Les publications

IF du Neurocentre

985 publications

* equal contribution
Les IF indiqués ont été collectés par le Web of Sciences en Juin 2021

In this study, we attempted to find out whether a social stress-induced increase in the vulnerability to acquire amphetamine self-administration was associated with a change in number of hippocampal corticosteroid receptors. This was examined in two types of sex-mixed colonies of rats. Animals were maintained for 4 weeks in: (1) 'stable social condition', membership did not change after constitution of the colony; (2) 'unstable social condition', the males were changed daily in a random design. The animals living in the 'stable social' conditions had: (1) a lower number of hippocampal type I corticosteroid receptors; (2) a longer duration of the increase in plasma corticosterone after exposure to novelty; (3) a higher vulnerability to acquire amphetamine self-administration. These findings suggest that a decrease in hippocampal type I corticosteroid receptors may be one of the biological mechanisms responsible for the impaired corticosterone feedback control observed in vulnerable animals. These findings throw more light on the role of hypothalamo-pituitary-adrenal axis in the modulation of adaptive behavior. The availability of drugs which are specific for corticosteroid receptors could represent a new approach to the therapy of certain behavioral disturbances.

15/03/1991 | Proc Natl Acad Sci U S A
Corticosterone levels determine individual vulnerability to amphetamine self-administration.
Piazza PV, Maccari S, Deminiere JM, Le Moal M, Mormede P, Simon H

Individual vulnerability to the reinforcing properties of drugs appears to be an essential characteristic predisposing humans to addiction. In animals, a greater behavioral reactivity to a mild stress, such as exposure to a novel environment, is an index of the vulnerability to acquire amphetamine self-administration. Biological responses to stress as well as behavioral reactivity may predict such a vulnerability. In the present study, rats with a longer duration of corticosterone secretion after exposure to novelty showed facilitation of acquisition of amphetamine self-administration. Furthermore, corticosterone administration in nonpredisposed individuals increased the reinforcing value of the drug and facilitated the acquisition of amphetamine self-administration. These results indicate that the stress-related activity of the hypothalamic-pituitary-adrenal axis may play a role in the pathogenesis of psychostimulant addiction.

02/1991 | Behav Pharmacol
Effects of tianeptine on spontaneous alternation, simple and concurrent spatial
Jaffard R, Mocaer E, Poignant JC, Micheau J, Marighetto A, Meunier M, Beracochea D

The effects of systemic administration of tianeptine, a new psychotropic agent

The aim of the present study was to test whether intrastriatal implants of embryonic dopaminergic neurons are able to normalize the lesion-induced dysfunction of striatal enkephalinergic neurons, one of the major output systems of the striatum. The ascending dopaminergic pathway of adult rats was unilaterally lesioned. Three weeks later a cell suspension obtained from the mesencephali of ED14 rat embryos was implanted into the denervated striatum and striatal methionin enkephalin immunostaining was quantified six months later by the use of an image analyser. Methionin enkephalin immunostaining was unevenly distributed in the striatum of control animals. Besides the classical patch/matrix pattern, a mediolateral gradient was also present and, moreover, immunostaining decreased towards caudal levels. Seven months after the lesion of the nigrostriatal dopaminergic pathway, methionin enkephalin immunostaining was found to be increased in the denervated striatum by about 50%. However, relative increases were more sustained in the areas where basal methionin enkephalin immunostaining were lowest, i.e. the lateral striatum and posterior striatal areas. This resulted in an attenuation of the global gradients seen in the normal striatum. Increased immunostaining was also found in the ipsilateral globus pallidus. The implantation, into the denervated striatum, of embryonic dopaminergic neurons led to a reversal of the lesion-induced increase of striatal and pallidal methionin enkephalin immunostaining six months later. Moreover, this reversal resulted in an overshoot, as the level of immunostaining in the graft-bearing striatum was found to be lower than the levels found in the normal striatum. It is concluded that grafts of embryonic dopaminergic neurons can normalize the function of one of the major output systems of the striatum and, through it, influence more distant targets of this structure. This suggests a physiological basis for the behavioral effects observed previously with such grafts.

