Biomedical subjects

M Le Moal

Publications and source records attributed to M Le Moal.

At least 145 records · Page 8Linked to original sources

PubMed1993

Corticosterone in the range of stress-induced levels possesses reinforcing properties: implications for sensation-seeking behaviors.

In both humans and animals certain individuals seek stimuli or situations that are considered stressful and consequently avoided by others. A common feature of such situations is an activation of the hypothalamo-pituitary-adrenal axis leading to secretion of glucocorticoids. Since glucocorticoids have euphoric effects in some individuals and have been shown to potentiate the reinforcing properties of drugs of abuse in animals, we hypothesized that corticosterone secretion during stress-like situations may have reinforcing effects and that a higher sensitivity to the reinforcing effects of glucocorticoids might be a biological basis of sensation seeking. In this report we show that (i) corticosterone has reinforcing properties, as evidenced by the development of intravenous self-administration, (ii) self-administration of corticosterone is observed at plasma levels that are comparable to those induced by stress, and (iii) there are individual differences in corticosterone self-administration, which are related to individual reactivity to novelty and sensitivity to drugs of abuse, behavioral features akin to certain traits of high-sensation seekers. These findings provide insight into the physiological role of glucocorticoids and the biology of sensation seeking and may have clinical implications.

Analysis of Variance↗

PubMed1993

Individual differences in the psychomotor effects of morphine are predicted by reactivity to novelty and influenced by corticosterone secretion.

Clinical observations show that individual vulnerability to the reinforcing properties of drugs plays an important part in the subsequent development of addition. In animals, individual vulnerability to psychostimulants has been found to be predicted by their locomotor response to novelty as well as their corticosterone response. Rats with a high locomotor response to novelty (High Responders or HR) relative to Low Responders (LR), show a higher sensitivity to both the psychomotor and reinforcing effects of psychostimulants and a longer lasting corticosterone secretion in response to stress. In this study, we addressed two main questions. First, does the locomotor response to novelty also predict the psychomotor effects of morphine? Second, do differences in corticosterone secretion underlie individual differences in the stimulant effects of morphine? We compared the locomotor response to morphine (2 mg/kg s.c.) in: (i) HR and LR rats with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) HR and LR rats in which stress-induced corticosterone secretion was suppressed by adrenalectomy but basal levels of corticosterone were maintained by implantation of subcutaneous corticosterone pellets. In animals with an intact HPA axis, HR rats showed a higher locomotor response than did LRs to morphine. In animals in which corticosterone secretion was suppressed, the enhanced locomotor response of the HRs to morphine fell to that observed in the LRs. In conclusion our data show that, (1) individual reactivity to novelty can predict individual vulnerability to the psychomotor effects of opioids, and (2) stress-induced corticosterone secretion may play a role in determining individual differences in sensitivity to these drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗

PubMed1993

Basal and stress-induced corticosterone secretion is decreased by lesion of mesencephalic dopaminergic neurons.

There is evidence that certain psychopathological conditions are accompanied by a dysfunction in both the hypothalamo-pituitary-adrenal axis and dopaminergic systems, although the relationship between these two systems is as yet unclear. In the present study we investigated the effect of a specific lesion of dopamine mesencephalic neurons (Ventral Tegmental Area) on basal and stress-induced corticosterone secretion. Three weeks after injection of 6-OHDA, there was a depletion in dopamine in the frontal cortex and in the ventral and dorsal striatum, whereas norepinephrine and serotonin levels were unchanged. The dopamine-lesioned rats exhibited a lower basal and stress-induced corticosterone secretion than the sham-lesioned animals. The results indicate that the dopaminergic system may have a stimulatory influence on the hypothalamo-pituitary-adrenal axis.

Animals↗

PubMed1993

Rats orally self-administer corticosterone.

