Dopamine Neuron Activity and Stress Signaling as Links Between Social Hierarchy and Psychopathology Vulnerability.

Background: Social status in humans, generally reflected by socioeconomic status, has been associated, when constrained, with heightened vulnerability to pathologies including psychiatric diseases. Social hierarchy in mice translates into individual and interdependent behavioral strategies of animals within a group. The rules leading to the emergence of a social organization are elusive, and detangling the contribution of social status from other factors, whether environmental or genetic, to normal and pathological behaviors remains challenging.

Review of industry reports on EU priority tobacco additives part B: Methodological limitations.

The Tobacco Products Directive (TPD) defines enhanced reporting obligations applying to 15 priority additives added to cigarettes and roll-your-own tobacco. A consortium of 12 international tobacco companies submitted 14 reports that were reviewed by an independent scientific body within the Joint Action on Tobacco Control (JATC). The reports were evaluated in accordance with the TPD with regard to their comprehensiveness, methodology and conclusions.

Review of industry reports on EU priority tobacco additives part A: Main outcomes and conclusions.

The European Union Tobacco Products Directive (EU TPD) mandates enhanced reporting obligations for tobacco manufacturers regarding 15 priority additives. Within the Joint Action on Tobacco Control (JATC), a review panel of independent experts was appointed for the scientific evaluation of the additive reports submitted by a consortium of 12 tobacco manufacturers. As required by the TPD, the reports were evaluated based on their comprehensiveness, methodology and conclusions.

Behavioral and Noradrenergic Sensitizations in Vulnerable Traumatized Rats Suggest Common Bases with Substance Use Disorders.

The aim of the present study was to strengthen our hypothesis of a common physiological basis for post-traumatic stress disorder (PTSD) and substance use disorders. This paper investigates the possibility that rats exposed to a PTSD model exhibit noradrenergic and behavioral sensitization, as observed following repeated drugs of abuse injections. First, rats received a single prolonged stress (SPS), combining three consecutive stressors.

5-HT receptors in the ventral tegmental area, but not in the arcuate nucleus, mediate the hypophagic and hypolocomotor effects of the selective 5-HT receptor agonist AR231630 in rats.

Central serotonin systems have long been associated with the control of feeding behavior and the modulation of behavioral effects of psychostimulants. 5-HT receptors are present in hypothalamic centers such as the arcuate nucleus (ARC), controlling homeostatic regulation of food intake, as well as in the ventral tegmental area (VTA), a region involved in motivation aspects in multiple behaviors, including feeding. In the present study, we investigated whether the 5-HT receptors control amphetamine-evoked locomotor activity and regulate food consumption.

The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence.

Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, α1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies.

Sustained impairment of α2A-adrenergic autoreceptor signaling mediates neurochemical and behavioral sensitization to amphetamine.

Background: In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhance this response. This effect, called behavioral sensitization, persists months after the last administration. It has been shown that behavioral sensitization to amphetamine develops parallel to an increased release of norepinephrine (NE) in the prefrontal cortex (PFC).

Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons.

Repeated traumatic events induce long-lasting behavioral changes that are key to organism adaptation and that affect cognitive, emotional, and social behaviors. Rodents subjected to repeated instances of aggression develop enduring social aversion and increased anxiety. Such repeated aggressions trigger a stress response, resulting in glucocorticoid release and activation of the ascending dopamine (DA) system.

α7 and β2 nicotinic receptors control monoamine-mediated locomotor response.

Earlier studies reported exacerbated locomotor response to stress and tranylcypromine in β2 nicotinic acetylcholine receptor (nAChR) knockout (KO) mice. This study aimed to further assess the role of β2 and coexpressed nAChR subunits in the brain (α4, α6 and α7) to control monoamine-mediated locomotor response, that is, response to novelty, saline, nicotine with tranylcypromine pretreatment, cocaine, d-amphetamine and morphine treatments. Results show that β2 KO mice were hyperreactive to novelty, cocaine and morphine.

Inhibition of monoamine oxidases desensitizes 5-HT1A autoreceptors and allows nicotine to induce a neurochemical and behavioral sensitization.

Although nicotine is generally considered to be the main compound responsible for addictive properties of tobacco, experimental data indicate that nicotine does not exhibit all the characteristics of other substances of abuse. We recently showed that a pretreatment with mixed irreversible monoamine oxidases inhibitors (MAOIs), such as tranylcypromine, triggers a locomotor response to nicotine in mice and allows maintenance of behavioral sensitization to nicotine in rats. Moreover, we showed by microdialysis in mice that behavioral sensitization induced by compounds belonging to main groups of drugs of abuse, such as amphetamine, cocaine, morphine, or alcohol, was underlain by sensitization of noradrenergic and serotonergic neurons.

