1,721,069 research outputs found
Sex-specific susceptibility to psychotic-like states provoked by prenatal THC exposure: Reversal by pregnenolone
Full text linkSociocultural attitudes towards cannabis legalization contribute to the common misconception that it is a relatively safe drug and its use during pregnancy poses no risk to the fetus. However, longitudinal studies demonstrate that maternal cannabis exposure results in adverse outcomes in the offspring, with a heightened risk for developing psychopathology. One of the most reported psychiatric outcomes is the proneness to psychotic-like experiences during childhood. How exposure to cannabis during gestation increases psychosis susceptibility in children and adolescents remains elusive. Preclinical research has indicated that in utero exposure to the major psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), deranges brain developmental trajectories towards vulnerable psychotic-like endophenotypes later in life. Here, we present how prenatal THC exposure (PCE) deregulates mesolimbic dopamine development predisposing the offspring to schizophrenia-relevant phenotypes, exclusively when exposed to environmental challenges, such as stress or THC. Detrimental effects of PCE are sex-specific because female offspring do not display psychotic-like outcomes upon exposure to these challenges. Moreover, we present how pregnenolone, a neurosteroid that showed beneficial properties on the effects elicited by cannabis intoxication, normalizes mesolimbic dopamine function and rescues psychotic-like phenotypes. We, therefore, suggest this neurosteroid as a safe “disease-modifying” aid to prevent the onset of psychoses in vulnerable individuals. Our findings corroborate clinical evidence and highlight the relevance of early diagnostic screening and preventative strategies for young individuals at risk for mental diseases, such as male PCE offspring
Endocannabinoid signalling in midbrain dopamine neurons: more than physiology?
No full textDifferent classes of neurons in the CNS utilize endogenous cannabinoids as retrograde messengers to shape afferent activity in a short- and long-lasting fashion. Transient suppression of excitation and inhibition as well as long-term depression or potentiation in many brain regions require endocannabinoids to be released by the postsynaptic neurons and activate presynaptic CB1 receptors. Memory consolidation and/or extinction and habit forming have been suggested as the potential behavioral consequences of endocannabinoid-mediated synaptic modulation. However, endocannabinoids have a dual role: beyond a physiological modulation of synaptic functions, they have been demonstrated to participate in the mechanisms of neuronal protection under circumstances involving excessive excitatory drive, glutamate excitotoxicity, hypoxia-ischemia, which are key features of several neurodegenerative disorders. In this framework, the recent discovery that the endocannabinoid 2-arachidonoyl-glycerol is released by midbrain dopaminergic neurons, under both physiological synaptic activity to modulate afferent inputs and pathological conditions such as ischemia, is particularly interesting for the possible implication of these molecules in brain functions and dysfunctions. Since dopamine dysfunctions underlie diverse neuropsychiatric disorders including schizophrenia, psychoses, and drug addiction, the importance of better understanding the correlation between an unbalanced endocannabinoid signal and the dopamine system is even greater. Additionally, we will review the evidence of the involvement of the endocannabinoid system in the pathogenesis of Parkinson's disease, where neuroprotective actions of cannabinoid-acting compounds may prove beneficial. The modulation of the endocannabinoid system by pharmacological agents is a valuable target in protection of dopamine neurons against functional abnormalities as well as against their neurodegeneration
From surface to nuclear receptors: the endocannabinoid family extends its assets
No full textPeroxisome proliferator-activated receptors (PPARs) have long been known as mediators of several physiological functions, among which the best characterized are lipid metabolism, energy balance and anti-inflammation. Their rather large and promiscuous ligand binding site has been recently discovered to accommodate, among a plethora of lipid molecules and metabolic intermediates, endocannabinoids and their cognate compounds, specifically belonging to the N-acylethanolamine group. In fact, oleoylethanolamide, palmitoylethanolamide and probably anandamide bind with relatively high affinity to PPARs and have now been included among their endogenous ligands. Through activation of PPARs these molecules exert a variety of physiological processes. Particularly, both long-term effects via genomic mechanisms and rapid non-genomic actions have been described, which in several instances are opposite to those evoked by activation of "classical" surface cannabinoid receptors.