The anatomical and functional characteristics of dopamine neuron-rich grafts implanted into rat pups were compared with those of identical grafts implanted into adult hosts. The host nigrostriatal dopaminergic pathway was unilaterally destroyed by an intrahypothalamic injection of 6-hydroxydopamine. This was followed five days later by the implantation of a cellular suspension obtained from rat embryonic mesencephali. Identical operations were carried out on adult and infant (PD3) rats. The survival rate of implanted tyrosine hydroxylase-positive cells was lower in the neonates. On the other hand, in the neonate hosts, surviving immunoreactive cells migrated extensively throughout the host striatum coursing preferentially below the corpus callosum and towards the subependymal zone. The structural integrity of the host parenchyma was well maintained after the neonatal implantation, in contrast to that observed in the adults. Despite a difference in the cell survival rate, there was no major difference in reinnervation density between the two types of host. The functional capacities of the implants were evaluated by measuring the rotational responses of the animals to dopaminergic agonists. The implants compensated the lesion-induced contralateral rotational response to the mixed agonist apomorphine and the D1 agonist SCH-38393 in both neonates and adults. However, the response to the D2 agonist LY-171555 was not significantly attenuated by the implant. The ipsilateral rotational response to amphetamine observed in the lesioned animals was also compensated and even reversed by the graft. It is concluded that with respect to rotational behavior, similar functional benefits were observed following adult stage or neonatal implantation, despite differences in their anatomical development.

The atypical neuroleptic clozapine has clinical and behavioral properties that differ not only from the typical compounds, but also from atypical ones. It interacts with the dopaminergic systems, but also produces effects on the serotoninergic, GABA-ergic, cholinergic systems. In spite of the amount of papers devoted to its study, the profile of the neurochemical action of this drug is still confuse. In this paper we investigated the DA2-, opiate- and benzodiazepine-receptor modifications induced by the long term (21 days) treatment with clozapine 20 mg/kg/day in the rat brain. We found a decrease of DA2 receptor density in the target areas of the mesolimbocortical system (ventral n. caudate-putamen, cerebral cortex except for the anterior cingulate at the most anterior level and the n. accumbens) and a decrease of opiate and benzodiazepine receptors in the cerebral cortex and in the olfactory tubercle. Opiate receptors increase in the patches of the striatum. We also compared these effects with those produced by long-term (21 days), low-dosage (0.5 mg/kg day) haloperidol.

Typical and atypical neuroleptic drugs show several clinical and behavioral effects, possibly related to the different anatomical sites of the action in the mesolimbocortical or mesostriatal dopaminergic systems. Because of the interaction between dopamine (DA) and neurotensin (NT) in the target areas of these systems, and in order to study if the different action of typical and atypical neuroleptic drugs could be related to a modification of the DA/NT balance, we investigated DA2 and NT receptor modifications--by means of quantitative receptor autoradiography--after chronic treatment with low dosage of haloperidol, chlorpromazine, thioridazine and clozapine. We described a decrease of NT receptor density in the target areas of the mesolimbocortical system produced by all the treatments. This effect does not match with DA2 receptor modifications. On the contrary, the block of DA transmission obtained by high dosage of haloperidol induces an increase of NT receptor density. Our results further demonstrate the regulation of NT transmission by DAergic drugs.

The ascending dopaminergic system of adult or 3-day-old rats has been unilaterally lesioned by the intraparenchymal injection of 6-hydroxydopamine aimed at the medial forebrain bundle at the level of the lateral hypothalamus. Nigral dopaminergic neurons disappeared following the lesion on the lesioned side in both experimental groups while the depletion of the ventral tegmental area was less extensive, especially following the neonatal lesion. Striatal regions were markedly depleted of their dopaminergic innervation, although the magnitude of the depletion was slightly higher following the adult stage lesion as judged on the basis of biochemical measurements (99% vs. 96%). Amphetamine (5 mg/kg) evoked an identical ipsilateral rotational response in both experimental groups. Moreover, this rotational response was blocked both by the specific D1 receptor blocker SCH-23390 (0.1 mg/kg) and the specific D2 receptor antagonist raclopride (2 mg/kg). Likewise, contralateral rotational responses to the directly acting D1 and D2 dopamine receptor agonists SKF-38393 (2.5 mg/kg) and LY-171555 (0.15 mg/kg) were similar in both experimental groups, both qualitatively and quantitatively. These results confirm conclusions obtained in earlier works, and indicate that reported differences in behavioral deficits between animals lesioned as neonates or adults are not related to differing modifications of striatal DA receptor sensitivities.

