Biomedical subjects

G Di Scala

Publications and source records attributed to G Di Scala.

At least 19 recordsLinked to original sources

PubMed2003

Bilateral lesions of the entorhinal cortex differentially modify haloperidol- and olanzapine-induced c-fos mRNA expression in the rat forebrain.

Lesions of the entorhinal cortex are now an accepted model for mimicking some of the neuropathological aspects of schizophrenia, since evidence has accumulated for the presence of cytoarchitectonic abnormalities within this cortex in schizophrenic patients. The present study was undertaken to address the functional consequences of bilateral entorhinal cortex lesions on antipsychotic-induced c-fos expression. After a 15-day recovery period, the effect of a typical antipsychotic, haloperidol (1 mg/kg), on c-fos mRNA expression was compared with that of an atypical one, olanzapine (10 mg/kg), in both sham-lesioned and entorhinal cortex-lesioned rats. In sham-lesioned rats, both haloperidol and olanzapine induced c-fos expression in the caudal cingulate cortex, dorsomedial and dorsolateral caudate-putamen, nucleus accumbens core and shell and lateral septum. In addition, olanzapine, but not haloperidol, increased c-fos expression within the central amygdala. In entorhinal cortex-lesioned rats, haloperidol-induced c-fos expression was markedly reduced in most areas. In contrast, the olanzapine-induced c-fos expression was not altered in the nucleus accumbens shell and lateral septum of the lesioned rats. These findings reveal that entorhinal cortex lesions affect c-fos expression in a compound- and regional-dependent manner. Our results further emphasize the importance of the exploration of the mechanisms of action of antipsychotic drugs in the context of an associated cortical pathology.

Animals↗

PubMed2000

Odor regulates the expression of the mitogen-activated protein kinase phosphatase gene hVH-5 in bilateral entorhinal cortex-lesioned rats.

Since it is known that several immediate early genes are induced by olfactory stimuli, we determined whether an olfactory stimulus also induces the expression of the mitogen-activated protein kinase (MAPK) phosphatase gene hVH-5 (homologue of vaccinia virus H1 phosphatase gene, clone 5), a member of a novel class of immediate early genes encoding dual-specificity protein phosphatases. The expression was studied by in situ hybridization in different brain structures involved in odor processing, in control and bilateral entorhinal cortex (EC) lesioned rats. EC-lesion did not significantly affect hVH-5 gene expression in the glomerular cell layer of the olfactory bulb (OB), while odor stimulation induced it in both control and EC-lesioned groups. In contrast, odor-induced expression of hVH-5 gene in mitral/granular cell layers was only evident after lesion of the EC. Similar results were obtained in the piriform cortex (PCx), a structure intimately connected to the mitral cell layer. In the CA1 hippocampal subfield, odor stimulation induced hVH-5 gene expression in both control and EC-lesioned animals, the increase being potentiated in lesioned rats. CA3 and dentate gyrus exhibited a similar pattern of gene expression, the odor stimulating gene expression in both control and lesioned groups. The amygdala (Am) displayed no significant change. It appears that through the induction of a MAPK phosphatase, the EC controls MAPK activities differently after odor stimulation in OB, PCx and hippocampus (Hip). The results illustrate the notion that odor representation in the brain requires plastic modifications at both anatomical and functional levels.

Amygdala↗

PubMed2000

Restoration of latent inhibition by olanzapine but not haloperidol in entorhinal cortex-lesioned rats.

