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G Sandner

Publications and source records attributed to G Sandner.

At least 37 records · Page 2Linked to original sources

Distribution of lithium in the rat brain after a single administration known to elicit aversive effects.

In order to get insight into the brain areas involved in the initial unpleasant effects resulting from the administration of lithium (Li+), its distribution was mapped in the rat brain using the 6Li(n,alpha)3H nuclear reaction after a single injection of 6Li2SO4 at doses and latencies corresponding to the elicitation of such unpleasant effects. An improved method for visualization and measurement of local Li+ concentrations was used consisting in diffracting light along the tracks left by alpha particles in a dielectric detector. The distribution of Li+ was found less homogeneous than when Li+ was administered chronically. Periaqueductal and periventricular structures were the brain areas containing the highest concentrations of Li+.

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Regional distribution of Fos-like immunoreactivity in the rat brain after exposure to fear-inducing stimuli.

Fos protein immunohistochemistry was used to identify the neural substrate of fear/anxiety. The structures activated by exposure of Long Evans male rats (280-300 g) to the elevated plus-maze, a widely used animal model of anxiety, were compared with those activated by chemical stimulation of two aversive areas of the brain, the dorsal periaqueductal gray matter and the medial hypothalamus. Three different patterns of activation were obtained: Pattern 1 resulted from microinjection of the excitatory amino acid kainate (60 pmol; N = 5) or of the GABA(A) receptor antagonist SR-95531 (16 pmol; N = 3) into the dorsal periaqueductal gray matter and consisted mainly of caudal structures; Pattern 2 was observed after kainate injection (60 pmol; N = 4) into the medial hypothalamus and had a predominantly prosencephalic distribution; Pattern 3 extended from rostral to caudal brain regions and was induced by microinjection of either SR-95531 (16 pmol; N = 1) or kainate (120 pmol; N = 3) into the medial hypothalamus, as well as by 15-min exposure to the plus-maze (N = 3). Control animals were either injected with saline into the MH (N = 3) or the PAG (N = 3) or were exposed for 15 s to the elevated plus maze (N = 3) and exhibited no significant labeling. These results further support the participation of periventricular structures in the regulation of fear and aversion.

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What brain structures are active during emotions? Effects of brain stimulation elicited aversion on c-fos immunoreactivity and behavior.

Aversive behavior is produced by stimulating some brain structures, such as the dorsal periaqueductal gray and the medial hypothalamus. We have used c-fos immunoreactivity to map brain areas which are influenced by stimulation of these two structures. Stimulation was produced in freely moving rats by electrical stimulation or by microinjections of either excitatory amino acids or GABA blocking drugs. Behavior was monitored to detect emotional changes. The effects on labeling induced by the stimulation of either structure were then compared. Structures labeled include the amygdala, the stria terminalis, the supramamillary area, the hypothalamus, the periaqueductal gray, the superior colliculus, the nucleus cuneiformis, and the locus coeruleus. Regardless whether chemical or electrical stimulation was used or the structure stimulated, there was a large overlap among the brain areas labeled. We then compared our results with data from the literature where other methods of inducing aversion have been used, including pain and stress. There was remarkable similarity in the patterning of labeling irrespective of the type of stimulation (central-peripheral, chemical-electrical). There was, however, one interesting difference produced by central vs. peripheral stimulation. Labeling was unilateral in the former case and bilateral in the latter case. Our results suggest that there is a neural substrate that mediates aversive behavior, no matter how it is produced. Nevertheless, that peripheral stimulation produces mainly bilateral activation of this substrate whereas central stimulation produces mainly unilateral activation suggests that natural peripheral stimuli are also integrated at a higher functional level. Future work could be directed toward explicit comparisons of central versus peripheral stimulation to identify the structures involved in higher level integration of aversive behavior.

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Induction of Fos immunoreactivity in the brain by exposure to the elevated plus-maze.

The Fos protein immunohistochemistry technique was used to map the brain areas activated by a 15-min exposure of rats to the elevated plus maze, an ethologically based animal model of anxiety. Two hours after the test, labeling was found mainly in the piriform and entorhinal cortices, amygdala, midline thalamic nuclei, several medial hypothalamic nuclei, periaqueductal gray matter, superior and inferior colliculus, cuneiform nucleus, dorsal raphe nucleus and locus coeruleus. These results support a participation of these structures in anxiety.

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Evidence for state-dependent retrieval in conditioned place aversion.