09/1990 | Neurobiol Aging
A comparison of the working memory performances of young and aged mice combined
Lebrun C, Durkin TP, Marighetto A, Jaffard R

The spatial working memory performances of young (2 months) and aged (24-26

The ascending mesotelencephalic dopaminergic systems of rat pups of 3 days of age were bilaterally lesioned using 6-hydroxydopamine injected at the level of the lateral hypothalamus. A sub-group of lesioned pups received, 5 days after the lesion, a dopamine neuron-rich cell suspension graft implanted bilaterally into the striatum and nucleus accumbens. Behavioral tests were conducted 6 months later. The lesion induced an increase in the locomotor activation induced by D-Ala2-Met5-enkephalinamide injected into the nucleus accumbens (2.5 micrograms/side) as compared to the activation observed in control animals. Locomotor activation by systemic apomorphine (0.1 mg/kg s.c.) was also increased while that induced by amphetamine (1.5 mg/kg i.p.) was abolished. The presence of DA neuron implants reversed each of these post-lesion modifications.

Individual vulnerability to drug addiction may be an important factor in the prognosis of this pathological behavior in man. However, experimental investigations have largely neglected the psychobiological substrate of predisposition to addiction. In this study, we show using a self-administration (SA) acquisition paradigm that previous repeated exposure to a stressful experience (tail-pinch) or to amphetamine, increase the locomotor response to this drug (behavioral sensitization) and enhance vulnerability to acquire amphetamine SA. These results show that vulnerability to develop amphetamine SA may be influenced by stressful experiences, and that previous contact with the drug may enhance a predisposition to amphetamine-taking behavior. As tail-pinch and amphetamine sensitization affect both the dopamine (DA) neural system and the propensity to self-administer amphetamine (behavior also modulated by DA activity), stress may influence SA via an action on the DA system.

Chronic thioridazine administration (5 mg/kg for 22 days) caused both behavioral and dopamine (DA) receptor modifications in rats. After chronic thioridazine administration, a significant increase in both locomotion and stereotypies induced by apomorphine was observed. In particular, only sniffing increased significantly, whereas grooming behavior decreased and the number of rearings did not change. Autoradiographic data were consistent with the behavioral results. Chronic thioridazine caused an up-regulation of DA receptors both in the striatum and in the olfactory tubercle (O.T.). The striatal effect may account for the increase of stereotypies, whereas the effect in the olfactory tubercle may account for the increase in locomotion. An increase in DA receptors was also found in the medial (MCTX) and dorsal cortex (DCTX). However, a decrease in DA receptors appeared in the nucleus accumbens septi (NAS) and in the lateral cortex (LCTX). This decrease, selectively localized in the mesolimbic DA system, may represent the neurobiological substrate of the depolarization block observed in A10 neurons after chronic thioridazine treatment.

05/02/1990 | Neurosci Lett
Thioridazine chronic administration: a behavioural and autoradiographic study.
Calza L, Giardino L, Piazza PV, Amato G

In rats the effects of chronic treatment with thioridazine (5 mg/kg orally administered for 22 days) were studied by means of behavioural supersensitivity to apomorphine and by means of dopamine (DA) receptors quantitative autoradiography. Locomotion and stereotypies induced by apomorphine increased after thioridazine chronic administration, whereas grooming behaviour decreased. Autoradiographic data showed an increase in DA receptors density both in the striatum and in the olfactory tubercle, to which the increase in stereotypies and locomotion could be respectively attributed. DA receptors increased also in the medial and dorsal frontal cortex. Moreover a decrease in DA receptors density appeared in the nucleus accumbens septi and in the lateral frontal cortex. Receptors decrease found in these regions might be associated with thioridazine-induced chronic inactivation of A10 DA neurons, to which the antipsychotic effect of the drug is attributed.