RATIONALE: Latent inhibition (LI) refers to the decrease in conditioned response induced by the repeated non-reinforced pre-exposure to the conditioned stimulus before its pairing with the unconditioned stimulus during the conditioning stage. LI has been considered as a relevant animal model for the study of the biological bases of schizophrenia. LI has recently been demonstrated to depend on the integrity of the entorhinal cortex, as lesioning of this area disrupted LI. OBJECTIVES: The present study aimed to verify whether the classical neuroleptic haloperidol and/or the atypical antipsychotic olanzapine would prevent the effect of entorhinal cortex lesioning. METHODS: LI was studied in an off-baseline conditioned emotional response (CER) paradigm in which a tone is paired with a footshock. Entorhinal cortex lesions were produced by the electrolytic method. After a recovery period, both lesioned and control rats received either haloperidol (0.3 mg/kg), olanzapine (0.3 mg/kg) or vehicle before both the pre-exposure and conditioning stages of the experiment. RESULTS: In control rats, pre-exposure to the tone induced LI, which was affected by neither haloperidol nor olanzapine. Lesioning of the entorhinal cortex produced a deficit of LI, which was restored by olanzapine but not by haloperidol. CONCLUSIONS: This result suggests a dissociation of the anatomical and pharmacological targets of the two drugs. The possible involvement of dopamine D3 receptors in the effects of olanzapine is discussed.

Animals↗

PubMed2000

Facilitative effects of EGb 761 on olfactory recognition in young and aged rats.

The aim of the present study was to evaluate the effects of chronic and acute treatment by the Gingko biloba extract, EGb 761 (IPSEN, France) on olfactory short-term memory in rats, using a spontaneous recognition procedure. The effects of a daily EGb 761 treatment (30 or 60 mg/kg) over a period of 30 days (Experiment 1) were evaluated in young male rats. Those of a single injection of EGb 761 were assessed either in young male rats at 60 or 120 mg/kg (Experiment 2) or in aged female rats at 60 mg/kg (Experiment 3). Results showed that, at the highest dose (60 mg/kg), chronic EGb 761 treatment enhanced the recognition performances, allowing recognition at delays at which control animals did not show any recognition. Acute treatment enhanced recognition at both doses tested. The results of the third experiment showed that EGb 761 had an overall enhancement effect on the performances of aged rats. In summary, our results provide evidence for a short-term memory enhancement effect of EGb 761 in both young and aged rats.

Age Factors↗

PubMed2000

GABA and muscimol as reversible inactivation tools in learning and memory.

Reversible inactivation of brain areas is a useful method for inferring brain-behavior relationships. Infusion of GABA or of the GABA receptor agonist muscimol is considered one interesting reversible inactivation method because it may not affect fibers of passage and may therefore be compared to axon-sparing types of lesions. This article reviews the data obtained with this method in learning and memory experiments. A critical analysis of data, collected in collaboration with Simon Brailowsky, with chronic GABA infusion is presented, together with an illustration of data obtained with muscimol-induced inactivation.

Animals↗

PubMed2000

Basolateral amygdala NMDA receptors are selectively involved in the acquisition of taste-potentiated odor aversion in the rat.

In the taste-potentiated odor aversion (TPOA) paradigm, animals acquire a strong aversion to an odor that is followed by delayed intoxication only if a gustatory stimulus is presented with the odor during conditioning. Although previous work has shown that N-methyl-D-aspartate (NMDA) receptors in the basolateral nucleus of the amygdala (BLA) play a role in the acquisition of TPOA, the present study aimed at describing the process in which NMDA receptors in the BLA are involved during acquisition of TPOA. Male Long-Evans rats received intra-BLA infusions of the competitive NMDA receptor antagonist D,L-2-2-amino-5-phosphonovalerate (D-APV; 0.05 and 0.50 microg) immediately before or after the odor-taste conditioned stimulus (CS) presentation, or immediately before the test. Results showed that D-APV impaired acquisition of TPOA when infused before, but not after, the CS presentation, but did not affect retrieval. These results suggest that NMDA receptors of the BLA are involved in the formation of potentiation--by taste--of the olfactory memory trace, but not in the maintenance of this process.

Amygdala↗

PubMed1999

Entorhinal but not hippocampal or subicular lesions disrupt latent inhibition in rats.