In this review, we describe how these effects are relevant under diverse physiological and pathophysiological circumstances, such as lipid metabolism and feeding behaviour, neuroprotection and epilepsy, circadian rhythms, addiction and cognition. A picture is emerging where nuclear receptors are involved in anorexiant, anti-inflammatory, neuroprotective, anti-epileptic, wakefulness-and cognitive-enhancing, and anti-addicting properties of endocannabinoid-like molecules. Further studies are necessary to fully understand cellular mechanisms underlying the interactions between endocannabinoids and PPARs, but also between their surface and nuclear receptors, and to exploit their potential therapeutic applications
Individual differences and vulnerability to drug addiction: a focus on the endocannabinoid system
No full textVulnerability to drug addiction depends upon the interactions between the biological makeup of the individual, the environment, and age. These interactions are complex and difficult to tease apart. Since dopamine is involved in the rewarding effects of drugs of abuse, it is postulated that innate differences in mesocorticolimbic pathway can influence the response to drug exposure. In particular, higher and lower expression of dopamine D2 receptors in the ventral striatum (i.e. a marker of dopamine function) has been considered a putative protective and a risk factor, respectively, that can influence one's susceptibility to continued drug abuse as well as the transition to addiction. This phenomenon, which is phylogenetically preserved, appears to be a compensatory change to increased impulse activity of midbrain dopamine neurons. Hence, dopamine neuronal excitability plays a fundamental role in the diverse stages of the drug addiction cycle. In this review, a framework for the evidence that modulation of dopamine neuronal activity plays in the context of vulnerability to drug addiction will be presented. Furthermore, since endogenous cannabinoids serve as retrograde messengers to shape afferent neuronal activity in a short- and long-lasting fashion, their role in individual differences and vulnerability to drug addiction will be discussed
Interplay between synaptic endocannabinoid signaling and metaplasticity in neuronal circuit function and dysfunction
No full textSynaptic neuromodulation acts across different functional domains to regulate cognitive processing and behavior. Recent challenges
are related to elucidating the molecular and cellular mechanisms through which neuromodulatory pathways act on multiple time scales to signal state-dependent contingencies at the synaptic level or to stabilise synaptic connections during behavior. Here, we present a framework with the synaptic neuromodulators endocannabinoids (eCBs) as key players in dynamic synaptic changes. Modulation of various molecular components of the eCB pathway yields interconnected functional activation states of eCB signaling (prior, tonic, and persistent), which may contribute to metaplastic control of synaptic and behavioral functions in health and disease. The emerging picture supports aberrant metaplasticity as a contributor to cognitive dysfunction associated with several pathological states in which eCB signaling, or other neuromodulatory pathways, are deregulated
Increase in meso-prefrontal dopaminergic activity after stimulation of CB1 receptors by cannabinoids
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Hub and switches: endocannabinoid signalling in midbrain dopamine neurons
No full textThe last decade has provided a wealth of experimental data on the role played by lipids belonging to the endocannabinoid family in several facets of physiopathology of dopamine neurons. We currently suggest that these molecules, being intimately connected with diverse metabolic and signalling pathways, might differently affect various functions of dopamine neurons through activation not only of surface receptors, but also of nuclear receptors. It is now emerging how dopamine neurons can regulate their constituent biomolecules to compensate for changes in either internal functions or external conditions. Consequently, dopamine neurons use these lipid molecules as metabolic and homeostatic signal detectors, which can dynamically impact cell function and fitness. Since dysfunctions of dopamine system underlie diverse neuropsychiatric disorders including schizophrenia and drug addiction, the importance of better understanding the correlation between an unbalanced endocannabinoid signal and the dopamine system is even greater. Particularly, since dopamine neurons are critical in controlling incentive-motivated behaviors, the involvement of endocannabinoid molecules in fine-tuning dopamine cell activity opened new avenues in both understanding and treating drug addiction. Here, we review recent advances that have shed new light in the understanding of differential roles of endocannabinoids and their cognate molecules in the regulation of the reward circuit, and discuss their anti-addicting properties, particularly with a focus on their potential engagement in the prevention of relapse
Sex differences in impulsive and compulsive behaviors: a focus on drug addiction
No full textSex differences in inhibition and self-regulation at a behavioral level have been widely described. From an evolutionary point of view, the different selection pressures placed on male and female hominids led them to differ in their behavioral strategies that allowed our species to survive during natural selection processes. These differences reflect changes in neural and structural plasticity that might be the core of sex differences, and of the susceptibility towards one psychiatric condition rather than another. The goal of the present review is to summarize current evidence for such a dichotomy in impulsive and compulsive behavior with a focus on drug addiction. Sex-dependent differences in drug abuse and dependence will be examined in the context of pathophysiological regulation of impulse and motivation by neuromodulators (i.e. gonadal hormones) and neurotransmitters (i.e. dopamine). Advances in the understanding of the sex differences in the capability to control impulses and motivational states is key for the determination of efficacious biologically based intervention and prevention strategies for several neuropsychiatric disorders where loss of impulse control and compulsivity are the core symptoms
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