Biomedical subjects

P Cazala

Publications and source records attributed to P Cazala.

At least 19 recordsLinked to original sources

PubMed2006

Genetic dissociation of two behaviors associated with nicotine addiction: beta-2 containing nicotinic receptors are involved in nicotine reinforcement but not in withdrawal syndrome.

RATIONALE: Nicotine addiction is characterized by two distinct behaviors, chronic compulsive self-administration and the induction of a withdrawal syndrome upon cessation of nicotine consumption. OBJECTIVE: To examine if these two processes rely on beta2-containing nicotinic receptors--beta2*nAChRs--we analyzed the behavior of mice lacking these receptors in the two situations. RESULTS: First, we showed that, in contrast to wild-type (WT) mice, beta2-knockout (beta2-/-) mice exhibit no intra-ventral tegmental area (VTA) nicotine self-administration, whereas their ability to self-administer morphine is intact. However, beta2-/- mice showed some sensitivity to locomotor effects of nicotine, implying an effect of the drug on other nicotinic subtypes. Then, we observed that beta2-/- mice exhibited a normal nicotine withdrawal syndrome, i.e., increased levels of rearing and jumping upon precipitated withdrawal. Thus, the beta2*nAChRs are not involved in the behaviors induced by cessation of nicotine consumption. CONCLUSION: Taken together, the present data demonstrated a genetic dissociation of two distinct behavioral patterns associated with nicotine addiction. They further suggested that independent molecular mechanisms underlie these two aspects, offering the possibility of controlling them separately.

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PubMed2006

Targeted in vivo expression of nicotinic acetylcholine receptors in mouse brain using lentiviral expression vectors.

Nicotinic acetylcholine receptors (nAChRs) in the brain exhibit diverse functional properties and ubiquitous distribution. Yet, except for providing a receptor for the exogenously applied nicotine of tobacco products, their role in the normal functioning of the brain has remained elusive. We have used a lentiviral expression vector to re-express the beta2 subunit specifically in the ventral tegmental area (VTA) of beta2-/- mice. The viral vector efficiently expresses beta2- subunit protein leading to new nAChR-binding sites. VTA neurons transduced by the lentiviral vector are responsive to intravenous nicotine when analyzed using in vivo electrophysiology. Nicotine-induced dopamine release from the nucleus accumbens (NuAcc) was also restored in re-expressing beta2-/- mice. Intra-VTA injection of nicotine was found to be reinforcing in both wild-type and beta2-subunit re-expressing beta2-/- mice, but not in beta2-/- mice. Furthermore, in the absence of applied nicotine, the spontaneous slow exploratory behavior of the mice was restored, whereas fast navigation did not change. This latter behavioral analysis suggests a role for beta2* nAChR, specifically expressed in the VTA, in mammalian cognitive function.

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PubMed2005

Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors.

Worldwide, 100 million people are expected to die this century from the consequences of nicotine addiction, but nicotine is also known to enhance cognitive performance. Identifying the molecular mechanisms involved in nicotine reinforcement and cognition is a priority and requires the development of new in vivo experimental paradigms. The ventral tegmental area (VTA) of the midbrain is thought to mediate the reinforcement properties of many drugs of abuse. Here we specifically re-expressed the beta2-subunit of the nicotinic acetylcholine receptor (nAChR) by stereotaxically injecting a lentiviral vector into the VTA of mice carrying beta2-subunit deletions. We demonstrate the efficient re-expression of electrophysiologically responsive, ligand-binding nicotinic acetylcholine receptors in dopamine-containing neurons of the VTA, together with the recovery of nicotine-elicited dopamine release and nicotine self-administration. We also quantified exploratory behaviours of the mice, and showed that beta2-subunit re-expression restored slow exploratory behaviour (a measure of cognitive function) to wild-type levels, but did not affect fast navigation behaviour. We thus demonstrate the sufficient role of the VTA in both nicotine reinforcement and endogenous cholinergic regulation of cognitive functions.

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PubMed2001

Anxiogenic-like effects limit rewarding effects of cocaine in balb/cbyj mice.