The aim of the present experiments was to test whether adrenal chromaffin cells implanted into the striatum of rats could exert a functional effect through a release of catecholamines. A cell suspension obtained from bovine adrenal medulla was implanted unilaterally into the striatum. The striatal dopaminergic input was extensively destroyed beforehand to preclude the possibility of reinnervation of the striatum by endogenous dopaminergic neurons. The functional influence of the implant was tested through the measurement of drug-induced rotation, while catecholamine release was measured subsequently in the same animals by in vivo electrochemistry. Transplant survival, as shown by the immunohistochemical analysis performed at the end of the in vivo experiments, was highly variable. Surviving chromaffin cells maintained their endocrine morphology and no reinnervation of the host striatum could be detected. Rotation of the animals evoked by apomorphine (0.1 mg/kg, sc) or amphetamine (5.0 mg/kg, ip) following the lesion was left uninfluenced following transplantation, even when a large transplant was recovered. On the other hand, nicotine (0.5 mg/kg, sc) evoked a strong contraversive rotational response in the transplant-bearing animals. This response could not be ascribed to the central effect of substances released peripherally and entering the nervous system through the blood-brain barrier opened by the implantation procedure, as it could not be found in animals bearing implants of other peripheral endocrine tissue, viz, pituitary. The effect of nicotine was not blocked by the pretreatment of the animals with either the opiate antagonist naloxone (2.5 mg/kg, 10 min) or the dopamine receptor blocker pimozide (0.5 mg/kg, 1 h), although the latter pretreatment blocked the amphetamine-evoked rotation. No spontaneous catecholamine release could be detected from the implanted chromaffin cells by in vivo electrochemistry, while treatment with amphetamine or nicotine did evoke a release. The results suggest that the functional effects of such intrastriatal grafts of chromaffin cells, reported in previous studies, cannot be explained by the secretion from the grafted cells of catecholamines into the denervated striatum. On the other hand the results obtained following the pharmacological stimulation of these cells indicate that adrenal grafts can, under suitable conditions, influence the functioning of the host nervous system.

01/1990 | J Psychopharmacol
Opiate receptor modifications in the rat brain after chronic treatment with haloperidol and suipiride.
Giardino L, Calza L, Piazza PV, Zanni M, Sorbera F, Amato G
doi: 10.1177/026988119000400102

Anatomical, electrophysiological and pharmacological data support the existence of a pronounced interaction between dopamine (DA) and opioids. In particular, chronic administration of DA antagonist drugs modifies opiate peptides and opiate receptors. In this paper we focused, by means of quantitative receptor autoradiography, on the modifications induced by chronic neuroleptic treatment, in patches versus diffuse distribution, of opiate receptors in the striatum, and we also studied the different effects of haloperidol and sulpiride on striatal and cortical receptors. We found a significant decrease of the number of (3H)- naloxone binding sites in the striatal patches of treated animals but no effects in the matrix. We also observed, in haloperidol-treated animals, an increase of (3H)-naloxone binding sites in the medial cortex, and in sulpiride-treated animals an increase in the lateral and dorsal cortex. Two main observations arise from our data: (a) a differential effect is produced by neuroleptic treatment on opiate receptors in patches and in matrix; (b) an opposite influence is exerted by sulpiride and haloperidol on opiate receptors in the cortex and in striatum.

