Simona Cabib

Stress, depression and the mesolimbic dopamine system

Abstract The present review was aimed at re-evaluating results obtained from animal models of depression based on experimental stressors in the light of the most recent data on the effects of stress on mesolimbic dopamine (DA) functioning. The data reviewed reveal that the effects of stressful experiences on behaviour and on mesoaccumbens DA functioning can be very different or even opposite depending on the behavioural controllability of the situation, the genetic background of the organism and its life history. Exposure to a single unavoidable/uncontrollable aversive experience leads to inhibition of DA release in the accumbens as well as to impaired responding to rewarding and aversive stimuli. Moreover, the data reviewed indicate a strong relationship between these neurochemical and behavioural effects and suggest that they could model stress-induced expression and exacerbation of some depressive symptoms such as anhedonia and feeling of helplessness caused by life events as well as syndromal depression provoked by traumatic experiences in humans. Repeated and chronic stressful experiences can reduce the ability of stressors to disrupt behaviour, induce behavioural sensitisation to psychostimulants and promote adaptive changes of mesolimbic DA functioning. Opposite neural and behavioural changes, however, can be promoted in specific environmental conditions (repeated variable stressful experiences) or in genetically predisposed individuals. Thus, depressive symptoms may not represent the necessary outcome of stress experiences but be promoted by specific environmental conditions and by a genetically determined susceptibility.

Acute stress induces time-dependent responses in dopamine mesolimbic system

Exposure to either restraint or footshock (3-60 min) induced similar biphasic alterations of 3-methoxytyramine (3-MT) concentrations (initial increase followed by decrease below control levels) in the nucleus accumbens septi (NAS) of mice, as revealed by tissue analysis. The only difference between the two stressors was the earlier onset of the decrease phase in the restrained mice. In both stressful conditions acid metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) increased throughout stress, while no significant changes in dopamine (DA) concentrations occurred. These data suggest biphasic alteration of DA release during prolonged stress exposure. The analysis of release in restrained conscious rats by in vivo microdialysis (10-240 min) showed a similar biphasic DA evolution (initial increase followed by decrease below baseline levels) in the NAS. The only difference from the previous experiment was the delayed onset of the decrease phase. Similar changes in DOPAC and HVA were also evident. Moreover, freed rats showed an immediate increase of DA release over baseline levels, also indicating that depletion of the neurotransmitter cannot account for the reduction of released DA. Taken together, these results support the hypothesis that biphasic alteration of DA transmission in the mesolimbic system is a general response to stress and suggest that the initial increase of DA release represents an arousal response while the subsequent decrease in DA release may be related to coping failure.

The mesoaccumbens dopamine in coping with stress

Mesoaccumbens dopamine (DA) is involved in the stress response. Although neural mechanisms involved in stress are of paramount importance for both clinical and preclinical research, the results of studies on the stress response by mesoaccumbens DA have received little attention. Therefore, we aimed to review these results and propose a role for mesoaccumbens DA in coping with stress. The data reviewed support the view that fluctuations of tonic levels characterize the mesoaccumbens DA stress response. Stress-induced increase of tonic DA levels in nucleus accumbens (NAc) supports expression of responses aimed at removing and avoiding the stressor through activation of DA D2 receptors, whereas inhibition of DA is associated with cessation of active defensive responses. In novel unescapable/uncontrollable stressful conditions tonic levels of DA in NAc show an initial increase followed by a decrease below pre-stress levels that lasts as long as the stressful situation. This biphasic response fits with the dynamics of the primary and secondary appraisal of a stressor that cannot be removed, escaped or controlled by the organism. In fact, NAc DA fluctuations are controlled by the medial pre-frontal cortex, which is involved in stress appraisal. We propose that enhanced mesoaccumbens DA supports expression of active coping strategies against an event appraised as a stressor and that inhibition of DA is required for passive coping with stressful situations appraised as unescapable/uncontrollable.