Corticosterone, the major glucocorticoid in the rat, may modulate the reinforcing properties of addictive drugs as well as act as a positive reinforcer for intravenous self-administration. Since glucocorticoids are generally administered to humans via the oral route, we examined the ability of corticosterone to induce oral self-administration in the rat. In a first experiment, animals with free access to food could choose between a corticosterone solution and water. Three doses (25, 50 and 100 micrograms/ml) were tested. The group receiving the 100 micrograms/ml dose was also submitted to an extinction followed by a reversal test. In a second experiment, we examined whether the reinforcing properties of corticosterone could induce drinking independently of food intake. In the pre-test phase rats had access to food only during a fixed period of the day (11.00 h to 14.00 h). Corticosterone solution (200 micrograms/ml) or tap water were available during this period, with free access to tap water for the rest of the day. During the test period, access to food was shifted forward in time, while the availability of the corticosterone solution remained the same. The first experiment showed that rats preferred a corticosterone solution to tap water, developing self-administration in a dose-dependent manner. This preference could be extinguished, but was regained during the reversal phase. In the second experiment, animals that had access to the corticosterone solution drank more than rats that had access to water in the absence of food. These results indicate that corticosterone has reinforcing properties after oral administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1993

Relationship between schedule-induced polydipsia and amphetamine intravenous self-administration. Individual differences and role of experience.

It has been suggested that drug abuse belongs to a larger class of addictive behaviors, including smoking, eating or gambling, which are mediated by common processes. Since laboratory animals can be induced to develop drug self-administration as well as indulge in compulsive eating or drinking, the present experiments were designed to find out if the same animals were susceptible to both behaviors. Only certain rats develop amphetamine intravenous self-administration (SA), and this susceptibility can be predicted from their enhanced locomotor response in a novel environment. Furthermore, excessive, non-regulatory drinking, referred to as schedule-induced polydipsia (SIP), in response to the periodic delivery of small amounts of food is only observed in certain rats. Since the propensity to SA has been shown to be influenced by experimental factors and testing for SIP was found to modify behavioral and biological parameters related to the propensity for drug-seeking, we also investigated whether experience of SIP influenced the subsequent development of SA. In Expt. 1, the rats that developed SA also acquired SIP, and had a higher locomotor response to novelty. The results of Expt. 2 showed that testing for SIP influenced the predisposition to develop amphetamine SA. When animals were tested for SIP first, the polydipsic rats subsequently failed to acquire SA, and had a reduced locomotor response to novelty. These changes seemed to be specific to the experience of SIP, as individual differences in the locomotor response to novelty were unchanged when animals were housed in standard laboratory conditions over a period of one month between the two tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Psychological↗

PubMed1993

Sensitization to the psychomotor effects of amphetamine and morphine induced by food restriction depends on corticosterone secretion.

Food restriction has been shown to enhance the behavioral sensitivity to addictive drugs. The biological factors involved in this effect are largely unknown. Since food restriction, among other factors, increases corticosterone secretion, the role of this hormone in the effects of food restriction on the response to psychostimulants and opioids was investigated. The effects of food restriction on amphetamine- and morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal axis; (ii) animals in which food restriction-induced corticosterone secretion was suppressed by adrenalectomy, but which received exogenous corticosterone from a subcutaneous implant, which slowly releases corticosterone, producing a stable plasma level within the normal physiological range over a period of 20 days. It was found that food restriction enhanced sensitivity to the psychomotor effects of amphetamine (1 mg/kg i.p.) and morphine (1 mg/kg i.p.) in animals with an intact hypothalamo-pituitary-adrenal axis, but not in animals in which endogenous corticosterone secretion was eliminated. These results suggest that corticosterone secretion may be one of the mechanisms by which food restriction amplifies the behavioral responses to amphetamine and morphine. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings point to a role for glucocorticoids in the susceptibility to drug abuse.

Adrenalectomy↗

PubMed1993

Infusion of neurosteroids into the nucleus basalis magnocellularis affects cognitive processes in the rat.

The neurosteroids, pregnenolone sulfate (PREG-S) and tetrahydroprogesterone (TH-PROG), act on the GABAA receptor with antagonist or agonist-like properties, respectively. In this study the effect of the infusion of PREG-S and TH-PROG into the nucleus basalis magnocellularis (NBM) of the rat was examined in a two-trial memory task. The results show that PREG-S (5 ng in 0.5 microliter) enhances memory performance when injected after an acquisition trial; conversely TH-PROG (2 ng in 0.5 microliter) disrupts performance when injected before an acquisition trial. A role for neurosteroids in memory processes subserved by the nucleus basalis magnocellularis is of interest in view of the implication of this structure and these substances in neurodegenerative processes.