Latent inhibition (LI) is the deficit of conditioning resulting from repeated nonreinforced preexposure to a conditioned stimulus before its pairing with an unconditioned stimulus. There are cumulative data showing that large lesions of the hippocampal formation disrupt LI. However, the effects of selective lesions of the different components of the hippocampal formation have never been directly addressed in the same study and conditioning paradigm. The first experiment of the present study aimed at investigating the effects of excitotoxic lesions of the hippocampus, subiculum, or entorhinal cortex on LI in an "off-baseline"-conditioned emotional response procedure. Hippocampus or subiculum lesions had no effect on either LI or conditioning. In contrast, entorhinal cortex lesions disrupted LI without modifying conditioning. In Experiment 2, locomotor activity in a novel environment was assessed in the same rats. Whereas lesions of hippocampus increased locomotor activity, lesions of the subiculum or the entorhinal cortex were devoid of effect. Although both LI and habituation to novel environmental cues are thought to involve interactions between the hippocampal formation and the mesolimbic pathway, these results indicate a functional dissociation between the hippocampus and the entorhinal cortex.

Animals↗

PubMed1999

Functional interaction between entorhinal cortex and basolateral amygdala during trace conditioning of odor aversion in the rat.

In rats, conditioned odor aversion (COA) occurs only if the time interval separating the odor from the subsequent intoxication is very short suggesting that the memory trace of the odor is subject to rapid decay. Recent results from our laboratory have found that lesion of the entorhinal cortex (EC), and activation of the basolateral nucleus of the amygdala (BLA) rendered COA tolerant to long interstimulus interval. The present study examined whether the odor memory trace depends on the interaction between the EC and the BLA. Rats lesioned in the EC received infusions of muscimol (a GABA(A) receptor agonist) into the BLA immediately after the odor presentation during acquisition of COA. Injection of muscimol into BLA prevented tolerance of COA to long interstimulus interval induced by EC lesions. This suggests that EC modulates the short-term memory trace of the odor by controlling the GABAergic activity of the BLA during acquisition of COA.

Amygdala↗

PubMed1999

Effect of nonsedative doses of propofol on an innate anxiogenic situation in rats.

BACKGROUND: The effect of propofol on anxiety has not been well studied. In humans, such investigations are confused by the fact that sedation often coexists with anxiolysis. Therefore, the authors evaluated the effects of minimal sedation with propofol in rats placed in an innate anxiogenic situation, the elevated plus-shaped maze. METHODS: In experiment 1, spontaneous locomotor activity was determined in rats as a measure of sedative effect induced by propofol (0-9 mg/kg administered intraperitoneally). In experiment 2, groups of rats received propofol (0-9 mg/kg) or diazepam (0-2 mg/kg) and then were placed on a plus-shaped maze elevated above the ground that was composed of two opposite closed arms and two opposite open arms. On an initial exposure to the maze, undrugged rats avoid the open arms, with the number of entries into and time spent within the open arms constituting approximately 20% of their total activity. This reflects normal anxiety in a rodent for any elevated open platform. RESULTS: In experiment 1, 0-9 mg/kg propofol did not alter spontaneous activity in rats. In experiment 2, propofol and diazepam significantly increased the number of entries into and the time spent within the open arms. Propofol at a dose of 9 mg/kg significantly increased the rats' level of exploration of the open arms to about 50% of all exploratory activity, and a similar observation was made with 2 mg/kg diazepam. CONCLUSIONS: In a standard animal model, propofol has anxiolytic properties at doses that do not produce sedation.

Animals↗

PubMed1998

Facilitation of olfactory recognition by lateral entorhinal cortex lesion in rats.