Identifying Molecular Substrates in a Mouse Model of the Serotonin Transporter × Environment Risk Factor for Anxiety and Depression

BACKGROUND A polymorphism in the serotonin transporter (5-HTT) gene modulates the association between adverse early experiences and risk for major depression in adulthood. Although human imaging studies have begun to elucidate the neural circuits involved in the 5-HTT x environment risk factor, a molecular understanding of this phenomenon is lacking. Such an understanding might help to identify novel targets for the diagnosis and therapy of mood disorders. To address this need, we developed a gene-environment screening paradigm in the mouse. METHODS We established a mouse model in which a heterozygous null mutation in 5-HTT moderates the effects of poor maternal care on adult anxiety and depression-related behavior. Biochemical analysis of brains from these animals was performed to identify molecular substrates of the gene, environment, and gene x environment effects. RESULTS Mice experiencing low maternal care showed deficient gamma-aminobutyric acid-A receptor binding in the amygdala and 5-HTT heterozygous null mice showed decreased serotonin turnover in hippocampus and striatum. Strikingly, levels of brain-derived neurotrophic factor (BDNF) messenger RNA in hippocampus were elevated exclusively in 5-HTT heterozygous null mice experiencing poor maternal care, suggesting that developmental programming of hippocampal circuits might underlie the 5-HTT x environment risk factor. CONCLUSIONS These findings demonstrate that serotonin plays a similar role in modifying the long-term behavioral effects of rearing environment in diverse mammalian species and identifies BDNF as a molecular substrate of this risk factor.

D1 and D2 receptor antagonists differently affect cocaine-induced locomotor hyperactivity in the mouse

Pretreament with small, per se ineffective doses of the selective D1 antagonist SCH 23390 inhibited hyperactivity induced by cocaine. On the other hand, the classic neuroleptic haloperidol and the selective D2 antagonist metoclopramide prevented the stimulatory effects of cocaine on locomotion only at hypokinetic doses, while the atypical neuroleptic (−)-sulpiride, a selective D2 antagonist, did not produce significant effects when administered at the hypokinetic dose of 12 mg/kg. Finally, at low doses (−)-sulpiride dose-dependently potentiated the locomotor-stimulating effects of cocaine, an effect that is not shared either with haloperidol or with metoclopramide. These results are discussed in terms of different roles of DA receptor subtypes in the modulation of the stimulant effects of cocaine on locomotion.

Effects of immobilization stress on dopamine and its metabolites in different brain areas of the mouse: role of genotype and stress duration

Immobilization stress induced, in mice of both C57BL/6 (C57) and DBA/2 (DBA) strains, an increase in dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) and homovanillic acid (HVA)/DA ratios and a reduction of 3-methoxytyramine (3-MT)/DA ratio in the caudatus putamen (CP) and nucleus accumbens septi (NAS). These effects were already evident after 30 min stress in the NAS, while in the CP 120 min were needed in order to show the effects of stress. Immobilization did not produce any effects on dopaminergic metabolism in the frontal cortex (FC) of the C57 strain either after 30 or after 120 min stress while in mice of the DBA strain a time-dependent effect of stress on the HVA/DA ratio was evident. When B6D2F1 hybrids were considered, the effects produced by 120 min immobilization in the CP and the NAS paralleled those observed in parental strains, while in the FC 120 min stress induced the same increase of HVA observed in DBA mice, thus suggesting that the pattern of response in the FC that characterizes the DBA strain may be inherited through a dominant pattern of inheritance.

Dopamine in the medial prefrontal cortex controls genotype-dependent effects of amphetamine on mesoaccumbens dopamine release and locomotion.

