Michel Le Moal

Drug Addiction, Dysregulation of Reward, and Allostasis

This paper reviews recent developments in the neurocircuitry and neurobiology of addiction from a perspective of allostasis. A model is proposed for brain changes that occur during the development of addiction that explain the persistent vulnerability to relapse long after drug-taking has ceased. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in the compulsive use and loss of control over drug-taking. The development of addiction recruits different sources of reinforcement, different neuroadaptive mechanisms, and different neurochemical changes to dysregulate the brain reward system. Counteradaptive processes such as opponent-process that are part of normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to form an allostatic state. Allostasis from the addiction perspective is defined as the process of maintaining apparent reward function stability by changes in brain reward mechanisms. The allostatic state represents a chronic deviation of reward set point and is fueled not only by dysregulation of reward circuits per se, but also by the activation of brain and hormonal stress responses. The manifestation of this allostatic state as compulsive drug-taking and loss of control over drug-taking is hypothesized to be expressed through activation of brain circuits involved in compulsive behavior such as the cortico-striatal-thalamic loop. The view that addiction is the pathology that results from an allostatic mechanism using the circuits established for natural rewards provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and relapse.

Maternal Glucocorticoid Secretion Mediates Long-Term Effects of Prenatal Stress

There is growing evidence that stressors occurring during pregnancy can impair biological and behavioral adaptation to stress in the adult offspring. Mechanisms by which stress in the pregnant rat can influence development of the offspring are still unknown. In the present study, we investigated the involvement of maternal corticosterone secretion during pregnancy on the hypothalamo–pituitary–adrenal axis activity of adult offspring. We investigated stress-induced corticosterone secretion and hippocampal type I and type II corticosteroid receptors in male adult rats submitted to prenatal stress born to either mothers with intact corticosterone secretion or mothers in which stress-induced corticosterone secretion was blocked by adrenalectomy with substitutive corticosterone therapy. Repeated restraint during the last week of pregnancy was used as prenatal stressor. Furthermore, the specific role of an injection of corticosterone before the restraint stress on adrenalectomized mothers with substitutive corticosterone treatment was also studied. We report here that blockade of the mother’s stress-induced glucocorticoid secretion suppresses the prolonged stress-induced corticosteroid response and the decrease in type I hippocampal corticosteroid receptors usually observed in prenatally stressed adults. Conversely, corticosterone administered during stress, to mothers in which corticosterone secretion is blocked, reinstates the effects of prenatal stress. These results suggest for the first time that stress-induced increases in maternal glucocorticoids may be a mechanism by which prenatal stress impairs the development of the adult offspring’s glucocorticoid response.

Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis

Neurogenesis occurs within the adult dentate gyrus of the hippocampal formation and it has been proposed that the newly born neurons, recruited into the preexistent neuronal circuits, might be involved in hippocampal-dependent learning processes. Age-dependent spatial memory impairments have been related to an alteration in hippocampal plasticity. The aim of the current study was to examine whether cognitive functions in aged rats are quantitatively correlated with hippocampal neurogenesis. To this end, we took advantage of the existence of spontaneous individual differences observed in aged subjects in a hippocampal-dependent task, the water maze. We expected that the spatial memory capabilities of aged rats would be related to the levels of hippocampal neurogenesis. Old rats were trained in the water maze, and, 3 weeks after training, rats were injected with 5-bromo-2′-deoxyuridine (BrdUrd, 50 or 150 mg/kg) to label dividing cells. Cell proliferation was examined one day after the last BrdUrd injection, whereas cell survival and differentiation were determined 3 weeks later. It is shown that a quantitative relationship exists between learning and the number of newly generated neurons. Animals with preserved spatial memory, i.e., the aged-unimpaired rats, exhibited a higher level of cell proliferation and a higher number of new neurons in comparison with rats with spatial memory impairments, i.e., the aged-impaired rats. In conclusion, the extent of memory dysfunction in aged rats is quantitatively related to the hippocampal neurogenesis. These data reinforce the assumption that neurogenesis is involved in memory processes and aged-related cognitive alterations.

Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration

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.