1990 | Behav Pharmacol
Individual reactivity to novelty predicts probability of amphetamine self-administration.
Piazza PV, Deminiere JM, Maccari S, Mormede P, Le Moal M, Simon H

The present study demonstrates a relationship between individual responses to environmental activation, such as novelty, and propensity to acquire amphetamine self-administration. Locomotor activity cumulated over 2 h of exposure to a circular corridor was a stable and novelty-dependent feature of behaviour in individual rats. The differences between subjects in this behaviour were maintained over two trials at 1 months intervals, but disappeared over 4 days when the animals were tested daily, i.e. when the environment was no longer novel. The subjects with the higher locomotor response to novelty (HR group) also showed a higher propensity to acquire amphetamine self-administration, while the subjects with the lower response to novelty (LR group) did not acquire self-administration over 7 days of testing. Differences in self-administration of HR animals could not be accounted for by differences in exploratory behaviour. Thus, HR animals did not show higher investigative responses in a hole exploration test. Animals with the higher locomotor response to novelty also showed a greater release of corticosterone in the same environment. Since dopaminergic (DA) neurons are activated by both amphetamine and novelty, it is possible that differences in the propensity to acquire amphetamine self-administration may be accounted for by differences in the activity of DA neurons.

11/1989 | Pharmacol Biochem Behav
Septal alpha-noradrenergic antagonism in vivo blocks the testing-induced
Marighetto A, Durkin T, Toumane A, Lebrun C, Jaffard R

In order to test the hypothesis that alpha-noradrenergic receptors in the septum

29/09/1989 | Science
Factors that predict individual vulnerability to amphetamine self-administration.
Piazza PV, Deminiere JM, Le Moal M, Simon H

Clinical observations show that there is considerable individual variability in the response to the addictive properties of drugs. This individual variability needs to be taken into account in animal models of addiction. Like humans, only some rats readily self-administer low doses of psychostimulants. The individual animals at risk can be identified on the basis of their response to environmental or pharmacological challenges. This predisposition to develop self-administration can be induced by repeated treatment with amphetamine. These results may help elucidate the neurobiological basis of addiction liability observed in both rats and humans.

09/1989 | Behav Neural Biol
The durations of hippocampal and cortical cholinergic activation induced by
Toumane A, Durkin T, Marighetto A, Jaffard R

Sodium-dependent high-affinity choline uptake velocities in P2 fractions of the

01/01/1989 | Behav Brain Res
The influence of dopaminergic A10 neurons on the motor pattern evoked by substantia nigra (pars compacta) stimulation.
Piazza PV, Ferdico M, Russo D, Crescimanno G, Benigno A, Amato G

The influence of the mesolimbic-mesocortical dopaminergic (DA) system on the motor pattern evoked by substantia nigra pars compacta (SNpc) stimulation was studied. Electrical stimulation of the A10 group of neurons caused an inhibitory effect preferentially directed towards the orientation movement. Sulpiride administration at low dosages (50 mg/kg i.p.) did not modify this movement at the basal condition, but abolished the increase of its duration induced by ventral tegmental area (VTA) co-stimulation. Mesolimbic activation opposes the effects of SNpc stimulation, restraining the animal in its antero-posterior axis by means of orientation movement inhibition. The results suggest a role of the DA mesolimbic-mesocortical system in the maintenance of focused attention.

01/01/1989 | Behav Brain Res
Circling behavior: ethological analysis and functional considerations.
Piazza PV, Ferdico M, Russo D, Crescimanno G, Benigno A, Amato G

Head-turning and circling movements evoked by substantia nigra (pars compacta) (SNpc) stimulation have been ethologically analyzed in order to attribute a functional meaning to these lateralization processes. It has been shown that these motor acts, separated by a constant interval, may be considered a fixed action pattern. The duration of the single acts depends on the SNpc stimulation parameters: the increase in the stimulus strength produces an increase in the number of turns but does not induce the disappearance of the orientation movement. The body movement is always preceded by the head-movement. Haloperidol administration induces a dose-related increase of the orientation component of the motor pattern. These data together with others in the literature suggest the participation of the SNpc in the mechanism of shift in the focus of attention from one point to another in the contralateral surrounding environment.