Previous studies have reported intravenous cocaine self-administration behavior in several strains of mice with the exception of BALB/cByJ, a strain considered a mouse model of high emotional reactivity. The present experiments further investigated acquisition of self-administration in BALB/cByJ mice using a low dose and a habituation session. Following evidence of an initial drug-seeking behavior, we observed a progressive decline of intravenous self-administration. Pretreatment with diazepam (0.5 mg/kg, IP), reinstated cocaine-maintained responding. To test the hypothesis that injections directly into a reward-relevant brain region might support consistent cocaine-seeking behavior, BALB/cByJ mice implanted in the nucleus accumbens (NAc) or the caudate-putamen nucleus (CPu) were trained to discriminate between the arm enabling a microinjection of cocaine (30 pmol/50 nl or 150 pmol/50 nl) and the neutral arm of a Y-maze. Only NAc subjects exhibited a spatial discrimination toward the cocaine-reinforced arm and the D2 antagonist, sulpiride (50 mg/kg, IP) eliminated intra-NAc cocaine self-administration. However, after several days of cocaine self-injection, animals developed an approach/avoidance-like behavior between the start box and the reinforced arm. This behavior was suppressed by systemic diazepam (1 mg/kg, IP) pretreatment. We conclude that: (1) medio-ventral NAc is involved both in the rewarding (via a D2 dopaminergic mechanism) and aversive effects of cocaine in mice; and (2) anxiolytic pretreatment (diazepam) indirectly enhanced the reinforcing properties of cocaine in BALB/cByJ, suggesting that emotionality can act as a protective mechanism against stimulant abuse.

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PubMed2000

Anatomical and pharmacological specificity of the rewarding effect elicited by microinjections of morphine into the nucleus accumbens of mice.

RATIONALE: The involvement of nucleus accumbens (NAc) in initiating opiate-induced reward has been difficult to demonstrate in rats, and has not been studied in mice. OBJECTIVES: To determine whether a reward-sensitive strain of mice (BALB/c) would self-administer morphine directly into the NAc or sub-regions of the dorsal striatum. METHODS: BALB/c mice were unilaterally implanted with a guide-cannula above either the NAc, the anterior caudate putamen, or the posterior caudate putamen. On each experimental day, a stainless-steel injection cannula was inserted into the guide cannula to test the capacity for morphine self-administration (6.5 pmol or 65 pmol/50 nl) using a spatial discrimination task in a Y maze. RESULTS: Only the ventro-medial NAc group discriminated between the arm enabling a microinjection of morphine and the neutral arm. Once self-administration had been acquired, the effects of a pretreatment with two doses of the opiate antagonist naloxone (0.4 mg/kg or 4 mg/kg) were tested. Both doses slightly disrupted self-administration on the first 2 days. Only subjects receiving the 4-mg/kg dose exhibited an extinction of self-administration, related to an increasing number of jump attempts; none of the other opiate withdrawal-associated signs were observed. Self-administration was reinstated when naloxone was replaced with saline. CONCLUSIONS: (1) Medio-ventral NAc is involved in acute rewarding effects of opiates in mice. (2) Neither anterior nor posterior dorsal striatum seem to participate in these effects. (3) NAc is involved in jumping caused by naloxone-induced extinction, a behavior presumably revealing an aversive state associated with the unexpected suppression of reward.

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PubMed1998

Differential involvement of the lateral and medial divisions of the septal area on spatial learning processes as revealed by intracranial self-administration of morphine in mice.

The present study was conducted to investigate the effects of morphine self-administration into either the medial or lateral divisions of the septal region on spatial discrimination abilities in mice. To this end, BALB/c mice received a dose of 5 ng/50 nl of morphine sulfate, via a stainless steel injection cannula, inserted into either the medial septal area (MS) or the lateral septal nucleus (LS), when they are close to the end of one of the two choice arms of a Y-maze (acquisition period). In these conditions a discrimination between the reinforced arm and the neutral arm is acquired in MS as well as in LS mice. However both acquisition and subsequent extinction (vehicle only available) was more rapid in the LS group than in the MS group. Moreover, during the extinction period, numerous escape attempts from the Y-maze were observed for MS mice. When the dose of morphine was raised to 50 ng the pattern of acquisition was unchanged in the LS group. In contrast animals of the MS group learned to avoid the arm where the higher dose of morphine was delivered thus allowing us to conclude that in MS animals the drug effect became aversive at this higher dose. This possibility was directly investigated in a second experiment by closing the access to the neutral arm. Thus, for a 5-ng dose the rewarding effect of morphine was demonstrated in both MS and LS groups by the decrease of self-administration latencies which, furthermore, were notably lower than in the discrimination situation. Moreover, with the dose of 50 ng of morphine the latencies were identical for the two groups and at their lowest value thus indicating that morphine had similar appetitive effects in MS as well as in LS mice in this situation. Thus, the previously observed deficit of MS subjects, including escape attempts, disappeared when the dose of morphine was raised and the experimental context simplified. These results which demonstrate differential functional properties of these two septal divisions are discussed in terms of conflict resulting from the strongly appetitive effects of the morphine which induces, in parallel, deleterious consequences on cognitive processing in MS self-injected mice.