Prenatal Stress Increases the Hypothalamo‐Pituitary‐Adrenal Axis Response in Young and Adult Rats

Prenatal stress is considered as an early epigenetic factor able to induce long‐lasting alterations in brain structures and functions. It is still unclear whether prenatal stress can induce long‐lasting modifications in the hypothalamo‐pituitary‐adrenal axis. To test this possibility the effects of restraint stress in pregnant rats during the third week of gestation were investigated in the functional properties of the hypothalamo‐pituitary‐adrenal axis and hippocampal type I and type II corticosteroid receptors in the male offspring at 3, 21 and 90 days of age. Plasma corticosterone was significantly elevated in prenatally‐stressed rats at 3 and 21 days after exposure to novelty. At 90 days of age, prenatally‐stressed rats showed a longer duration of corticosterone secretion after exposure to novelty. No change was observed for type I and type II receptor densities 3 days after birth, but both receptor subtypes were decreased in the hippocampus of prenatally‐stressed offspring at 21 and 90 days of life. These findings suggest that prenatal stress produces long term changes in the hypothalamo‐pituitary‐adrenal axis in the offspring.

Neurobiological mechanisms for opponent motivational processes in addiction

The conceptualization of drug addiction as a compulsive disorder with excessive drug intake and loss of control over intake requires motivational mechanisms. Opponent process as a motivational theory for the negative reinforcement of drug dependence has long required a neurobiological explanation. Key neurochemical elements involved in reward and stress within basal forebrain structures involving the ventral striatum and extended amygdala are hypothesized to be dysregulated in addiction to convey the opponent motivational processes that drive dependence. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission such as dopamine and opioid peptides in the ventral striatum, but also recruitment of brain stress systems such as corticotropin-releasing factor (CRF), noradrenaline and dynorphin in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, anxiety-like responses and extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence and to contribute to stress-induced relapse. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for the long hypothesized opponent motivational processes responsible for the negative reinforcement driving addiction.

Efferents and afferents of the ventral tegmental-A10 region studied after local injection of [3H]leucine and horseradish peroxidase.

Abstract The efferents and the afferents of the VMT-A10 region were studied by using anterograde ([3H]leucine) and retrograde (HRP) tracing techniques. In order to produce very small injections in various parts of the VMT-A10 region, a slow diffusion technique for [3H]leucine labelling and a microiontophoretic injection for horseradish peroxidase labelling were developed. According to the histochemical and biochemical data, the [3H]leucine anterograde results were separated into three main types of projections. (1) Projections to regions rich in DA terminals. These projections certainly correspond to the efferents of the dopaminergic A10 neurones. According to various injection sites, we have been able to identify mesolimbic projections originating from the VMT-A10, pars medialis and mesostriatal-mesolimbic projections originating from the VMT-A10, pars lateralis. The mesolimbic projections include the prefrontal cortex, the medial part of the lateral septum, the interstitial nucleus of the stria terminalis, the accumbens nucleus and the olfactory tubercle. The mesostriatal-mesolimbic projections include the anteromedial part of the caudate nucleus, the cingular cortex, the entorhinal cortex, the amygdaloid complex, the accumbens nucleus, the olfactory tubercle and the piriform cortex to a lesser extent. (2) Projections to regions suspected of containing DA terminals. These ascending and descending projections which could represent the dopaminergic efferents of the VMT-A10 neurones have been demonstrated. Ascending projections originating either from the VMT-A10 pars medialis or pars lateralis region were found in the claustrum, the nucleus of the tractus diagonalis, the olfactory nuclei, the lateral habenula, the medial hypothalamus and the median eminence. The projections observed in the medial hypothalamus included the periventricular region, the arcuate nucleus, the ventral part of the ventromedial nucleus and the dorsomedial nucleus. The labelling of the anteromedial part of the dorsal hippocampus appeared to originate from the VMT-A10, pars posterior. The projections to the medial hypothalamus, median eminence and hippocampus may have a great functional significance, but further proof of their dopaminergic nature is needed. Descending projections were found ipsilateally to the dorsal raphe and to the cerebellum, and bilaterally to the locus coeruleus. The projections to the cerebellum are distributed to the nuclei interpositus and dentatus and to the Purkinje cell layer and granular layer of the cortex. These results raise the problem of descending dopaminergic projections from the A10 neurones. (3) Projections to regions not known to contain DA terminals. Anterior projections were found ipsilaterally to the supraoptic nucleus and bilaterally to the anterodorsal thalamic nucleus. Posterior projections were traced ipsilaterally to the limbic midbrain area, including the median raphe, the ventral and dorsal tegmental nucleus and the central gray. The horseradish peroxidase experiment supplied some clues as to the posterior afferents of the VMT-A10 region. Some labelled cells were found ipsilaterally in the substantia nigra, the medain raphe and the ventral tegmental nucleus. Numerous cells were labelled ipsilaterally in the dorsal raphe nucleus, and nuclei interpositus and dentatus of the cerebellum, and contralaterally in the locus coeruleus. These structures are likely to play an important role in the modulation of the activity of VMT-A10 neurones. The results of [3H]leucine and HRP experiments permitted us to demonstrate reciprocal connections between VMT-A10 region and anterior raphe nuclei, locus coeruleus and cerebellum.