1989 | Arch Gerontol Geriatr Suppl
Experimental dissociation of memory systems in mice: behavioral and neurochemical
Jaffard R, Durkin T, Toumane A, Marighetto A, Lebrun C

Evidence for different types of memory in mice may lead to development of animal

1989 | Neurosci Biobehav Rev
Experimental approach to individual vulnerability to psychostimulant addiction.
Deminiere JM, Piazza PV, Le Moal M, Simon H

Vulnerability to the development of drug-intake has been studied by using the acquisition of intravenous amphetamine self-administration in the rat. In a series of neurobiological experiments we provoked imbalances in the functioning of the dopaminergic (DA) network by performing lesions of the DA cell bodies in the ventral tegmental area, DA terminals in the amygdala or median raphe nucleus. These imbalances which resulted in enhanced DA transmission ratio between the nucleus accumbens and the prefrontal cortex led to an increase in the rapidity of self-administration acquisition. With a psychobiological approach, we showed that individual differences in vulnerability to develop self-administration in rats of the same strain were correlated with locomotor responses to stress and to an acute injection of amphetamine. Moreover, activation of DA transmission by repeated amphetamine injections changed animals resistant to drug-intake into vulnerable ones. It is suggested that some inherited or acquired factors, at least in part by affecting the activity of DA network, can predispose individuals to drug abuse.

10/1988 | Behav Brain Res
Differential hippocampal and cortical cholinergic activation during the
Toumane A, Durkin T, Marighetto A, Galey D, Jaffard R

Possible differentiation of the intervention of cholinergic septohippocampal and

Male rats received a dopaminergic implant aimed either at the nucleus accumbens or the ventral tegmental area (VTA) following 6-hydroxydopamine lesion of their mesocorticolimbic dopaminergic system. Exposure to electrical footshock stress 6 months later markedly activated the mesocorticolimbic neurons in control animals as shown by the increase of dihydroxyphenylacetic acid (DOPAC) levels both in the nucleus accumbens and the VTA. However, no stress-induced activation was seen for the grafted neurons, irrespective of the area of implantation. These results indicate the lack of reinnervation and modulation of the grafted dopaminergic neurons by one of the important afferent systems regulating the activity of endogenous mesencephalic dopaminergic neurons.

The aim of the study was to obtain a description of some aspects of the development of intracerebral dopaminergic grafts, namely, the time course of the glial reaction and its relation to cell division on one hand, and the development of graft-originated innervation and its dependence on adequate matching of the implanted neurons and target site on the other hand. Cell suspensions obtained from the mesencephalon or hypothalamus of embryonic day (ED) 14 rat embryos were implanted into the striatum or lateral hypothalamus of adult rats following the destruction of the nigrostriatal system of the hosts. Animals were sacrificed at different postimplantation times, and the development of the graft was followed by immunohistochemistry by using antisera directed against tyrosine hydroxylase (TH) or glial fibrillary acidic protein (GFA). Furthermore, the existence of cell division at various times following implantation was examined by performing autoradiography on immunostained sections after prior intraventricular administration of 3H-thymidine to the host. The first stage of the development of intracerebral grafts was characterized by the existence of intense cell division within the grafted tissue, lasting about 2 weeks, and also in the host tissue surrounding the graft, lasting only about 6 days. The cell division in the host tissue was paralleled by the existence of a strong glial reaction which, however, did not extend into the graft itself. Glial reaction in the host tissue gradually decreased at later times and disappeared by 4 weeks postimplantation without leaving behind a noticeable glial scar. The graft itself was, however, transiently filled with a population of reactive astroglial cells between 3 and 6 weeks postimplantation. Within grafts of mesencephalic tissue located in the striatum TH-positive neurons were distributed evenly at short times postimplantation (2-6 days). At later time a compartmentation could be observed, with TH-positive neurons being aligned along the graft-host interface or clustered within the graft itself. Innervation of the host tissue by TH-positive fibers increased between 1 and 6 weeks postimplantation. On the other hand, no compartmentation and reinnervation of surrounding host tissue was observed for intrahypothalamic grafts of mesencephalic tissue or intrastriatal grafts of hypothalamic tissue. This last observation indicates that adequate matching of implanted neurons and target tissue plays an important role in the development of intracerebral dopaminergic grafts.