Animals↗

PubMed1993

Central administration of corticotropin releasing factor induces long-term sensitization to D-amphetamine.

Corticotropin releasing factor (CRF) has been shown to initiate neuroendocrine and behavioral responses to stress. As stress and amphetamine (AMPH) show cross-sensitization, we investigated the role of endogenous CRF in behavioral sensitization to D-AMPH. In order to evaluate the participation of the central action and the pituitary-adrenocortical (PA) stimulatory effect of CRF, we compared the effects of repeated intracerebroventricular (i.c.v.) administration of CRF (0, 0.5, 2.5 micrograms/2 microliters), which have central and neuroendocrine consequences, with those of repeated subcutaneous administration of CRF (0, 0.1, 0.5, 2.5 micrograms/250 microliters), doses which only stimulate the PA axis, on the development of sensitization to AMPH-induced motor activation administered 1 week later. Repeated i.c.v. administration of CRF induced a long-lasting enhancement of the hyperactivity induced by 0.75 mg/kg peripheral administration of D-AMPH, whereas no sensitization to D-AMPH was observed following repeated subcutaneous administration of CRF. These results favor the hypothesis that a centrally mediated action of CRF is involved in the cross-sensitization of psychostimulants and stress.

Animals↗

PubMed1993

Intrastriatal transplants of embryonic dopaminergic neurons counteract the increase of striatal enkephalin immunostaining but not serotoninergic sprouting elicited by a neonatal lesion of the nigrostriatal dopaminergic pathway.

The aim of the our experiment was to compare the ability of intrastriatal implants of embryonic dopaminergic neurons to reverse two kinds of postlesion modification in the host brain: the change in the activity level of neurons in the denervated area and morphological modifications, e.g. collateral sprouting. The ascending dopaminergic system of 3-day-old rat pups was unilaterally lesioned by an intrahypothalamic injection of the neurotoxin 6-hydroxydopamine. This lesion has been described previously to induce an increase in the level of activity of striatal enkephalinergic neurons. The same lesion leads also to sprouting of the serotoninergic afferents in the striatum, leading to hyperinnervation of this structure. The existence of these modifications thus offers the possibility of testing the influence of grafts in one structure of the same animal on two lesion-induced reactions of different nature. A cell suspension obtained from mesencephali of embryonic day 14 rats and containing dopaminergic neurons was implanted into the denervated striatum of lesioned animals 5 days after the lesion. Nine months later the animals were killed and immunohistochemistry was performed on striatal sections using antibodies directed against tyrosine hydroxylase, methionine enkephalin and serotonin. Intensity of immunostaining (methionine enkephalin and serotonin) as well as innervation density (serotonin) was quantified through the use of a computer-assisted image analyser. The lesion led to the disappearance of striatal dopaminergic innervation. Implanted dopaminergic neurons were found scattered in the striatum and restored a dopaminergic innervation in a large portion of this structure. There was a marked increase in striatal methionine enkephalin immunostaining in lesioned animals, which was most pronounced in the dorsolateral part of the striatum (+ 150% compared to control values), while in the ventral part it was slight or non-existent. The density of striatal serotoninergic innervation was also increased by approximately 250% relative to control values. In grafted animals striatal enkephalin immunostaining was similar to that observed in control animals. On the other hand, the serotoninergic hyperinnervation was still present in the graft-bearing striata. These results suggest that while intrastriatal implants of embryonic dopaminergic neurons are able to counteract modifications in the functioning of local striatal neuronal systems such as the increase in enkephalinergic activity or receptor hypersensitivity occurring as a result of the lesion, they might be unable to reverse postlesion morphological modifications.

Animals↗

PubMed1993

Higher and longer stress-induced increase in dopamine concentrations in the nucleus accumbens of animals predisposed to amphetamine self-administration. A microdialysis study.