An original olfactory recognition task was developed in order to examine the effect of lateral entorhinal cortex (LEC) lesion on olfactory mnesic processes. The task was based on the spontaneous exploratory behavior of rats toward odor sources. It consisted of a learning phase during which an odor was presented twice and in a recognition test, during which the same odor plus a new one was presented. The time rats spent sniffing the odor sources was measured. Olfactory recognition was identified by a short investigatory duration for the familiar odor as compared to a normal investigatory duration for the new odor during the test. The first three experiments aimed to validate the procedure. Experiment 1 was designed to show the decay of investigatory behavior caused by repeated exposure of the rats to one odor. Experiment 2 showed that normal rats display recognition when a short (5 or 40 min) pre-test delay was used, but not when a long pre-test delay (120 min) was used. Experiment 3 showed that FG7142, a well-known promnesic drug, enhanced the performance of the rats in this test as it allowed recognition at longer pre-test delays. The last experiment aimed at testing the effects of aspirative lesion of the LEC. Therefore, LEC-lesioned and sham-lesioned rats were submitted to variable pre-test delays. The experiment showed that an entorhinal lesion did not produce an impairment, but on the contrary facilitated olfactory recognition, as lesioned rats displayed recognition for delays at which sham-operated rats did not. These results show that LEC lesion apparently prolongs the duration of the olfactory mnesic trace. This effect might result from a modification of the functioning of structures innervated by the LEC. In this regard, it is noteworthy that LEC lesion produced a sprouting of septo-hippocampal fibers in the dentate gyrus of the hippocampus as assessed by acetylcholinesterase staining. Although the functional significance of this regrowth is not fully understood, the possible role of this sprouting should be considered.

Animals↗

PubMed1997

Bicuculline administration into basolateral amygdala facilitates trace conditioning of odor aversion in the rat.

This study investigated the effect of bicuculline methiodide (BMI) microinjection into basolateral amygdala (BLA) on conditioned odor aversion. Bilateral injections of BMI (39 or 59 pmol/0.2 microliter) or artificial CSF were done in the BLA 5 min after the presentation of the conditioned stimulus (water intake at an almond-scented tube). This was followed 30 min later by lithium chloride-induced toxicosis. Whereas under these experimental conditions control rats (CSF injected) did not develop a conditioned odor aversion, BMI-treated rats (59 pmol) did so, suggesting that the blockade of GABAA receptors facilitated this learning. This facilitation was unlikely due to an unconditioned action of BMI, as a group microinjected with 59 pmol of BMI but not intoxicated did not display conditioned aversion. This result suggest that blockade of the GABAA receptors can prolong the olfactory trace duration, making it accessible to association with delayed toxicosis. Combined with previous results, these data support the hypothesis that the GABAergic system of the basolateral amygdala exerts control over the duration of a short-term odor trace in our conditioned odor aversion paradigms.

Amygdala↗

PubMed1997

Effect of midazolam on propofol-induced positive affective state assessed by place conditioning in rats.

BACKGROUND: The effect of either midazolam or the combination of midazolam and propofol on the affective state was assessed in rats at subanesthetic doses and at recovery from anesthesia. METHODS: The putative drug(s)-induced affective states were repeatedly paired with one of two distinguishable compartments of an experimental cage, whereas the vehicle(s)-induced effect was repeatedly paired with the other compartment. During a subsequent choice test for one compartment over the other, the rats' preference for the drug(s)-paired compartment over the vehicle(s)-paired compartment is indicative of a pleasant state induced by the drug(s). In experiment 1, rats were conditioned with different doses of midazolam either at subanesthetic states or at recovery from anesthesia. In experiment 2, groups of rats were conditioned with different combinations of midazolam and propofol either at subanesthetic states or at recovery from anesthesia induced jointly by midazolam (10 mg/kg) and propofol (60 mg/kg). Experiment 3 was conducted in the same way as experiment 2, except that midazolam was paired with both compartments. In addition, these groups were tested not only in an undrugged state but also in a drugged (with midazolam) state. RESULTS: In experiment 1, rats exhibited a place preference for the environment previously associated with midazolam, at subanesthetic and anesthetic doses. Experiment 2 showed that a propofol-induced place preference was found to be dose-dependently suppressed by midazolam. Experiment 3 replicated the findings of experiment 2 and extended them to the mechanism by which midazolam blocked a propofol-induced place preference. CONCLUSIONS: Midazolam administered before propofol blocked the expression of a propofol-induced pleasant state.