Local lesion of the dopaminergic (DA) terminals of the nucleus accumbens have been described to reproduce part of the behavioral deficits evoked by the lesion of the whole mesocorticolimbic DA system. The most straightforward interpretation of these results would be that the DA innervation of the nucleus accumbens is necessary for and critically involved in the normal performance of the given behaviors. However, while giving some indication as to the necessity of the integrity of this DA innervation for normal behaviors, such an approach cannot reveal whether the presence of the DA innervation of other mesocorticolimbic areas (e.g. amygdala, septum, etc.) is also required. In order to approach this question, the behavioral effects of DA grafts implanted into the nucleus accumbens of rats were evaluated following two different 6-hydroxydopamine-induced lesions: a lesion restricted to the anterior DA field (DA terminals of the nucleus accumbens and to a lesser degree the frontal cortex and anteromedial striatum) or a lesion of the whole mesocorticolimbic DA system. The latter lesion induces a disappearance of the DA innervation of the nucleus accumbens as well as the amygdala, septum, etc. Both kinds of lesions led to locomotor hypoactivity, loss of locomotor activation by amphetamine, increased locomotor stimulation to apomorphine, decrease of exploratory activity and loss of hoarding behavior. These deficits were not seen in grafted animals bearing a local lesion of the DA innervation of this structure. For some of these recoveries, however, a pharmacological stimulation of the grafted neurons was required to reveal the effect of the graft. In the case of the total lesion of the mesocorticolimbic DA system, only locomotor dysfunctions were compensated by the intra-accumbens DA implants, while the other deficits remained intact, irrespective of a stimulation of the graft. These results indicate that the re-establishment of the DA innervation of the nucleus accumbens is a sufficient condition for the compensation of locomotor deficits, irrespective of the presence of the DA terminals in more posterior limbic structures, while for deficits of more complex behaviors the simultaneous presence of posterior DA innervations is also required. This latter requirement suggests the existence of some cooperativity between the different central DA terminal areas for the normal performance of behaviors.

Cortical cells obtained from rat embryos (ED14 to ED20) were implanted in various regions of rat brain and the presence of tyrosine hydroxylase (TH)-, neuropeptide Y (NPY)- and Met-enkephalin (ENK)-immunoreactive neurons within the grafts were tested using an immunohistochemical approach. TH-like immunoreactive (TH-LI) neurons were present within the implants obtained from ED14, but not ED18 or ED20, embryos up to 10 months post-implantation and their presence was not dependent on the age of the host (adult or neonate) at the time of implantation. Furthermore, the density of such cells varied with the site of implantation, being the highest in the dorsomedial corner of the striatum. This distorted development seems to affect also other cell populations, such as NPY-LI neurons which could be observed within the implants in a density much higher than that found in the normal cortex and which presented generally a rather immature morphology. It has been described that the rat cortex contains TH-LI neurons only during a limited period of development. The survival of such neurons within intracerebral grafts of cortical tissue indicates that their disappearance during normal cortical development is dependent upon environmental cues. The survival of TH-LI cells in grafts implanted to neonatal hosts suggests that these cues are not some humoral factors appearing postnatally. On the other hand, the present observations are compatible with several other hypothesis concerning the nature of such cues: humoral factors present during the late embryonic period, signals dependent on neuronal connectivities (input and/or outputs) established during embryonic or postnatal life.(ABSTRACT TRUNCATED AT 250 WORDS)

1988 | Exp Brain Res
Intrastriatal dopaminergic grafts restore inhibitory control over striatal cholinergic neurons.
Herman JP, Lupp A, Abrous N, Le Moal M, Hertting G, Jackisch R