Individual vulnerability to the reinforcing effects of drugs appears to be a crucial factor in the development of addiction in humans. In the rat, individuals at risk for psychostimulant self-administration (SA) may be identified from their locomotor reactivity to a stress situation such as exposure to a novel environment. Animals with high locomotor responses to novelty (high responders, HR) acquire amphetamine SA, while animals with low responses (low responders, LR) do not. In this study we examined by microdialysis whether stress-induced extracellular dopamine (DA) concentrations in the nucleus accumbens differed between these two groups of animals. This neurotransmitter was studied because it is thought to be involved in the reinforcing effects of psychostimulants. Furthermore, previous studies have shown that HR animals have a higher basal DOPAC/DA ratio in the nucleus accumbens and higher extracellular concentrations of dopamine in this structure in response to cocaine. The stress procedure used in this experiment consisted of a 10 min tail-pinch. HR animals displayed a higher and longer stress-induced changes in DA concentrations than the LR group. Regression analysis showed that stress-induced changes in DA levels accounted for 75% of the variance observed in the locomotor response to a novel environment. Since higher DA activity in the nucleus accumbens has been reported in animals in which the propensity to psychostimulant SA is induced by brain lesions or life events, this biochemical modification may be one neurobiological substrate of the predisposition to acquire psychostimulant self-administration.

Amphetamine↗

PubMed1993

Transplantation of fetal nigral cells reverses the increase of preproenkephalin mRNA levels in the rat striatum caused by 6-OHDA lesion of the dopaminergic nigrostriatal pathway: a quantitative in situ hybridization study.

Unilateral 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal dopamine (DA) pathway causes a significant increase of preproenkephalin (PPE) messenger RNA (mRNA) levels in the DA-depleted striatum in rat brain. Using an in situ hybridization (ISH) technique and computer-assisted microdensitometry, we quantified the changes in PPE mRNA levels in the striatum. Seven months after lesion, levels of PPE mRNA were 75% higher in the DA-depleted striatum than in the contralateral control striatum of the same animal or in the striatum of sham control animals. The implantation of embryonic dopaminergic neurons into the denervated striatum led to a complete reversal of this increase and, in grafted animals, levels of PPE mRNA were at control values. Moreover, this reversal extended beyond the areas reinnervated by the grafted dopaminergic neurons.

Animals↗

PubMed1993

Effects of intracerebral dopaminergic grafts on behavioural deficits induced by neonatal 6-hydroxydopamine lesions of the mesotelencephalic dopaminergic pathway.

The functional capabilities of dopamine neuron-rich grafts implanted into the accumbens and striatal regions in neonatal rats were evaluated in a series of behavioural tests. The ascending mesotelencephalic dopaminergic system of three-day-old rat pups was bilaterally lesioned by injecting 6-hydroxydopamine at the level of the lateral hypothalamus. Five days later a suspension containing dopaminergic neurons obtained from embryonic day 14 mesencephali was injected bilaterally into the striatal complex. The functional effects of such grafts were evaluated using behavioural tests for which it was known that the performance of the animals is changed following the lesion of the mesotelencephalic pathway and for which the influence of dopaminergic grafts implanted into adult hosts have previously been described. The dopamine-rich grafts compensated for the modifications of the locomotor responsiveness to amphetamine and apomorphine induced by neonatal dopamine depletion. However, the grafts were unable to restore more complex behaviours such as hoarding for food pellets, schedule-induced polydipsia and learning behaviours. Moreover, the neonatal transplants induced additional deficits such as catalepsia, nocturnal hyperactivity and day-time hyperactivity during food deprivation. It was concluded that, at least in the present paradigm, the implantation into neonatal brain does not lead to any greater functional recovery than that observed after implantation during adulthood.

Animals↗

PubMed1993

Mechanisms of amphetamine-induced rotation in rats with unilateral intrastriatal grafts of embryonic dopaminergic neurons: a pharmacological and biochemical analysis.

