Neural Correlates of Competing Fear Behaviors Evoked by an Innately Aversive Stimulus

Environment and experience influence defensive behaviors, but the neural circuits mediating such effects are not well understood. We describe a new experimental model in which either flight or freezing reactions can be elicited from mice by innately aversive ultrasound. Flight and freezing are negatively correlated, suggesting a competition between fear motor systems. An unfamiliar environment or a previous aversive event, moreover, can alter the balance between these behaviors. To identify potential circuits controlling this competition, global activity patterns in the whole brain were surveyed in an unbiased manner by c-fos in situ hybridization, using novel experimental and analytical methods. Mice predominantly displaying freezing behavior had preferential neural activity in the lateral septum ventral and several medial and periventricular hypothalamic nuclei, whereas mice predominantly displaying flight had more activity in cortical, amygdalar, and striatal motor areas, the dorsolateral posterior zone of the hypothalamus, and the vertical limb of the diagonal band. These complementary patterns of c-fos induction, taken together with known connections between these structures, suggest ways in which the brain may mediate the balance between these opponent defensive behaviors

The serotonergic and noradrenergic systems of the hippocampus : their interactions and the effects of antidepressant treatments

Since the formulation of the monoaminergic hypotheses of depression, several investigations have established that the serotonin (5-HT) as well as the noradrenaline (NA) systems are altered by antidepressant treatments. In the last few years, several studies have indicated that interactions between these two systems might also be important in the mechanism of action of antidepressant drugs. We have thus undertaken: (1) to elucidate the nature of some interactions between the 5-HT and NA systems in the rat hippocampus using in vivo electrophysiology and in vitro superfusion techniques; and (2) to determine whether antidepressant treatments alter these interactions. It was found that NA tonically inhibits 5-HT neurotransmission via $alpha sb2$-adrenergic heteroreceptors. In addition, the presence of 5-HT$sb3$ receptors facilitating the release of NA was also documented in this brain region. These receptors were shown to be activated by elevated levels of endogenous 5-HT, but did not appear to be activated by basal levels of this neurotransmitter. Long-term administrations of antidepressant drugs commonly known to increase the synaptic concentration of NA, i.e. monoamine oxidase and NA reuptake inhibitors, were found to desensitize the $alpha sb2$-adrenoceptors that inhibit the release of 5-HT. This effect was also produced by atypical antidepressant drugs that have $alpha sb2$-adrenergic antagonist properties (e.g. mianserin and idazoxan), but not by other antidepressant treatments, (e.g. selective 5-HT reuptake inhibitors or electroconvulsive shocks). In contrast to $alpha sb2$-adrenergic heteroreceptors, 5-HT$sb3$ receptors that enhance the release of NA did not become desensitized following long-term treatments with drugs that elevate the synaptic concentration of their endogenous neurotransmitter. Rather, the responsiveness of these 5-HT$sb3$ receptors became blunted following an antidepressant treatment (desipramine) that caused a large increase in the

Antidepressant and anxiolytic action on the Serotonin1A binding site

Several lines of evidence suggest an involvement of serotonin$sb{ rm 1A}$ (5-HT$sb{ rm 1A}$ receptors in the regulation of emotions. In order to investigate the molecular basis of recent electrophysiological findings which implicated 5-HT$sb{ rm 1A}$ receptors in the mechanism of action of antidepressants and anxiolytics, radioligand binding and autoradiographic studies using tritiated 8-hydroxy-2-(di-N-propylamino)-tetralin ( ($sp3$H) -8-OH-DPAT) were done in rat brain following various treatments. These included: the tricyclic antidepressant imipramine; the reuptake blockers paroxetine and indalpine; the monoamine oxidase inhibitor clorgyline; electroconvulsive shock; lithium; the classic benzodiazepine diazepam; and the 5-HT$sb{ rm 1A}$ partial agonist gepirone. None of these treatments, nor the fluctuation in 5-HT availability provoked by the circadian cycle, gave any significant changes, with the exception of clorgyline which initially appeared to decrease the affinity of ($sp3$H) -8-OH-DPAT for its receptor. A further series of studies in vitro and in vivo ascertained the possibility that the 5-HT$sb{ rm 1A}$ receptors may display two interconvertible affinity states and that, in fact, clorgyline induces a shift of the high to the lower affinity state. The findings from this second series of experiments suggested that labile changes, which may possibly be disrupted during membrane preparation, in the coupling between the 5-HT$sb{ rm 1A}$ receptor and a guanine nucleotide binding protein (G-protein) may account for the effects that certain treatments have on 5-HT$sb{ rm 1A}$ receptor responsiveness