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PubMed1998

Rewarding effects elicited by the microinjection of either AMPA or NMDA glutamatergic antagonists into the ventral tegmental area revealed by an intracranial self-administration paradigm in mice.

In order to study the functional role of the trans-synaptic neuronal interaction between glutamatergic afferents and mesolimbic dopaminergic neurons in internal reward processes, BALB/c male mice were unilaterally implanted with a guide-cannula, the tip of which was positioned 1.5 mm above the ventral tegmental area (VTA). On each day of the following experimental period, a stainless steel injection cannula was inserted into the VTA in order to study the eventual self-administration behaviour of either the competitive N-methyl-D-aspartate antagonist, D(-)-2-amino-7-phosphonoheptanoic acid (AP-7) or the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX) (3 ng/50 nL) using a spatial discrimination task in a Y maze. Mice rapidly discriminated between the arm enabling a microinjection of either of these glutamatergic antagonists and the neutral arm of the maze, and a robust self-administration of either of these compounds was observed from the first session of acquisition. These data provide strong evidence that the intra-VTA microinjection of either of these subclasses of glutamatergic antagonist produces an effect which is interpreted centrally by the experimental subjects as being highly rewarding. Once the self-administration response had been fully acquired by the experimental subjects, preinjection of the dopaminergic D2 antagonist, sulpiride (50 mg/kg i.p.), 30 min before the test, produced a rapid extinction of the self-administration response. This latter result demonstrates the dopaminergic D2 receptor dependence of this intra-VTA self-administration of both of these subclasses of glutamatergic antagonist. We conclude that the different glutamatergic afferent neuronal inputs to the VTA globally exert, in vivo, via the mediation of interposed endogenous GABAergic interneurons, a tonic trans-synaptic inhibitory regulation of neuronal activity in the mesolimbic dopaminergic pathway and that this complex neuronal interaction in the VTA plays a significant functional part in the modulation of internal reward processes.

2-Amino-5-phosphonovalerate↗

PubMed1997

Self-administration of the GABAA antagonist bicuculline into the ventral tegmental area in mice: dependence on D2 dopaminergic mechanisms.

BALB/c mice were unilaterally implanted with a guide cannula, the tip of which was positioned 1.5 mm above the ventral tegmental area (VTA). On each day of the experimental period, a stainless steel injection cannula was inserted into the VTA in order to study the eventual self-administration of a low dose (1.5 ng/50 nl) of bicuculline, a GABAA-antagonist, using a spatial discrimination task in a Y maze. Mice rapidly discriminated between the arm enabling a micro-injection of bicuculline and the neutral arm of the maze, and robust self-administration of this GABAergic antagonist was observed. Once this self-administration response for bicuculline had been fully acquired, the systemic injection of the dopaminergic D2 antagonist sulpiride (50 mg/kg), 30 min before the test, produced a rapid extinction of the self-administration response. Moreover, if this same sulpiride pretreatment was given during the initial acquisition period mice did not discriminate between the two arms of the Y-maze. These data demonstrate the dopamine D2 dependence of this bicuculline self-administration behavior, and confirm that GABAergic interneurons and/or inputs normally transynaptically inhibit neuronal activity in the mesocorticolimbic dopamine system.

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PubMed1995

Dose-discrimination performance of mice for self-administration of morphine into the lateral hypothalamus.