Affect↗

PubMed1996

Amphetamine-induced conditioned activity does not result from a failure of rats to habituate to novelty.

Psychostimulant-induced conditioned activity is characterized by the presence of a hyperactivity in drug-free rats exposed to an environment previously paired with the effects of a psychostimulant. According to the habituation hypothesis, conditioned activity arises not through a Pavlovian conditioning process but rather because rats under the effects of the psychostimulant would be unable to habituate normally to the environment paired with these effects. This hypothesis predicts that conditioned activity should not develop in a previously habituated environment. This prediction was tested using a within-subject design. In this design, conditioned activity is evidenced when a group of rats, following a vehicle injection, was more active in a previously amphetamine-paired environment than in a previously vehicle-paired environment. The drug-environment pairing involved administering rats with d-amphetamine (1.25 mg/kg; SC) immediately prior to their placement in one of two distinctive environments. On alternate days, the rats received the vehicle and were placed in the other environment. With this design, it was found that: a) conditioned activity developed in a previously habituated environment; b) its magnitude was independent of the number of amphetamine-environment pairings (two, four or eight pairings); c) this development of conditioned activity did not result from a forgetting of the habituated environment due to a state-dependent retention of the habituation. Taken together, these results do not support the habituation hypothesis of psychostimulant-induced conditioned activity.

Animals↗

PubMed1996

Facilitation of conditioned odor aversion by entorhinal cortex lesions in the rat.

This study examined the role of the entorhinal cortex (EC) in conditioned odor aversion learning (COA). Lateral EC lesions did not impair but rather facilitated COA. In the experiments the delay separating the odor cue presentation from the subsequent toxicosis was varied during acquisition. EC-lesioned rats demonstrated COA for delays up to 2 hr, whereas sham-operated rats displayed COA only if toxicosis immediately followed the odor cue. This facilitation was not dependent on the intensity of the odor and corresponded to a facilitated long-delay learning. EC lesion did not affect conditioned taste aversion, confirming that the facilitation effect does not correspond to a general facilitation of conditioned aversion learning. Taken together, these results indicate that the removal of the EC may allow odor-toxicosis associations across longer delays by extending the duration of the olfactory trace.

Animals↗

PubMed1996

Effect of propofol on affective state as assessed by place conditioning paradigm in rats.

BACKGROUND: Whether propofol produces a pleasant affective state remains unclear from clinical studies. In the current study, the effect on affective state of subanesthetic and anesthetic doses of propofol was assessed at a preclinical level with rats in a place conditioning paradigm. Propofol was compared with methohexital. METHODS: In the place conditioning paradigm, propofol-induced effect was repeatedly paired with one of two distinguishable compartments of the apparatus, whereas the vehicle-induced effect was repeatedly paired with the other compartment. During a subsequent free-choice test, a preference for the drug-paired compartment over the vehicle-paired compartment would be indicative of pleasant state induced by the drug. For all experiments, the conditioning session lasted 8 days and consisted of four pairings of the drug with one compartment and four pairings of the equivalent volume of vehicle with the other compartment. In experiment 1A, four groups of rats were designated according to the dose of propofol that they received intraperitoneally: 0,30,60, or 90 mg/kg. In experiment 1B, the same procedure was used with subanesthetic doses of intraperitoneal methohexital: 0,10,20, or 30 mg/kg. In experiment 2, the rats were conditioned during the recovery period from short-term anesthesia. For one group, anesthesia was induced by propofol (100 mg/kg) whereas for the other group, anesthesia was induced by an equivalent anesthetic dose of methohexital (40 mg/kg). RESULTS: In experiment 1A, the 30-mg/kg, 60-mg/kg, and 90-mg/kg groups showed a place preference for the drug-paired compartment, but only the group conditioned with 60 mg/kg propofol significantly differed from the 0-mg/kg group. In experiment 1B, the groups conditioned with methohexital showed no place preference for the drug-paired compartment. In experiment 2, the rats showed a place preference for the compartment in which they recovered from propofol-induced anesthesia but no place preference for the compartment in which they recovered from methohexital-induced anesthesia. CONCLUSIONS: Propofol, but not methohexital, induced a pleasant affective state in rats at subanesthetic doses as well as during recovery from an anesthetic dose.