Utilisation des psychédéliques en psychiatrie : lien avec les neurotrophines

Les psychédéliques, souvent appelés hallucinogènes, sont une classe de psychotropes très singulière. Les effets subjectifs et comportementaux qu’ils induisent sont très impressionnants, et malgré leur toxicité potentielle, le risque d’addiction est relativement faible par rapport à la nicotine, l’alcool ou les opiacés. Depuis la découverte des effets antidépresseurs de la kétamine, il existe un regain d’intérêt pour cette classe de molécules. En effet, la psilocybine et l’acide lysergique diéthylamide (LSD) gagnent de la popularité en tant que traitement pour la dépression et l’addiction, la 3,4-méthylènedioxyméthamphétamine (MDMA) pour l’état de stress post-traumatique, et l’ibogaïne pour l’addiction. Malgré des profils pharmacologiques distincts, ces différentes drogues partagent une cinétique d’action similaire : leurs effets thérapeutiques se font ressentir dans les heures suivant l’administration et perdurent au-delà de leur élimination par l’organisme. Ceci suggère des mécanismes plastiques et neurogéniques impliquant entre autres des facteurs trophiques. Cette revue explorera la littérature concernant les effets de ces différents composés sur les neurotrophines, ainsi que les adaptations plastiques qui sont mises en place dans les heures et jours suivant l’administration, afin de comprendre leur potentiel thérapeutique étonnant

Traumatic Stress-Induced Vulnerability to Addiction: Critical Role of the Dynorphin/Kappa Opioid Receptor System

International audienceSubstance use disorders (SUD) may emerge from an individual’s attempt to limit negative affective states and symptoms linked to stress. Indeed, SUD is highly comorbid with chronic stress, traumatic stress, or post-traumatic stress disorder (PTSD), and treatments approved for each pathology individually often failed to have a therapeutic efficiency in such comorbid patients. The kappa-opioid receptor (KOR) and its endogenous ligand dynorphin (DYN), seem to play a key role in the occurrence of this comorbidity. The DYN/KOR function is increased either in traumatic stress or during drug use, dependence acquisition and DYN is released during stress. The behavioural effects of stress related to the DYN/KOR system include anxiety, dissociative and depressive symptoms, as well as increased conditioned fear response. Furthermore, the DYN/KOR system is implicated in negative reinforcement after the euphoric effects of a drug of abuse ends. During chronic drug consumption DYN/KOR functions increase and facilitate tolerance and dependence. The drug-seeking behaviour induced by KOR activation can be retrieved either during the development of an addictive behaviour, or during relapse after withdrawal. DYN is known to be one of the most powerful negative modulators of dopamine signalling, notably in brain structures implicated in both reward and fear circuitries. KOR are also acting as inhibitory heteroreceptors on serotonin neurons. Moreover, the DYN/KOR system cross-regulate with corticotropin-releasing factor in the brain. The sexual dimorphism of the DYN/KOR system could be the cause of the gender differences observed in patients with SUD or/and traumatic stress-related pathologies. This review underlies experimental and clinical results emphasizing the DYN/KOR system as common mechanisms shared by SUD or/and traumatic stress-related pathologies, and suggests KOR antagonist as a new pharmacological strategy to treat this comorbidity

Traumatic stress-induced vulnerability to addiction: critical role of the dynorphin/kappa opioid receptor system.