Two experiments were performed in BALB/c mice implanted bilaterally with guide cannulae. In the first experiment, the tips of the guide cannulae were positioned 1.5 mm above the lateral hypothalamus (LH). On each experimental day, injection cannulae were inserted into each side of the LH. The experiment, carried out in a Y-maze, was composed of two phases. During the initial acquisition period, which lasted 4 days, animals were allowed to self-inject, successively, on alternate days, one dose of morphine into one side of the LH and a different dose in the other side. From the fifth day, the subjects were given the possibility of choosing between these two doses by entering into a given arm of the Y-maze. When the two doses available were 5 ng and 50 ng or 15 ng and 50 ng, the subjects rapidly discriminated them and preferentially triggered the injection of the higher dose (50 ng). When the two doses available were 30 ng and 50 ng, the mice triggered indifferently the two doses during the first three sessions. A discrimination between these two doses began to become apparent from the fourth session, with the subjects preferring to trigger the dose of 50 ng. In a second experiment, the tips of the guide cannulae were positioned either 1.5 mm or 2.6 mm above the LH, the bilateral injection cannulae consequently being inserted either into the LH or into the overlying ventral thalamus (TH). Experimental conditions were the same as that of Experiment 1.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1994

A comparative study of self-administration of morphine into the amygdala and the ventral tegmental area in mice.

BALB/c mice were unilaterally implanted with a guide-cannula, the tip of which was positioned 1.5 mm above either the amygdala (AMY) or the ventral tegmental area (VTA). On each experimental day, a stainless-steel injection cannula was inserted into these structures in order to compare the self-administration of two doses of morphine (5 ng or 50 ng) in independent groups using a spatial discrimination task in a Y-maze. During the acquisition phase, both AMY and VTA injected mice showed a regular self-administration response at the two doses used. The latency to trigger the injection was short, particularly in the VTA group. Subcutaneous injection of naloxone (4 mg/kg) in trained mice reduced the number of self-administrations to a level near to chance in both groups, which suggests that the drug-seeking behavior observed is effectively dependent on an opiate receptor-mediated mechanism. However the rate of extinction was more rapid in AMY than in VTA injected mice. The 'perseveration' response exhibited by the VTA group during the withdrawal precipitated by naloxone may probably be due to the strong motivational and/or rewarding effect of morphine when injected in this brain structure during acquisition.

Amygdala↗

PubMed1994

Differentiation of intracranial morphine self-administration behavior among five brain regions in mice.

BALB/c mice were unilaterally implanted with a guide cannula, the tip of which was positioned 1.5 mm above either the lateral hypothalamus (LH) the medial hypothalamus (MH), the mesencephalic central gray area (CG), or either the dorsal (DRF) or ventral parts (VRF) of the reticular formation. On each day of the experimental period a stainless steel injection cannula was inserted into these brain structures to compare the self-administration of two doses of morphine (5 ng or 50 ng), using a spatial discrimination task in a Y-maze. At the dose of 5 ng, LH-, MH-, CG-, and VRF-injected mice all showed a regular self-administration response. At the dose of 50 ng, a discrimination between the reinforced arm and the neutral arm of the Y-maze was observed in LH-, MH-, and VRF-injected mice. Animals of the MH group exhibited the highest level of discrimination performance. At this dose, long injection latencies (> 15 min) were recorded in the CG group, which constrained us to reduce the number of daily trials from 10 to 4. In these modified conditions, CG animals clearly self-injected the dose of 50 ng of morphine. Subcutaneous injections of naloxone (4 mg/kg) reduced the number of self-administrations of morphine at each of the four responding structures. Marked signs of physical dependence (escape attempts) were observed in the four groups but with a higher frequency in CG and MH animals. When the injections of naloxone were suspended, a regular self-administration reappeared.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1991

Differential effects of naloxone on approach and escape responses induced by electrical stimulation of the lateral hypothalamus or the mesencephalic central gray area in mice.