Affect↗

PubMed1996

[New antipsychotic agents: new paths of research on the notion of atypical agents].

The synthesis of new compounds called atypical neuroleptics such as amisulpride, clozapine, risperidone and now olanzapine has roused interest in the psychopharmacology of atypical antipsychotics. Since the synthesis of chlorpromazine in the early 1950s, subsequent therapeutic research has had two main goals: to define the mechanism of action of atypical neuroleptics and to search new compounds with both clinical efficacy and fewer side effects. The first one has widely been achieved, as it is clear that classical neuroleptics exert their effects by blockade of dopamine D2 receptors located in the ventral striatum. As a matter of fact, non specific blockade of dopaminergic receptors in the dorsal striatum also predicts extrapyramidal side effects. Moreover, classical neuroleptics have poor effects on negative and cognitive symptoms. That is why the search for new compounds has focused on two main goals: first, understanding the interactions of the neurotransmitters involved by the new drugs, second, characterizing their brain site of action. Achieving these two goals might enable us to precise the notion of atypicity as well as the classification of these new drugs.

Antipsychotic Agents↗

PubMed1995

Effects of GABAB receptor antagonists on two models of focal epileptogenesis.

The acute effects of two GABAB receptor antagonists (phaclofen and CGP-35348) were studied in two types of epileptogenic activity: that produced by intracortical injections of baclofen and that appearing after withdrawal of chronic intracerebral GABA infusion (the GABA-withdrawal syndrome, GWS). Intracortical baclofen induced two types of electrographic paroxysmal discharges: one consisting of single spike-and-wave (pattern I) and another of polyspike-and-wave patterns (pattern II). Both patterns showed similar latencies and temporal evolution of spike frequency discharges. Phaclofen, applied directly into the baclofen-induced epileptogenic focus, suppressed pattern II but was ineffective in modifying both pattern I and the GWS. CGP-35348, administered systemically, inhibited both patterns I and II. Intracortical microinjection of baclofen or phaclofen in rats showing a GWS had no effect, nor the systematically given CGP 35348. These results indicate a differential participation of GABAB receptors in GABA-related epileptic syndromes of cortical origin.

Animals↗

PubMed1995

c-fos immunoreactivity in the brain following electrical or chemical stimulation of the medial hypothalamus of freely moving rats.

c-fos immunoreactivity was used to map brain areas in which neurons reacted either to electrical stimulation or to microinjection of the excitatory amino acid kainate and of the GABAA antagonist, SR-95531, applied to the medial hypothalamus of freely moving rats. All these stimulations induced flight behavior of moderate intensity. Immunoreactive cells were found within a radius of 0.5 mm around the stimulated area. Distally, clusters of labeled cells were found ipsilaterally in the piriform and entorhinal cortices, in several amygdaloid nuclei, in the bed nucleus of the stria terminalis, in the septo-hypothalamic nucleus, in the paraventricular, anterior and dorsomedial hypothalamic nuclei, the the paraventricular thalamic nucleus, in the dorsal periaqueductal gray extending to the cuneiform nucleus, and bilaterally in the supramammillary decussation and the locus coeruleus. The specificity of the brain areas thus labeled was indicated by the unilateral pattern of activation as well as by the different pattern obtained after control microinjection of saline. Therefore, these results are likely to provide sound information about the brain structures involved in defensive-aversive behavior evoked from the medial hypothalamus.

Animals↗