Sex differences in the effects of N-ethylpentylone in young CD1 mice: Insights on behaviour, thermoregulation and early gene expression.

BACKGROUND AND PURPOSE: New psychoactive substances such as N-ethylpentylone (NEP) are continuously emerging in the illicit drug market, and knowledge of their effects and risks, which may vary between sexes, is scarce. Our present study compares some key effects of NEP in male and female mice. EXPERIMENTAL APPROACH: Psychostimulant, rewarding and reinforcing effects were investigated by tracking locomotor activity, conditioned place preference (CPP) paradigm and through a self-administration (SA) procedure, respectively, in CD1 mice. Moreover, the expression of early genes (C-fos, Arc, Csnk1e, Pdyn, Pp1r1b and Bdnf in addiction-related brain areas) was assessed by qPCR. Finally, serum and brain levels of NEP were determined by UHPLC-MS/MS. KEY RESULTS: NEP-treated males experimented locomotor sensitisation and showed higher and longer increases in locomotion as well as higher hyperthermia after repeated administration than females. Moreover, while preference score in the CPP was similar in both sexes, extinction occurred later, and reinstatement was more easily established for males. Female mice self-administered more NEP than males at a higher dose. Differences in early gene expression (Arc, Bdnf, Csnk1e and Ppp1r1b) were found, but the serum and brain NEP levels did not differ between sexes. CONCLUSION AND IMPLICATIONS: Our results suggest that male mice are more sensitive to NEP psychostimulant and rewarding effects. These differences may be attributed to different early gene expression but not to pharmacokinetic factors. Moreover, males appear to be more vulnerable to the hyperthermic effects of NEP, while females might be more prone to NEP abuse.

The role of PPAR-γ in memory deficits induced by prenatal and lactation alcohol exposure in mice.

Patients diagnosed with fetal alcohol spectrum disorder (FASD) show persistent cognitive disabilities, including memory deficits. However, the neurobiological substrates underlying these deficits remain unclear. Here, we show that prenatal and lactation alcohol exposure (PLAE) in mice induces FASD-like memory impairments. This is accompanied by a reduction of N-acylethanolamines (NAEs) and peroxisome proliferator-activated receptor gamma (PPAR-γ) in the hippocampus specifically in a childhood-like period (at post-natal day (PD) 25). To determine their role in memory deficits, two pharmacological approaches were performed during this specific period of early life. Thus, memory performance was tested after the repeated administration (from PD25 to PD34) of: i) URB597, to increase NAEs, with GW9662, a PPAR-γ antagonist; ii) pioglitazone, a PPAR-γ agonist. We observed that URB597 suppresses PLAE-induced memory deficits through a PPAR-γ dependent mechanism, since its effects are prevented by GW9662. Direct PPAR-γ activation, using pioglitazone, also ameliorates memory impairments. Lastly, to further investigate the region and cellular specificity, we demonstrate that an early overexpression of PPAR-γ, by means of a viral vector, in hippocampal astrocytes mitigates memory deficits induced by PLAE. Together, our data reveal that disruptions of PPAR-γ signaling during neurodevelopment contribute to PLAE-induced memory dysfunction. In turn, PPAR-γ activation during a childhood-like period is a promising therapeutic approach for memory deficits in the context of early alcohol exposure. Thus, these findings contribute to the gaining insight into the mechanisms that might underlie memory impairments in FASD patients.

The FAAH inhibitor URB597 reduces cocaine intake during conditioned punishment and mitigates cocaine seeking during withdrawal.

The endocannabinoid system is prominently implicated in the control of cocaine reinforcement due to its relevant role in synaptic plasticity and neurotransmitter modulation in the mesocorticolimbic system. The inhibition of fatty acid amide hydrolase (FAAH), and the resulting increase in anandamide and other N-acylethanolamines, represents a promising strategy for reducing drug seeking. In the present study, we aimed to assess the effects of the FAAH inhibitor URB597 (1 mg/kg) on crucial features of cocaine addictive-like behaviour in mice. Therefore, we tested the effects of URB597 on acquisition of cocaine (0.6 mg/kg/inf) self-administration, compulsive-like cocaine intake and cue-induced drug-seeking behaviour during withdrawal. URB597 reduced cocaine intake under conditioned punishment while having no impact on acquisition. This result was associated to increased cannabinoid receptor 1 gene expression in the ventral striatum and medium spiny neurons activation in the nucleus accumbens shell. Moreover, URB597 mitigated cue-induced drug-seeking behaviour during prolonged abstinence and prevented the withdrawal-induced increase in FAAH gene expression in the ventral striatum. In this case, URB597 decreased activation of medium spiny neurons in the nucleus accumbens core. Our findings evidence the prominent role of endocannabinoids in the development of cocaine addictive-like behaviours and support the potential of FAAH inhibition as a therapeutical target for the treatment of cocaine addiction.