Glucocorticoids as a biological substrate of reward: physiological and pathophysiological implications.

The observations presented in this review suggest that glucocorticoids are one of the biological substrates of reward. These hormones are secreted in response to rewarding stimuli, such as food, a receptive sexual partner or drugs of abuse. Furthermore, manipulations of the secretion of glucocorticoids modify reward-related behaviours, and administration of these hormones, in the range of physiological stress levels, has positive reinforcing effects. The rewarding effects of glucocorticoids are probably mediated by a glucocorticoid-induced stimulation of the mesencephalic dopaminergic transmission, one of the principal neural substrates of reward. It is proposed that the rewarding effects of glucocorticoids play the role of counteracting the aversive effects of external aggressions, allowing a better coping with threatening situations. However, a sustained increase in the secretion of these hormones, or an hypersensitivity to their rewarding effects, could determine reward-related pathologies, such as a predisposed state to develop drug-abuse. In conclusion, through their reward-related effects, glucocorticoids may play a key role in tuning adaptation to stress and in determining reward-related behavioral pathologies.

Long-term effects of prenatal stress and postnatal handling on age-related glucocorticoid secretion and cognitive performance: a longitudinal study in the rat.

There is growing evidence that stress during prenatal and postnatal periods of life can modify adaptive capacities in adulthoods. The hypothalamo–pituitary–adrenal axis may mediate an animals responses to perinatal stressful events and thus serve as a neurobiological substrate of the behavioural consequences of these early events. However, little is known about the long‐term effects of prenatal stressors throughout the entire life of the animals. The focus of the present study was to examine the long‐term influences of a prenatal and postnatal stress on glucocorticoid secretion and cognitive performance. Prenatal stress of rat dams during the last week of pregnancy and postnatal daily handling of rat pups during the first 3 weeks of life were used as stressors. The long‐term effects of these manipulations were analysed using a longitudinal approach throughout the entire life of the animals, and were repeatedly tested in adulthood (4–7 months), middle age (13–16 months) and in later life (20–24 months). The study demonstrated that prenatal stress and postnatal handling induced opposite effects on both glucocorticoid secretion and cognitive performance. Prenatal stress accelerated the age‐related hypothalamo–pituitary–adrenal axis dysfunctions; indeed, circulating glucocorticoids levels of prenatally stressed middle‐aged animals are similar to old control ones, and also induced cognitive impairments. In contrast, postnatal handling protected from the age‐related neuroendocrine and behavioural alterations. These results show that the altered glucocorticoid secretion induced by early environmental manipulations is primary to the cognitive alterations observed only later in life and could be one cause of age‐related memory deficits.

Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus accumbens of rats predisposed to develop amphetamine self-administration

Individual vulnerability to the reinforcing effects of drugs appear 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 higher locomotor responses to novelty (High Responders, HR) tend to acquire amphetamine SA, while animals with the lower responses (Low Responders, LR) do not. In this study, we examined whether activity of dopaminergic (DA) and serotoninergic (5-HT) systems differed between HR and LR animals. These transmitter systems are thought to be involved in the reinforcing effects of psychostimulants. Animals from both groups were sacrificed under basal conditions and after exposure for 30 or 120 min to a novel environment, and the DA, 3,4-dihydroxyphenylacetic acid (DOPAC), 5-HT, and 5-hydroxyindolacetic acid (5-HIAA) contents were determined in the prefrontal cortex, nucleus accumbens and striatum. The HR rats displayed a specific neurochemical pattern: a higher DOPAC/DA ratio in the nucleus accumbens and striatum and a lower one in the prefrontal cortex. Furthermore, HR animals had lower overall 5-HT and 5-HIAA levels, corresponding to the mean of these compounds for the three structures studied over the three environmental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)