Amphetamine induces a pronounced rotation directed ipsilateral to the lesion and lasting about 2 h in rats bearing a unilateral lesion of the nigrostriatal dopaminergic pathway. Implantation of embryonic dopaminergic neurons into the lesioned striatum leads to a compensation of this rotation. However, graft-bearing animals display a strong biphasic contralateral rotation, lasting up to 5 h. To try to ascertain the mechanisms of this anomalous rotation, two separate experiments were performed. First, we tested whether the contralateral rotation presented by the grafted animals could be correlated to the persistence of the lesion-induced decoupling of striatal D1 and D2 receptors. Lesioned and grafted animals were submitted to a series of four amphetamine (5 mg/kg, i.p.) rotation tests. Preceding each test animals received, in a randomized order, one of four of the following treatments: physiological saline, a D1 receptor blocker (SCH-23390, 0.1 mg/kg, s.c.), a D2 receptor blocker (raclopride, 2.5 mg/kg, i.p.) or the combination of the D1 and D2 antagonists. The ipsilateral rotation observed in the lesioned animals was abolished by the separate blockade of both classes of dopamine receptor as well as by their combined blockade. Grafted animals could be separated into two subgroups, based on the effect of the antagonists during the first 2 h of amphetamine-induced rotation. In one subgroup, antagonists had the same effect on the amphetamine-induced contralateral rotation as they did on the ipsilateral rotation displayed by lesioned animals. In this group, D1 and D2 receptors were therefore recoupled by the implant in the lesioned striatum. In the other subgroup, the contralateral rotation could be antagonized only by the combined D1 and D2 blockade, while the separate blockade of D1 or D2 receptors did not decrease or even increased the amphetamine-induced rotation. This indicates that in this group the lesion-induced decoupling of D1 and D2 receptors persisted. Nevertheless, the characteristics of the amphetamine-induced rotation (magnitude, duration) were the same in the two subgroups. Likewise, hypersensitivities of both D1 and D2 receptors were completely abolished by the graft in both subgroups. From this experiment it is concluded that the amphetamine-induced rotation observed in grafted animals is not correlated with the state of coupling of striatal D1 or D2 receptors. In a second experiment, dopamine release was monitored by microdialysis in the graft-bearing and the contralateral normal striatum of awake, behaving animals following the administration of amphetamine to test whether the observed rotation could be explained by a higher than normal dopamine release from the implanted dopaminergic neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Amphetamine↗

PubMed1993

The mesolimbic dopaminergic system exerts an inhibitory influence on brain corticosteroid receptor affinities.

Central type I and type II corticosteroid receptors play a principle role in the regulation of corticosterone secretion. Although the binding capacity of these receptors is thought to be regulated essentially hormonally, there is also evidence for a direct neural control. For example, experimental manipulation of central serotoninergic and noradrenergic activities modifies the binding capacity of type I and type II corticosteroid receptors via a corticosterone-independent mechanism. In this study, we tested the effect of lesions of dopaminergic neurons in the ventral tegmental area on corticosteroid receptor binding capacity. The study was performed in adrenalectomized rats whose corticosterone levels were maintained within normal limits by corticosterone pellets and corticosterone in their drinking water during the dark period to generate the circadian rhythm. Binding properties of corticosteroid receptors were analysed in target regions of the lesioned neurons, including the ventral and dorsal striatum. Corticosteroid receptors in the hippocampus were also studied as a control as these lesions do not significantly affect dopamine content in this structure. Three weeks after the lesion, type II corticosteroid receptor affinity was increased in the ventral striatum. There was no effect on receptors in the dorsal striatum or hippocampus. Our results, together with other reports showing that dopamine inhibits the expression of corticosteroid receptors in the anterior pituitary, suggest that dopamine transmission exerts a negative control on central corticosteroid receptors.

Adrenalectomy↗

PubMed1993

Regulation of catecholamine-synthesizing enzymes in adrenals of Wistar rats under chronic stress.