Drugs of abuse specifically sensitize noradrenergic and serotonergic neurons via a non-dopaminergic mechanism.

A challenge in drug dependence is to delineate long-term neurochemical modifications induced by drugs of abuse. Repeated d-amphetamine was recently shown to disrupt a mutual regulatory link between noradrenergic and serotonergic neurons, thus inducing long-term increased responses to d-amphetamine and para-chloroamphetamine, respectively. We show here that such a sensitization of noradrenergic and serotonergic neurons also occurs following repeated treatment with cocaine, morphine, or alcohol, three compounds belonging to main groups of addictive substances.

Uncoupling between noradrenergic and serotonergic neurons as a molecular basis of stable changes in behavior induced by repeated drugs of abuse.

A challenge in drug dependence is to delineate long-term behavioral and neurochemical modifications induced by drugs of abuse. In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhance this response. This effect, called behavioral sensitization, persists many months after the last administration, thus mimicking long-term sensitivity to drugs observed in human addicts.

Paradoxical constitutive behavioral sensitization to amphetamine in mice lacking 5-HT2A receptors.

Rationale: Although locomotor response to d-amphetamine is considered as mediated by an increased release of dopamine in the ventral striatum, blockade of either alpha1b-adrenergic or 5-HT2A receptors almost completely inhibits d-amphetamine-induced locomotor response in mice. In agreement with this finding, mice lacking alpha1b-adrenergic receptors hardly respond to d-amphetamine. However, we show here that, paradoxically, mice lacking 5-HT2A receptors (5-HT2A-R KO) exhibit a twofold higher locomotor response to d-amphetamine than wild-type (WT) littermates.

Elevated dopamine D2High receptors in alpha-1b-adrenoceptor knockout supersensitive mice.

Although amphetamine induces hyperactivity by releasing dopamine (DA), mice that lack alpha1b-adrenoceptors do not release DA in response to amphetamine and do not, therefore, exhibit locomotor supersensitivity to amphetamine. However, such mice reveal hyperlocomotion to p-chloroamphetamine (PCA). Because these alpha1b-adrenoceptor knockout mice have no alterations in the striatal densities of DA D1 or D2 receptors, the basis for any possible dopaminergic contribution to the PCA-induced hyperlocomotion to PCA is unclear.

Irreversible blockade of monoamine oxidases reveals the critical role of 5-HT transmission in locomotor response induced by nicotine in mice.

Although nicotine is generally considered as the main compound responsible for addictive properties of tobacco, some experimental data indicate that nicotine does not exhibit all the characteristics of other substances of misuse such as psychostimulants and opiates. For example, nicotine generally fails to induce locomotor response in mice and self-administration of nicotine is difficult to obtain in rats. We have shown recently that a pretreatment with mixed irreversible monoamine oxidase inhibitors (MAOIs), such as tranylcypromine, triggers a locomotor response to nicotine in mice and induces a robust self-administration of nicotine in rats.

Behavioral sensitization to amphetamine results from an uncoupling between noradrenergic and serotonergic neurons.

In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhances this response. This effect, called behavioral sensitization, persists many months after the last administration, thus mimicking long-term sensitivity to drugs observed in human addicts. We show here that, in naïve animals, noradrenergic and serotonergic systems, besides their behavioral activating effects, inhibit each other by means of the stimulation of alpha1b-adrenergic and 5-HT(2A) receptors and that this mutual inhibition vanishes with repeated injections of d-amphetamine; this uncoupling may be responsible for behavioral sensitization and for an increased reactivity of dopaminergic neurons.

cAMP and extracellular signal-regulated kinase signaling in response to d-amphetamine and methylphenidate in the prefrontal cortex in vivo: role of beta 1-adrenoceptors.

d-Amphetamine and methylphenidate are widely used in the treatment of attention-deficit/hyperactivity disorder. Both drugs increase extracellular norepinephrine and dopamine in the prefrontal cortex, where they are believed to exert their therapeutic effects. However, the molecular mechanisms underlying their action are poorly understood.

Role of serotonin 2A receptors in the D-amphetamine-induced release of dopamine: comparison with previous data on alpha1b-adrenergic receptors.

D-amphetamine is known to induce an increase in dopamine release in subcortical structures, thus inducing locomotor hyperactivity in rodents. Previous data have indicated that only 15% of the D-amphetamine-induced release of dopamine in the nucleus accumbens is related to locomotor activity and that this 'functional' dopamine release is controlled by alpha1b-adrenergic receptors located in the prefrontal cortex. We show here that SR46349B (0.