested the role of the dorsal noradrenergic bundle and of the locus coeruleus proper in this long-term effect. Lesioning the dorsal noradrenergic bundle did not have a clear and consistent effect, whereas lesion of the nucleus coeruleus proper suppressed almost totally the beneficial effect of the stimulation. In the first experiment, the dorsal noradrenergic bundle was lesioned by local bilateral injection of 6-hydroxydopamine, 8 days before stimulation of the locus coeruleus. Four weeks after the stimulation, the rats were tested for acquisition of the operant task. Three control groups were used: not lesioned but stimulated, lesioned but not stimulated, and not lesioned/not stimulated. The locus coeruleus stimulation produced the same improvement of performance at the beginning of the acquisition, whether or not the dorsal noradrenergic bundle had been lesioned. However, a significant decrement of performance was observed in lesioned and stimulated rats during the last 40 min of the acquisition. In the second experiment, the locus coeruleus proper was destroyed by bilateral local injection of 6-hydroxydopamine and the locus coeruleus region was stimulated 15 days later. Three control groups were used, as in the first experiment. All the rats were tested 4 weeks later for acquisition of the operant task. The locus coeruleus lesion significantly attenuated the beneficial effect of the stimulation; however, the performance of the lesioned and stimulated rats was still significantly superior to that of the lesioned but not stimulated rats. These results suggest that the noradrenergic locus coeruleus system is involved in the long-term effect, but that the rostral projections passing through the dorsal bundle, in front of the lesion, are not critically involved in the observed effect.

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.

The purpose of the present study was to compare the consummatory behaviour of rats of the Wistar Kyoto Hyperactive (WKHA) strain, selected for their hyperactivity in a novel environment, with the normoactive Wistar-Kyoto (WKY) rats in three choice tasks: between water and increasing concentrations of saccharin, between water and increasing concentrations of quinine, and between water and a 10% (v/v) ethanol solution. The results of the present study show that: (1) WKHA rats exhibited a significantly higher acceptance of a 10% (v/v) alcohol solution than the normoactive control WKY rats when alcohol solution was the only available fluid; (2) WKHA rats also showed significantly larger alcohol intakes during the 15 days of choice between water and alcohol (WKY: 0.39 +/- 0.05; WKHA: 1.72 +/- 0.26 g/kg/day); (3) as frequently cited in the literature for other strains, the higher level of alcohol ingestion of WKHA rats was associated with a higher preference for saccharin; (4) no strain differences were observed in the water-quinine choice test. The discussion is mainly centred on the small alcohol consumption of the two strains, since the intake of WKHA rats is in the normal range for consumption of outbred strains, while the amount of alcohol consumption of WKY rats is very low and in the range of alcohol intake of non-preferring rat strains. It is concluded that the difference in alcohol consumption is mainly due to the low intake of the WKY rats and it is suggested that their different level of consumption might result from the particular behavioural profile of these rats.