BALB/c mice implanted with a bipolar electrode were trained in a shuttle-box to initiate and to terminate a continuous electrical stimulation applied in the lateral hypothalamus (LH) or in the mesencephalic central gray area (CG). Following stabilization of the baseline response latencies, the subjects were subcutaneously injected with isotonic NaCl or with naloxone HCl (0.5, 2 or 10 mg/kg) 15 min or 45 min before a test session. In LH-stimulated animals no modification of the behavioral responses was observed after injection of 0.5 mg/kg of naloxone. The 2 mg/kg dose increased the value of escape latency (ON time) but had no effect on approach latency (OFF time). The 10 mg/kg dose also increased ON time. At this dose, an increase of OFF time was simultaneously observed but only 15 min after the injection. In CG-stimulated mice an increase of OFF time and a reduction of ON time were recorded 15 min after the injection of 0.5 mg/kg. Only the reduction of ON time was detected for the 45-min delay. The 2 mg and 10 mg/kg doses simultaneously increased OFF time and reduced ON time for the two delays. These results demonstrate 1) that the effects of naloxone on self-stimulation varied as a function of the structure considered 2) that the predominant characteristic of the considered structure (essentially "rewarding" as the LH or "aversive" as the CG) governs the modulations induced by naloxone.

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PubMed1990

Dose-dependent effects of morphine differentiate self-administration elicited from lateral hypothalamus and mesencephalic central gray area in mice.

BALB/c mice were unilaterally implanted with a guide-cannula, the tip of which was positioned 1 mm above either the lateral hypothalamus (LH) or the mesencephalic central gray area (CG). On each experimental day, a stainless-steel injection cannula was inserted into the LH or the CG and self-administration of two doses of morphine (50 and 5 ng) was compared in the two brain structures using a spatial discrimination task in a Y-maze. At the dose of 50 ng, mice injected into the LH rapidly discriminated the reinforced arm from the neutral arm of the maze in order to self-administer morphine. In contrast, at this same dose, mice of the CG group do not show any regular self-administration behavior. At the dose of 5 ng, both LH and CG injected mice show a regular self-administration response. The rate of discrimination was similar in the two groups. When naloxone (5 ng) was mixed with morphine (5 ng), the number of self-administrations progressively decreased in both brain areas. This decrease was both larger and more rapid in CG than in LH. Marked signs of physical dependence (escapes from the maze) were observed in the two groups during this phase. Finally, when morphine alone (5 ng) was again made available, a regular self-administration response reappeared in the two brain structures. These data suggest (1) that morphine has reinforcing effects in both LH and CG and (2) that in these two brain structures self-injection of this drug is dependent on an opiate receptor mediated mechanism.

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PubMed1989

Intertrial interval dependent effect of lateral hypothalamic stimulation on spontaneous alternation behavior in a T-maze.

Spontaneous alternation behavior in a T-maze was studied in mice of the BALB/c strain implanted with a stimulation electrode in the lateral hypothalamus (LH). For animals receiving no electrical stimulation spontaneous alternation rates decreased as a function of the increasing time interval between the first and the second trial (intertrial interval ITI). Thus, as compared to chance rate alternation (41.4%), mice significantly alternated at the 30 sec ITI (73.2%), exhibited a slight but not significant tendency to alternate at 30 min (51.8%) and performed very close to chance at 6 hr (39.3%). Stimulation of the LH, using a low current intensity (5 microA) during the first arm-choice, modifies subsequent arm-choice tested on the second trial. The direction of the effect, however, is highly dependent on the ITI. Thus, as compared to nonstimulated animals, stimulated mice show a strong preference to return to the previously visited arm when the ITI was 30 min, while for an ITI of 6 hr they, in fact, significantly avoid that arm (alternation). These results indicate that LH stimulation induces facilitative effects on memory for events occurring on the 1st trial as clearly shown for the 6 hr ITI. In addition to its general facilitative effect, stimulation could induce a place-reward association of short-duration which could explain the fact that animals tend to return to the same arm at 30 min. Alternatively, it is suggested that stimulation might have short-lasting amnesiant properties. Both of these hypotheses are discussed.

Animals↗

PubMed1988

Electrical self-stimulation in the medial and lateral septum as compared to the lateral hypothalamus: differential intervention of reward and learning processes?