State-dependent retrieval (SDR) in conditioned place aversion (CPA) was observed using Long-Evans male rats, with three different aversive drugs injected ip: lithium chloride (31.8 mg/kg), FG 7142 (10 mg/kg), and naloxone (5 mg/kg). Experiment 1 showed that state-dependent dissociation was complete with lithium chloride following two conditioning trials, but disappeared when the number of learning sessions was increased. Experiment 2 showed that following two conditioning trials, such complete state-dependent dissociations were also observed when FG 7142 or naloxone were used during conditioning. The results of this study showed that the expression of SDR is not monotonic in CPA paradigm but depends on the stage of learning. In addition, SDR can be observed following administration of a variety of drugs known to produce CPA, but differing in their neurochemical targets and the nature of the aversive effects they induce. Finally, these results are discussed with regard to what is known about SDR in other paradigms.

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Effect of 5,7-dihydroxytryptamine lesion on mianserin-induced conditioned place aversion and on 5-hydroxytryptamine1C receptors in the rat brain.

The lesion of serotonergic neurons (by an intraventricular injection of 5,7-dihydroxytryptamine) potentiated the conditioned place aversion induced by the 5-hydroxytryptamine1C/5-hydroxytryptamine2 antagonist mianserin in rats. This effect was selective for mianserin as the same lesion suppressed the conditioned place aversion induced by the benzodiazepine inverse agonist FG-7142. Previous results had shown the involvement of the 5-hydroxytryptamine1C receptors in the conditioned place aversion induced by mianserin [Rocha et al. (1993) Behav. Pharmac. 4, 101-106]. It was thus of interest to investigate the effect of the lesion on these receptor binding sites. Autoradiographic binding studies showed that the lesion significantly increased the concentration of the 5-hydroxytryptamine1C binding sites in various brain regions, including the amygdala, the hippocampus and the nucleus accumbens. Contrastingly, in these same brain regions, in situ hybridization histochemistry did not reveal an alteration of the level of messenger RNA coding for these receptors. On the one hand, correlating potentiation of the aversive effects of mianserin and increase of 5-hydroxytryptamine1C binding sites in the limbic system represent an interesting step in the comprehension of the molecular and motivational effects of serotonergic drugs. On the other hand, showing a dissociation between the expression of 5-hydroxytryptamine1C receptors and their corresponding messenger RNA, suggest that post-transcriptional mechanisms are involved in the regulation of these receptors.

5,7-Dihydroxytryptamine↗

C-fos immunoreactivity in the brain following unilateral electrical stimulation of the dorsal periaqueductal gray in freely moving rats.

C-fos immunoreactivity was used to reveal brain areas in which neurons were influenced by electrical stimulations applied to the dorsal periaqueductal gray. These stimulations were applied in freely moving rats so that the resulting behaviors could be observed. Shortly afterwards, the brains of the rats were processed for C-fos immunoreactivity. In order to determine the specificity of the brain areas thus labeled, control stimulations were applied to the ventral tegmental area of other rats. Immunoreactive cells were found surrounding the tip of the stimulation electrode within a radius of 0.5 mm. This labeled area extended further along the rostro-caudal axis than along the medio-lateral or dorso-ventral axis in the periaqueductal gray. Distally, clusters of labeled cells were found ipsilaterally in the caudal periaqueductal gray extending to the nucleus cuneiformis, and bilaterally in the locus coeruleus and supramamillary decussation. More widespread labeling was found in most hypothalamic subareas and in the lateral habenula. The labeled brain areas following ventral tegmental area stimulations were totally distinct, and comprised the medial forebrain bundle, the nucleus accumbens, the vertical limb of the diagonal band and the medial septum. The pattern of labeling produced by periaqueductal gray stimulations was therefore specific, and provided information about brain structures involved in the motivational and behavioral effects of such stimulations.

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Wild running elicited by microinjections of bicuculline or morphine into the inferior colliculus of rats: lack of effect of periaqueductal gray lesions.

Bicuculline methiodide, a GABAA receptor antagonist, or a high dose of morphine was injected at the same site within the inferior colliculus (IC) of rats. Both drugs elicited the same behavioral activity (wild running). However, the time course and magnitude of the effects of the two drugs differed. Since the behavioral activation elicited was reminiscent of what was found with microinjections of bicuculline methiodide or morphine into the periaqueductal gray (PAG), we lesioned the PAG in another group of rats. It was found that extensive lesions of the PAG including those extending to the medial part of the superior colliculus did not significantly reduce the wild running.

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Conditioned place preference induced by Ro 16-6028, a benzodiazepine receptor partial agonist.