We have shown previously that chronic social stress has differential effects on adrenal weight and on tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) specific activity, depending on the experimental design. To determine the role of the sympathetic nervous system and of the hypothalamo-pituitary-adrenocortical axis (HPAA) in these modifications, we studied the mechanisms of regulation of these parameters in basal conditions as well as in response to reserpine treatment and chronic social stress in the Wistar strain of rats. We found that the adrenal weight is mostly dependent on the activity of the HPAA, which is increased in male rats living in mixed-sex colonies. PNMT specific activity is regulated by splanchnic innervation, confirming that its induction by social instability is a consequence of sympathetic nervous system hyperactivity. The increase of TH specific activity, as seen in unstable, mixed-sex colonies, is not under sympathetic control. However, we show that the pituitary may exert a tonic inhibitory influence, dependent on the sympathetic innervation. These data confirm that the HPAA and the sympathetic nervous system may be independently triggered in chronic social stress conditions.

Adrenal Glands↗

PubMed1992

Stress-induced sensitization to amphetamine and morphine psychomotor effects depend on stress-induced corticosterone secretion.

Repeated exposure to stressful situations has been shown to increase individual reactivity to addictive drugs. However, the biological factors involved in such stress-induced changes are largely unknown. In this study, we investigated the role of corticosterone in the effects of restraint stress on the response to psychostimulants and opioids. The effects of repeated stress on amphetamine- and morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) animals in which stress-induced corticosterone secretion was blocked by adrenalectomy, but who received exogenous corticosterone from a subcutaneous implant. The implanted pellets (50 mg) slowly release corticosterone producing a stable plasma level within the normal physiological range over a period of 20 days. Restraint stress increased the locomotor response to both amphetamine (1.5 mg/kg i.p.) and morphine (2 mg/kg s.c.) in animals with an intact HPA axis, but not in animals in which stress-induced corticosterone secretion was suppressed. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress amplifies behavioral responses to amphetamine and morphine. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings point to a role for glucocorticoids in the susceptibility to drug abuse.

Adrenal Glands↗

PubMed1992

Corticotropin-releasing factor induces a place aversion independent of its neuroendocrine role.

The purpose of the present experiment was to test the hypothesis that corticotropin-releasing factor (CRF), a polypeptide of 41 amino acids, when administered either intracerebroventricularly (i.c.v.) or subcutaneously (s.c.), has aversive properties in the conditioned place-preference paradigm. Five doses of CRF (0, 0.005, 0.05, 0.5, 5 micrograms) were tested. i.c.v. CRF induced a specific dose-dependent reduction of the amount of time spent in the environment previously paired with the administration of CRF. Furthermore, this CRF-induced place aversion was prevented by pretreatment with alpha-helical-CRF(9-41), a specific CRF antagonist, administered i.c.v. In order to test whether the aversive effects induced by i.c.v. CRF could result from the stimulation of the HPA axis accompanying i.c.v. CRF injection, the reinforcing properties of s.c. CRF were studied using the same dose range. Only the higher s.c. dose was effective in producing a place aversion suggesting that the aversive effects of CRF could not be due solely to the stimulation of the pituitary-adrenocortical system, measured by plasmatic levels of adrenocorticotropic hormone (ACTH) and corticosterone, because the lower doses consistently activate the pituitary-adrenocortical system without producing any behavioral changes. Altogether, these data indicate that the non-neurosecretory CRF neurons may mediate the aversive state occurring during stress.

Animals↗

PubMed1992

Cognitive enhancing properties of beta-CCM infused into the nucleus basalis magnocellularis of the rat.

Peripheral administration of various benzodiazepine derivatives or beta-carbolines (inverse agonists at benzodiazepine receptors), has been shown to affect memory. In this study, the effect of local infusion of a beta-carboline-methyl beta carboline-3-carboxylate (beta-CCM) into the nucleus basalis magnocellularis (NBM) of rats was examined in a two-trial recognition task. The results show that beta-CMM (3 micrograms/0.5 microliter) enhances recognition performance when injected both before or immediately after the acquisition trial. These effects appear to be mediated by a benzodiazepine (BZD) receptor since they were blocked by pretreatment with Ro 15-1788, a BZD receptor antagonist. This study supports the involvement of the NBM in cognitive processes, and demonstrates that these processes can be influenced by alteration of GABAergic neurotransmission.

Animals↗