Neutral sphingomyelinase controls acute and chronic alcohol effects on brain activity.

Alcohol consumption is a widespread phenomenon throughout the world. However, how recreational alcohol use evolves into alcohol use disorder (AUD) remains poorly understood. The Smpd3 gene and its coded protein neutral sphingomyelinase (NSM) are associated with alcohol consumption in humans and alcohol-related behaviors in mice, suggesting a potential role in this transition. Using multiparametric magnetic resonance imaging, we characterized the role of NSM in acute and chronic effects of alcohol on brain anatomy and function in female mice. Chronic voluntary alcohol consumption (16 vol% for at least 6 days) affected brain anatomy in WT mice, reducing regional structure volume predominantly in cortical regions. Attenuated NSM activity prevented these anatomical changes. Functional MRI linked these anatomical adaptations to functional changes: Chronic alcohol consumption in mice significantly modulated resting state functional connectivity (RS FC) in response to an acute ethanol challenge (i.p. bolus of 2 g kg-1) in heterozygous NSM knockout (Fro), but not in WT mice. Acute ethanol administration in alcohol-naïve WT mice significantly decreased RS FC in cortical and brainstem regions, a key finding that was amplified in Fro mice. Regarding direct pharmacological effects, acute ethanol administration increased the regional cerebral blood volume (rCBV) in many brain areas. Here, chronic alcohol consumption otherwise attenuated the acute rCBV response in WT mice but enhanced it in Fro mice. Altogether, these findings suggest a differential role for NSM in acute and chronic functional brain responses to alcohol. Therefore, targeting NSM may be useful in the prevention or treatment of AUD.

Behavioural effects of APH199, a selective dopamine D4 receptor agonist, in animal models.

RATIONALE: The dopamine D4 receptors (DRD4) play a key role in numerous brain functions and are involved in the pathogenesis of various psychiatric disorders. DRD4 ligands have been shown to moderate anxiety, reward and depression-like behaviours, and cognitive impairments. Despite a series of promising but ambiguous findings, the therapeutic advantages of DRD4 stimulation remain elusive. OBJECTIVES: The investigation focused on the behavioural effects of the recently developed DRD4 agonist, APH199, to evaluate its impact on anxiety, anhedonia, behavioural despair, establishment and retrieval of alcohol reinforcement, and amphetamine (AMPH)-induced symptoms. METHODS: Male C57BL/6 J mice and Sprague-Dawley rats were examined in five independent experiments. We assessed APH199 (0.1-5 mg/kg, i.p.) effects on a broad range of behavioural parameters in the open field (OF) test, conditioned place preference test (CPP), elevated plus maze (EPM), light-dark box (LDB), novelty suppressed feeding (NSF), forced swim test (FST), sucrose preference test (SPT), AMPH-induced hyperlocomotion test (AIH), and prepulse inhibition (PPI) of the acoustic startle response in AMPH-sensitized rats. RESULTS: APH199 caused mild and sporadic anxiolytic and antidepressant effects in EPM and FST, but no remarkable impact on behaviour in other tests in mice. However, we found a significant increase in AMPH-induced hyperactivity, suggesting an exaggeration of the psychotic-like responses in the AMPH-sensitized rats. CONCLUSIONS: Our data challenged the hypothesis of the therapeutic benefits of DRD4 agonists, pointing out a possible aggravation of psychosis. We suggest a need for further preclinical studies to ensure the safety of antipsychotics with DRD4 stimulating properties.

Pharmacotherapy of schizophrenia: Mechanisms of antipsychotic accumulation, therapeutic action and failure.

Schizophrenia is a multi-dimensional disorder with a complex and mostly unknown etiology, leading to a severe decline in life quality. Antipsychotic drugs (APDs) remain beneficial interventions in the treatment of the disorder, but vary significantly in binding profile, clinical effects and adverse reactions. The present review summarizes the main principles of APD mechanisms of action with a particular focus on recent findings in APD accumulation and its role in the therapeutic efficacy and treatment failure. High and low doses of APDs were shown to be effective in different dimensions of antipsychotic-like behaviour in rodent models. Efficacy of the APDs correlates with high dopamine D2 receptor occupancy, which occurs quickly after drug administration. However, onset and peak of action are delayed up to several days or weeks. APD accumulation via acidic trapping in synaptic vesicles is considered to underlie the time course of APD action. Use-dependent exocytosis, co-release with dopamine and serotonin and inhibition of ion channels impact on the neuronal transmission and determine effects of APDs. Disruption in accumulating properties leads to diminished APD effects. In addition, long-term APD administration at therapeutic doses leads to treatment failure both in animal models and in humans. APD failure was associated with treatment induced neuroadaptations, including a decline in extracellular dopamine levels, dopamine transporter upregulation, and altered neuronal firing. However, enhanced synaptic vesicle release has also been reported. APD loss of efficacy may be reversed through inhibition of the dopamine transporter or switching the administration regimen from continuous to intermittent. Thus, manipulating the accumulation properties of APDs, changes in the administration regimen and doses, or co-administration with dopamine transporter inhibitors may be considered to yield benefits in the development of new effective strategies in the treatment of schizophrenia.