Substance use disorders (SUD) may emerge from an individual's attempt to limit negative affective states and symptoms linked to stress. Indeed, SUD is highly comorbid with chronic stress, traumatic stress, or post-traumatic stress disorder (PTSD), and treatments approved for each pathology individually often failed to have a therapeutic efficiency in such comorbid patients. The kappa-opioid receptor (KOR) and its endogenous ligand dynorphin (DYN), seem to play a key role in the occurrence of this comorbidity. The DYN/KOR function is increased either in traumatic stress or during drug use, dependence acquisition and DYN is released during stress. The behavioural effects of stress related to the DYN/KOR system include anxiety, dissociative and depressive symptoms, as well as increased conditioned fear response. Furthermore, the DYN/KOR system is implicated in negative reinforcement after the euphoric effects of a drug of abuse ends. During chronic drug consumption DYN/KOR functions increase and facilitate tolerance and dependence. The drug-seeking behaviour induced by KOR activation can be retrieved either during the development of an addictive behaviour, or during relapse after withdrawal. DYN is known to be one of the most powerful negative modulators of dopamine signalling, notably in brain structures implicated in both reward and fear circuitries. KOR are also acting as inhibitory heteroreceptors on serotonin neurons. Moreover, the DYN/KOR system cross-regulate with corticotropin-releasing factor in the brain. The sexual dimorphism of the DYN/KOR system could be the cause of the gender differences observed in patients with SUD or/and traumatic stress-related pathologies. This review underlies experimental and clinical results emphasizing the DYN/KOR system as common mechanisms shared by SUD or/and traumatic stress-related pathologies, and suggests KOR antagonist as a new pharmacological strategy to treat this comorbidity

In Vivo Trans-Synaptic Tract Tracing From the Murine Striatum and Amygdala Utilizing Manganese Enhanced MRI (MEMRI)

Small focal injections of manganese ion (Mn^(2+)) deep within the mouse central nervous system combined with in vivo high-resolution MRI delineate neuronal tracts originating from the site of injection. Previous work has shown that Mn^(2+) can be taken up through voltage-gated Ca^(2+) channels, transported along axons, and across synapses. Moreover, Mn^(2+) is a paramagnetic MRI contrast agent, causing positive contrast enhancement in tissues where it has accumulated. These combined properties allow for its use as an effective MRI detectable neuronal tract tracer. Injections of low concentrations of MnCl_2 into either the striatum or amygdala produced significant contrast enhancement along the known neuronal circuitry. The observed enhancement pattern is different at each injection site and enhancement of the homotopic areas was observed in both cases. Ten days postinjection, the Mn^(2+) had washed out, as evidenced by the absence of positive contrast enhancement within the brain. This methodology allows imaging of neuronal tracts long after the injection of the ion because Mn^(2+) concentrates in active neurons and resides for extended periods of time. With appropriate controls, differentiation of subsets of neuronal pathways associated with behavioral and pharmacological paradigms should be feasible

Etude des mécanismes de régulation des récepteurs 5-HT2C dans des modèles murins de troubles émotionnels

Pas de résumé en françaisPas de résumé en anglaisPARIS5-Bibliotheque electronique (751069902) / SudocPARIS-BIUM-Bib. électronique (751069903) / SudocSudocFranceF

Contrasting effects of diazepam and repeated restraint stress on latent inhibition in mice

The effects on latent inhibition (LI; a delay in conditioning when a CS has been pre-exposed without consequences) of repeated restraint stress and the anxiolytic drug diazepam were examined in C57BL/6 mice to know whether previous aversive events or anxiolysis are factors determining the expression of LI. The LI model was optimized for this strain particularly sensitive to stress (using both the CER and the conditioned freezing procedures) and characterized with typical (haloperidol) and atypical (clozapine and olanzapine) antipsychotic drugs administered either during the conditioning or the pre-exposure phases. An acute challenge with amphetamine, a dopamine releaser, was done to verify the enhancement of hyperactivity in C57BL/6 mice after the restraint stress sensitization. At all doses tested, diazepam decreased latent inhibition when administered during the pre-exposure phase (similarly to atypical antipsychotic drugs). Repeated restraint stress enhanced LI by blocking the CS-induced freezing in pre-exposed mice. In contrast, pre-treatment with diazepam before pre-exposure allowed the expression of CS-induced freezing in stressed mice pre-exposed to the tone. It is suggested that stress and anxiolytic drugs can have opposite effects on attention or perseveration processes during learning of conflicting contingency responses