Mice of background DBA/2J are hyporesponsive to the behavioral effects of D-amphetamine in comparison with the widely exploited murine background C57BL/6J. In view of the important role of dopamine (DA) release in the nucleus accumbens (NAc) regarding the behavioral effects of psychostimulants, we tested the hypothesis of an inverse relationship between mesocortical and mesoaccumbens DA functioning in the two backgrounds. Systemic D-amphetamine induces a sustained increase in DA release in the medial prefrontal cortex (mpFC) accompanied by a poor increase in the NAc in mice of the low-responsive DBA/2J background, as shown by intracerebral microdialysis in freely moving animals. The opposite occurs in C57BL/6J mice, which show low prefrontal cortical DA outflow accompanied by high accumbal extracellular DA. Moreover, the DBA/2J background showed lower locomotor activity than C57BL/6J mice following D-amphetamine challenge. Selective DA depletion in the mpFC of DBA/2J mice produced a clear-cut increase in D-amphetamine-induced DA outflow in the NAc as well as locomotor activity that reached levels similar to those observed in C57BL/6J mice. Finally, local infusion of D-amphetamine by reverse microdialysis produced a similar increase in extracellular DA in both the mpFC and the NAc of DBA/2J mice. This finding points to similar transporter-related mechanisms in the two brain areas and supports the hypothesis that low accumbal DA release induced by systemic D-amphetamine in the DBA/2J background is determined by the inhibitory action of prefrontal cortical DA. The present results indicate that genotype-dependent susceptibility to addictive properties of D-amphetamine involves unbalanced DA transmission in the mesocorticolimbic system.

Repeated stressful experiences differently affect the time-dependent responses of the mesolimbic dopamine system to the stressor

The increase in mesolimbic dopamine (DA) release observed during the first 40 min of 120 min restraint in naive rats is not evident in repeatedly stressed animals (daily 60 min restraint, for 5 days). However, repeatedly stressed rats show a significant decrease in DA release from 80 min of restraint onwards which is not observable in naive rats. These results indicate that repeated stressful experiences do not produce habituation but alter the response of mesolimbic DA system to the stressor. Moreover, they point to a possible neuronal mechanism underlying stress-induced depression.

The contribution of comparative studies in inbred strains of mice to the understanding of the hyperactive phenotype

Attention-deficit hyperactivity disorder (ADHD) is a highly prevalent childhood psychiatric disorder characterized by impaired attention, excessive motor activity and impulsivity. Converging evidence, suggests a primary role of disturbances in brain dopamine (DA) transmission and a role of genetic factors in its pathology. Inbred provide a well-defined and stable genotype for analysis. C57BL/6 (C57) and DBA/2 (DBA) mice are amongst the most studied inbred strains in the behavioral pharmacology of DA, and they differ in several parameters of the DA system that relate directly to behavioral differences. These strains also exhibit several qualitatively different behavior patterns that rely on separate DA networks (e.g. mesoaccumbens vs. nigrostriatal) and on different modes of inheritance. C57 mice are good learners in most tasks also involving associative learning but are totally unable to learn active avoidance although being very active. Moreover, C57 mice show greater novelty-induced locomotor activity than DBA, which is modulated strongly by DA neurons in the ventral tegmental area (VTA) region. Pharmacological studies also indicate a facilitated mesoaccumbens DA transmission in C57 mice when compared to DBAs. Increased density of D2 autoreceptors located on VTA neurons, and lower D2 postsynaptic receptors in the NAS were observed in DBA relative to C57. Activation of D2 autoreceptors inhibits impluse flow, synthesis, and release rates of DA neurons. As would be predicted from their higher D2 autoreceptor: DBA compared to C57 mice show reduced DA synthesis and release within the mesoaccumbens DA system when challenged with DA direct agonists. However, DBA mice are by fare more susceptible than C57s to stress-induced enhanced mesoaccumbens DA release and in stressful situation, they show sustained active behavioral responses whilst C57 adopt extremely passive responses (behavioral despair). Finally, chronic or repeated stress promote opposite adaptation of VTA DA autoreceptors in the two strains and render the hypoactive DBAs as active as the C57 mice. These results indicate that a complex interaction between genetic and environmental factors controls, mesoaccumbens DA functioning and hyperactive phenotype.

Chronic stress enhances apomorphine-induced stereotyped behavior in mice: Involvement of endogenous opioids

Mice subjected to repeated stressful experiences showed an increase in stereotypic climbing behavior induced by apomorphine thus suggesting a modified sensitivity of dopaminergic receptors. Naltrexone, injected before each stressful experience, reversed this effect of chronic stress indicating an involvement of endogenous opioids.