Effects of fast-acting antidepressant drugs on a postpartum depression mice model.

Postpartum depression (PPD) is a severe psychiatric disorder with devastating consequences on child development and mother's health. Dysregulation of glutamatergic and GABAergic signalling has been described in the corticolimbic system of PPD patients, who also show a downregulation of allopregnanolone levels in serum. Consequently, a synthetic allopregnanolone-based treatment is the current eligible drug to treat PPD patients. Alternatively, ketamine appears to be a promising medication for preventing PPD, nevertheless the differences in efficacy between both treatments remains unknown due to the lack of comparative studies. On this basis, the present study aims to compare the effectiveness of allopregnanolone and ketamine on a PPD-like mouse model. Our results show that postpartum females undergoing a maternal separation with early weaning (MSEW) protocol show increased despair-like behaviour, anhedonia and disrupted maternal care. Such symptoms are accompanied by lower allopregnanolone serum levels, reduction of vesicular transporters of GABA (VGAT) and glutamate (VGLUT1) in the infralimbic cortex (IL), as well as decreased hippocampal cellular proliferation. Furthermore, both drugs prevent despair-like behaviour while only ketamine reverts anhedonia. Both treatments increase hippocampal neurogenesis, while only allopregnanolone raises VGAT and VGLUT1 markers in IL. These findings suggest that ketamine might be even more effective than allopregnanolone, which points out the necessity of including ketamine in clinical studies for PPD patients. Altogether, we propose a new mice model that recapitulates the core symptomatology and molecular alterations shown in PPD patients, which allows us to further investigate both the neurobiology of PPD and the therapeutic potential of antidepressant drugs.

Bmal1-knockout mice exhibit reduced cocaine-seeking behaviour and cognitive impairments.

Brain and Muscle Arnt-like Protein 1 (BMAL1) is an essential component of the molecular clock underlying circadian rhythmicity. Its function has been recently associated with mood and reward processing alterations. We investigated the behavioural and neurobiological impact of Bmal1 gene deletion in mice, and how this could affect rewarding effects of cocaine. Additionally, key clock genes and components of the dopamine system were assessed in several brain areas. Our results evidence behavioural alterations in Bmal1-KO mice, including changes in locomotor activity with impaired habituation to environments, short-term memory and social recognition impairments. In addition, Bmal1-KO mice experienced reduced cocaine-induced sensitisation and rewarding effects of cocaine as well as reduced cocaine-seeking behaviour. Furthermore, Bmal1 deletion influenced the expression of other clock-related genes in the mPFC and striatum, as well as alterations in the expression of dopaminergic elements. Overall, the present article offers a novel and extensive characterisation of Bmal1-KO animals. We suggest that reduced cocaine's rewarding effects in these mutant mice might be related to Bmal1 role as an expression regulator of MAO and TH, two essential enzymes involved in dopamine metabolism.

Reviewing the Role of the Endocannabinoid System in the Pathophysiology of Depression.

Major depressive disorder is a high-impact, debilitating disease and it is currently considered the most prevalent mental illness. It is associated with disability, as well as increased morbidity and mortality. Despite its significant repercussions in our society, its exact pathophysiology remains unclear and therefore, available antidepressant treatment options are limited and, in some cases, ineffective. In the past years, research has focused on the development of a multifactorial theory of depression. Simultaneously, evidence supporting the role of the endocannabinoid system in the neurobiology of neuropsychiatric diseases has emerged. Studies have shown that the endocannabinoid system strongly impacts neurotransmission, and the neuroendocrine and neuroimmune systems, which are known to be dysfunctional in depressive patients. Accordingly, common antidepressants were shown to have a direct impact on the expression of cannabinoid receptors throughout the brain. Therefore, the relationship between the endocannabinoid system and major depressive disorder is worth consideration. Nevertheless, most studies focus on smaller pieces of what is undoubtedly a larger mosaic of interdependent processes. Therefore, the present review summarizes the existing literature regarding the role of the endocannabinoid system in depression aiming to integrate this information into a holistic picture for a better understanding of the relationship between the two.