The aim of the study was to examine the influence of intrastriatal dopaminergic grafts on the functioning of striatal cholinergic neurons using an in vitro superfusion method. Rats bearing unilateral 6-hydroxydopamine lesion of the nigrostriatal dopaminergic system received a cell suspension obtained from ED 14 rat embryonic mesencephali which was injected into the denervated striatum. Lesioned animals displayed an ipsilateral rotation in response to amphetamine (5 mg/kg i.p.). This rotational response disappeared following grafting and there was even a significant contralateral rotation in response to the drug. Apomorphine (0.1 mg/kg s.c.) induced a contralateral rotation following the lesion. This latter response was attenuated in the grafted group. Three months after grafting 350 microns thick slices were prepared from striata from the control and experimental sides of lesioned and graft-bearing animals. The slices were preincubated either with 3H-dopamine (10(-7) M) or 3H-choline (10(-7) M) and then superfused with an oxygenated Krebs-Ringer solution. Stimulation with electrical pulses following preincubation with 3H-dopamine elicited a marked increase of tritium outflow from control slices. Stimulation-evoked overflow was of similar magnitude from slices from striata containing the graft, while it was much reduced in slices from lesioned striata. Amphetamine markedly potentiated the effect of electrical stimulation in slices obtained from control and graft-containing striata. Nomifensine (a dopamine uptake blocker) led to a significant decrease of the overflow of 3H-acetylcholine evoked by electrical stimulation from control striatal slices. This inhibition was antagonized by domperidone, a D2 dopamine receptor blocker, a finding which indicates that the action of nomifensine was indeed due to a potentiation of the action of endogenous dopamine released by the electrical stimulation. A similar, although somewhat attenuated, action of nomifensine and domperidone was observed for striatal slices containing the graft. Amphetamine inhibited the stimulation evoked overflow of 3H-acetylcholine in a dose-dependent manner from striatal slices obtained both from the intact and experimental sides of graft-bearing animals, while it had no action on slices from denervated striata. Finally, the dose-response curve for the inhibition of 3H-acetylcholine release by apomorphine was significantly shifted to the left for slices from the lesioned striata as compared with control slices. This leftward shift was totally abolished in the slices from the graft-containing striatum.(ABSTRACT TRUNCATED AT 400 WORDS)

Lateral hypothalamus (LH) stimulation in cats which do not spontaneously attack rats, produces an attack pattern which may be divided into 3 main stages: the first, defined as exploratory time (ET), begins with an environmental search and culminates in orienting towards the prey; in the second, defined as attack time (AT), the cat stalks the rat; the last is the biting stage in which the cat seizes and kills the prey by biting its head and neck. The effects of ventral tegmental area (VTA) stimulation on the latency of the whole sequence and on the different stages of the attack pattern were studied. VTA activation resulted in a significant decrease of biting latency, due to the reduction of exploratory time. Moreover, a significant period of prey fixation, seldom present during LH stimulation alone, was observed after VTA-LH co-stimulation. Sulpiride injection caused the disappearance of VTA effects on the predatory pattern. The results indicate that VTA activation induces a decrease in behaviour related to exploration of the environment, and an increase in the focusing of attention on the prey, which seems an important component in the regulation of the predatory pattern. Pharmacological evidence indicates that the VTA effect is mediated by the mesolimbic-mesocortical dopaminergic (DA) system.

31/10/1987 | Boll Soc Ital Biol Sper
[Device for the automatic recording of the latency of the mouth-opening reflex in the cat].
Cucinella F, Piazza PV, Amato G

Bradykinin (BK), a nonapeptide, originally discovered in blood, is also present in neurons and fibers of the hypothalamus. We tested the putative releasing factor properties of BK on prolactin (PRL) release from anterior pituitary cells in vitro. BK stimulated the release of PRL in a dose-dependent manner, the threshold concentration being in the range. 0.1-1.0 nM. The release of PRL induced by BK at 1 nM concentration was about 2-fold, delayed and sustained over many minutes. Higher concentrations of BK stimulated PRL release in two phases. The shape of the BK-induced PRL release was superficially similar to that induced by thyrotropin-releasing hormone (TRH). 10 nM BK and 10 nM TRH induced about a 4-fold increase in PRL release within 5 min, followed by a gradual recovery to basal secretion. These results indicate that this peptide can act directly at the anterior pituitary gland to release PRL. Phorbol ester also promoted PRL release over the range of 1-10 nM, but the time course of the release was somewhat different.

The influence of A10 region neurons of the ventral tegmental area (VTA) on the defence reaction evoked by stimulation of the ventromedial hypothalamic nucleus (VMH) was studied in the cat. The latency of the hissing in the defence reaction increased when the VTA was stimulated both ipsi- and contralaterally. A sulpiride (50mg/kg i.p.) injection totally abolished the VTA-provoked increase of the hissing latency without affecting the basal response.