A place conditioning situation was used to assess the putative affective properties of benzodiazepine receptor ligands in the rat. The benzodiazepine receptor partial agonist Ro 16-6028 induced a conditioned place preference, suggesting that this compound has rewarding properties. The benzodiazepine receptor antagonist Ro 15-1788 induced neither place preference nor aversion, but prevented the place preference induced by Ro 16-6028, suggesting that the rewarding effects of Ro 16-6028 are due to its action on the benzodiazepine receptor. The benzodiazepine receptor full agonist diazepam did not induce a conditioned place preference in our hands, in contrast with previous studies. The sensitivity of place conditioning with benzodiazepine ligands to situational factors, such as the existence of a preconditioning preference, is discussed.

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Periaqueductal gray spike trains recorded in frontal or horizontal mesencephalic brain slices from the rat.

Spontaneous spike trains were recorded from the periaqueductal gray matter (PAG) in frontal and horizontal mesencephalic slices in order to compare spontaneous activity of the slice preparation to previous in vivo records. The firing rates resembled those recorded in vivo. They were low notwithstanding the fact that the slicing procedure removed tonic inhibitory input to the PAG. The firing rates increased caudo-rostrally, a fact that had not been reported in vivo, and were lower in frontal sections. Several different spike trains were found, described and classified according to their temporal firing patterns. The spike sequences were usually simple stochastic processes, distributed as a Gaussian function with or without stochastic deletion of spikes.

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Discriminative properties of aversive electrical stimulations of the so-called "mesencephalic locomotor region": a parametric study.

The classical 2-lever food-reward-reinforced discrimination paradigm, although already successfully applied to study discriminative properties of positively reinforcing electrical brain stimulations (EBS), has not yet been used for negatively reinforcing (aversive) EBS. This study was aimed at assessing if such a discrimination paradigm could be used to demonstrate discriminative properties of aversive EBS of the so-called "mesencephalic locomotor region" (MLR). Fourteen rats were trained for food reward to press one lever in the presence of EBS of the MLR and the other lever in the absence of EBS. Discriminative control by EBS of the MLR was obtained in 11 rats, which were subsequently subjected to a parametric study. It was found that the discriminative properties of EBS of the MLR covaried with changes in the intensity, frequency and pulse duration of the EBS. Our data also suggest that the aversive dimension of the stimulation might constitute a component of the discriminative cue induced by these EBS.

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Wild running and switch-off behavior elicited by electrical stimulation of the inferior colliculus: effect of anticonvulsant drugs.

The behavioral and motivational effects of electrical stimulation of the inferior colliculus (IC) were investigated. Electrical stimulations of either the dorsal part or ventral part of the IC both elicited wild running (WR). Nevertheless, the ventral part was found more sensitive than the dorsal part, as lower intensities were needed to elicit WR. Moreover, WR differed depending on the part of the IC stimulated. It stopped as soon as the stimulation was switched off when the ventral IC was stimulated, whereas it further persisted in a poststimulus WR when the dorsal IC was stimulated. This poststimulus WR was abolished by anticonvulsant drugs such as diazepam, phenytoin or sodium valproate. In an operant escape conditioning paradigm (switch-off test), only stimulation of the ventral IC readily sustained switch-off learning. Dorsal IC stimulations did not, possibly because of the poststimulus enduring effects of the stimulation, as evidenced by poststimulus WR. Indeed, the anticonvulsant drugs which abolished this poststimulus WR also permitted switch-off of dorsal IC stimulations. It is concluded that electrical stimulations of the IC (dorsal or ventral) elicit aversive effects and that WR elicited either by ventral or dorsal stimulation may represent the overt expression of these aversive effects.

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Behavioral analysis of the effects of benzodiazepine receptor ligands in the conditioned burying paradigm.

In the conditioned burying paradigm, 10 mutually exclusive behavioral sequences were encoded in order to characterize the effects of various benzodiazepine receptor ligands. It was found that each ligand produced a specific behavioral pattern, the elements of which were consistent with results obtained in other experimental situations. Whereas anxiolytic (diazepam, Ro 16-6028) and 'anxiogenic' ligands (FG 7142) both decreased the mean duration of burying, these two classes of drugs largely differed when approaches to the prod and escape movements away from the prod were considered. The benzodiazepine receptor antagonist Ro 15-1788 was devoid of effects on all of the behavioral sequences considered. The main characteristics of these behavioral profiles persisted during an extinction test, although the animals were no longer treated. It is proposed that additional behavioral measures, or better, an ethological analysis of the behavior may increase the potency of the conditioned defensive burying paradigm.