The characteristics of the electrical self-stimulation behavior elicited from the lateral hypothalamus (LH) and from both medial (MS) and lateral (LS) parts of the septal nucleus have been compared in male mice of the BALB/c strain. Using two different experimental situations (the lever-press box and a spatial discrimination test in a Y-maze) the self-stimulation rate-current intensity relations and the performances during both acquisition and reversal of a spatial discrimination were tested successively. In the lever-press box, it was observed that highest self-stimulation rates were obtained from LH placements while both MS and LS rates were lower. However, MS animals showed higher self-stimulation rates and lower self-stimulation thresholds than LS animals. Acquisition of the spatial discrimination in the Y-maze was achieved by all 3 groups with similar time courses. However, when tested for the reversal of the discrimination, the LS implanted mice were much more perturbed than the two other groups and exhibited marked perseveration. The incidence of convulsive episodes was more frequent in LS mice than in either MS or LH implanted animals during both phases of the discrimination task. These differences in the self-stimulation behavior elicited from medial and lateral parts of the septal complex are discussed in relation to the operation of positive reinforcement mechanisms and to internal inhibition processes operating during acquisition and reversal of the spatial discrimination.

Animals↗

PubMed1988

Differential effects of intracerebral microinjection of morphine on approach and escape responses induced by lateral hypothalamic stimulation in the mouse.

BALB/c mice were implanted with a combined guide-cannula and bipolar stimulation electrode. The tip of the guide-cannula was positioned 1.0 mm above the electrode tip which was located in the lateral hypothalamus (LH). Mice were trained in a shuttle-box to initiate and terminate a continuous electrical stimulation of the LH. Following stabilization of the baseline response latencies two experiments were performed. In the first experiment, isotonic NaCl or morphine sulphate (0.5, 1.0 or 2.0 micrograms dissolved in NaCl) were injected into the LH (volume of the injection 0.5 mu 1). The lowest dose (0.5 microgram) of morphine rapidly decreased approach latency for LH stimulation over a period of two hours. The same result was observed with both 1.0 and 2.0 micrograms but with greater magnitude and a longer time course. In some animals, an increase in escape latency appeared but only at the dose of 1.0 microgram. In the second experiment, it was observed that intraperitoneal injection of naloxone (2.0 mg/kg) suppressed the shortening of latency of approach responses induced by the microinjection of 2.0 micrograms of morphine. These results suggest the involvement of opiate mechanisms in the regulation of LH self-stimulation.

Animals↗

PubMed1987

Self-administration of morphine into the lateral hypothalamus in the mouse.

BALB/c mice were chronically and unilaterally implanted with a guide cannula, the tip of which was positioned 1 mm above the lateral hypothalamus (LH). On each experimental day, a stainless-steel injection cannula was inserted into the LH, and self-administration of morphine or vehicle in this brain area was studied by using a spatial discrimination test in a Y-maze. In a first experiment, we observed that when mice had access to morphine (0.1 microgram by injection) they rapidly discriminated the reinforced arm from the neutral arm of the maze in order to self administer, with increasing frequency, the drug into the LH. In contrast when only vehicle was present, the two arms were no longer discriminated. In a second experiment we compared the effects of 3 doses of morphine (0.1 microgram, 0.05 microgram and 0.025 microgram by injection); optimal discrimination was obtained with the lowest dose used. In a third experiment we observed that subcutaneous injections of naloxone (4 mg/kg) progressively reduced the number of self-administrations of morphine into the LH, a result which suggests that this response is dependent on an opiate receptor mechanism.

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PubMed1987

Dorso-ventral variation in the attenuating effect of lateral hypothalamic stimulation on the switch-off response elicited from the mesencephalic central gray area.

Previous experiments have shown that the lateral hypothalamus (LH) is a heterogeneous structure with respect to self-stimulation and aversion. Specifically it has been reported that stimulation of the dorsal LH region entails consequences which are both more rewarding and more aversive than those due to ventral LH stimulation [5, 7, 8, 16, 18]. The aim of the present study was to compare the effects of electrical stimulation applied to either the dorsal or the ventral regions of the LH on the switch-off response elicited by activation of the dorsal part of the mesencephalic central gray area (CG). This experiment was performed using BALB/c mice. The results obtained show that whatever the LH site, hypothalamic stimulation reduces the aversive effects of CG stimulation; however, ventral LH activation was more effective than the dorsal one. In addition, a close relationship was observed between the tolerance in regard to LH stimulation alone, and the tolerance in regard to combined CG/LH stimulation. These data suggest that the more marked aversive consequences of dorsal LH stimulation represent a limiting factor for the attenuating effect on CG escape responding.

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