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Aversion induced by electrical stimulation of the mesencephalic locomotor region in the intact and freely moving rat.

Electrical stimulation of the so-called "mesencephalic locomotor region" (MLR) in the acute mesencephalic and restrained rat is known to induce locomotion. In the intact and freely moving rat, electrical stimulation of an area coextensive with MLR is reported to elicit an apparently aversive type of behavioral response. Indeed, the description of this behavioral response is very similar to the description of the prototypical escape reaction elicited by electrical stimulation of the periaqueductal gray (PAG), a structure of the so-called "brain aversive system." In this study, we investigated if, as is the case for PAG stimulations, these MLR electrical stimulations are also aversive in nature. To that end, MLR-stimulated rats were subjected to the switch-off test, in which the stimulated rat learns to interrupt the stimulation by pressing a bar. It was found that electrical stimulation of MLR sites, positive for apparently aversive behavior, supports the learning of the switch-off behavior, which demonstrates the aversive nature of such stimulations. Furthermore, the switch-off latency (time elapsed between the onset of the stimulation and its offset by a press of the bar) was shown to decrease when the intensity of the electrical stimulation is increased or when the interpulse interval is decreased, which suggests that the generated aversive state is graded by the strength of the stimulation. It is, hence, proposed to extend the "brain aversive system" to the MLR.

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Differential pharmacological reactivity of aversion induced by stimulation of periaqueductal gray or mesencephalic locomotor region.

Rats were trained to switch-off aversive electrical brain stimulations applied to the periaqueductal gray (PAG) or mesencephalic locomotor region (MLR) by pressing a bar (switch-off behavior). We investigated the effects of IP injections of the benzodiazepine (BZ) receptor inverse agonist FG 7142 (2.5, 5, 10 mg/kg) or BZ receptor agonist chlordiazepoxide (CDP: 5 mg/kg) on the switch-off latency, i.e., the time elapsed between the onset of the stimulation and its offset by a press of the bar. It was found that FG 7142 decreased, whereas CDP increased the mean switch-off latency for electrical stimulation of the PAG, which is interpreted as a potentiating effect of FG 7142 and a reducing effect of CDP on the electrically induced aversive state. By contrast, neither FG 7142 nor CDP were found to affect the mean switch-off latency for MLR stimulations. These results suggest a difference in the pharmacological sensitivity to BZ receptor ligands between aversive states elicited by electrical stimulation of the PAG or MLR.

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Treadmill locomotion and aversive effects induced by electrical stimulation of the mesencephalic locomotor region in the rat.

The effects of electrical stimulation of the "mesencephalic locomotor region" and adjacent dorsolateral tegmentum were assessed and compared in the same rats in freely moving conditions or when lightly anesthetized and suspended over a moving treadmill. In freely moving conditions, electrical brain stimulation (EBS) of this part of the mesencephalon elicited mainly aversive effects (escape reactions: violent running and explosive jumps), but also ipsiversive circling and "gnawing." On the treadmill, EBS induced flexions of hindlimbs followed by locomotion (stepping) or flexions only. In addition, it was found that locomotion and flexions on the treadmill were almost exclusively elicited by EBS of sites positive for escape reactions in freely moving conditions.

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Conditioned place aversion produced by microinjections of semicarbazide into the periaqueductal gray of the rat.

Previous studies have shown that the blockade of GABA-ergic neurotransmission in the periaqueductal gray (PAG) of the rat induce flight reactions. The present study examined whether a negative affective state was produced by such a blockade. Microinjections of semicarbazide, a GABA synthesis inhibitor, into the PAG were found to produce a conditioned place aversion. In a second experiment, it was found that the potent GABA agonist muscimol antagonized the effects of semicarbazide, without producing a conditioned place preference or aversion by itself. These results suggest that the blockade of the tonic inhibition exerted by GABAergic terminals in the PAG results in both an aversive experience and an overt flight reaction.

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Conditioned place aversion produced by FG 7142 is attenuated by haloperidol.

A place conditioning paradigm was used to examine the affective properties of FG 7142, a benzodiazepine receptor inverse agonist. At the highest dose tested (10 mg/kg, IP), FG 7142 produced a significant place aversion to the drug-paired compartment. In a second experiment, haloperidol injections were given before FG 7142. It was found that haloperidol (0.2 mg/kg) significantly reduced the measured conditioned place aversion produced by FG 7142, without exhibiting any aversive or rewarding effects by itself. These results suggest that dopamine receptors are involved in the learning or expression of conditioned place aversion induced by benzodiazepine receptor inverse agonists.

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