Pregnenolone sulphate improves memory processing in early-handled female rats

Early life experiences lead to sex-specific behavioural and neurochemical changes in adulthood. Indeed, early handling enhances learning and memory in male rats (Cannizzaro et al., 2005), whereas it impairs learning performance in female adult rats, a finding that has been correlated to decreased nitric oxide (NO) production in the hippocampus (Noschang et al., 2010). Pregnenolone sulfate (PREGS) is considered as one of the most potent memory-enhancing neurosteroids, since its activity as a potent positive modulator of N-methyl-d-aspartate receptors (NMDARs) and a negative modulator of gamma-aminobutyric acid(A) receptors (GABA(A)Rs) (Vallée et al., 2001). Given these premises, this study a…

Acetaldehyde as a drug of abuse: insight into AM281 administration on operant-conflict paradigm in rats

Increasing evidence focuses on acetaldehyde (ACD) as the mediator of the rewarding and motivational properties of ethanol. Indeed, ACD stimulates dopamine release in the nucleus accumbens and it is self-administered under different conditions. Besides the dopaminergic transmission, the endocannabinoid system has been reported to play an important role in ethanol central effects, modulating primary alcohol rewarding effect, drug-seeking and relapse behaviour. Drug motivational properties are highlighted in operant paradigms which include response-contingent punishment, a behavioural equivalent of compulsive drug use despite adverse consequences. The aim of this study was thus to characterize…

Manipulation of the DA signal on the onset of relapse of ACD

It's widely known that all addictive drugs show analogous pathological behaviours consisting in compulsive drug seeking,loss of self –control and propensity to relapse. This evidence is suggestive of a common brain mechanism involving the Ventral Tegmental Area and Nucleus Accumbens whereby mesocorticolimbimc dopamine pathway. Dfferent and apparently anthitetic classes of drugs of abuse manage to increase DA release, in the aforementioned areas (Di Chiara, 1988; 1995). Reductions in activity of the mesolimbic dopamine system in the nucleus accumbes occur during drug withdrawal in animal studies (Weiss F et al. 1992; 1996). Experimental evidences have proven D2 receptor involvement in drug s…

The role of pregnenolone sulphate in spatial orientation-acquisition and retention: An interplay between cognitive potentiation and mood regulation

Abstract Neurosteroids can alter neuronal excitability interacting with specific neurotransmitter receptors, thus affecting several functions such as cognition and emotionality. In this study, we investigated, in adult male rats, the effects of the acute administration of pregnenolone-sulfate (PREGS) (10 mg/Kg, s. c.) on cognitive processes using the Can test, a non aversive spatial/visual task which allows the assessment of spatial information-acquisition during the baseline training, and of memory retention in the longitudinal study. Furthermore, on the basis of PREGS pharmacological profile, the modulation of depressive-like behaviour was also evaluated in the forced swim test (FST). Our…

Addictive-like behaviour for Acetaldehyde: involvement of D2 receptors

Acetaldehyde (ACD), ethanol's first metabolite, is centrally active and shows rewarding and motivational properties. It is able to activate mesolimbic dopamine system, since it enhances neuronal firing of dopamine cells in ventral tegmental area and exerts dopamine release in the nucleus accumbens (Foddai et al., 2004; Melis et al., 2007; Deehan et al., 2013). ACD motivational properties are demonstrated by self-administration studies in rodents (Rodd et al., 2005), particularly behavioural evidence suggests that ACD could produce positive reinforcing effects in operant-conflict paradigms (Cacace et al., 2012). In order to shed light on neurobiological substrate underpinning ACD-related beh…

PHARMACOLOGICAL MODULATION OF OPERANT BEHAVIOUR FOR ACETALDEHYDE. INVOLVEMENT OF D2 AND CB1 RECEPTORS.

Acetaldehyde (ACD), the first metabolite of ethanol, has rewarding and motivational properties, as shown by behavioural studies specifically tailored for studying addictive-like behaviour (1, 2). The rewarding and incentive effects of alcohol and others addictive substances, result from their capability to enhance mesolimbic dopamine (DA) transmission, as well as to affect the cannabinoid system, which is able to fine-tune the activity of DA neurons (3). ACD directly increases DA neurotransmission (4), but the neural underpinning the operant behaviour for oral-self administered ACD still remains poorly understood. Since D2 and CB1 receptors are involved in alcohol addiction (3), as well as …

Acetaldehyde operant self-administration in rats: focus on D2-receptor activation.

Acetaldehyde (ACD), ethanol first metabolite, is rewarding in rodents and humans; it induces “place preference”, is self-administer directly in the VTA, orally in an operant/conflict paradigm and increases DA neurons’ firing. This research aims at investigating DA2-receptor role in the reinstatement of acetaldehyde operant-drinking behaviour, following induction, maintenance and abstinence in the rat. Male Wistar rats are trained to orally self-administer ACD solution (3.2% v/v) or water, in an operant chamber under a FR1. Afterwards animals undergo cyclic periods of deprivation and relapse to ACD. The effect ofD2-receptor activation by quinpirole (0.03mg/kg,i.p.) on operant ACD self-admini…

Dopamine restores limbic memory loss, dendritic spine structure, and NMDAR-dependent LTD in the nucleus accumbens of alcohol-withdrawn rats

Alcohol abuse leads to aberrant forms of emotionally salient memory, i.e., limbic memory, that promote escalated alcohol consumption and relapse. Accordingly, activity-dependent structural abnormalities are likely to contribute to synaptic dysfunctions that occur from suddenly ceasing chronic alcohol consumption. Here we show that alcohol-dependent male rats fail to perform an emotional-learning task during abstinence but recover their functioning byl-3,4-dihydroxyphenylalanin (l-DOPA) administration during early withdrawal.l-DOPA also reverses the selective loss of dendritic “long thin” spines observed in medium spiny neurons of the nucleus accumbens (NAc) shell of alcohol-dependent rats d…

Serotonergic versus non-serotonergic dorsal raphe projection neurons differential participation in reward circuitry

In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

Background:Cannabinoid consumption during pregnancy has been increasing on the wave of the broad-based legalisation of cannabis in Western countries, raising concern about the putative detrimental outcomes on foetal neurodevelopment. Indeed, since the endocannabinoid system regulates synaptic plasticity, emotional and cognitive processes from early stages of life interfering with it and other excitability endogenous modulators, such as neuropeptide Y (NPY), might contribute to the occurrence of a vulnerable phenotype later in life.Aims:This research investigated whether in utero exposure to Δ9-tetrahydrocannabinol (THC) may induce deficits in emotional/cognitive processes and alcohol vulner…

EFFECT OF ACETALDEHYDE INTOXICATION AND WITHDRAWAL ON NEUROPEPTIDE Y EXPRESSION. FOCUS ON CB1 RECEPTOR ROLE.

Neuropeptide Y (NPY) acts as an endogenous anxiolytic, and, like endocannabinoids, plays an important role in the regulation of neuronal excitability during ethanol withdrawal (Rubio et al., 2011). Since acetaldehyde is considered a mediator of ethanol central effects, this research aims at investigating, following intoxication and during withdrawal, the effects of acetaldehyde on NPY expression in brain areas particularly vulnerable to alcohol, and the influence of cannabinoid system on it. Rats underwent acetaldehyde intoxication (450mg/kg, i.g., 4 times daily for 4 days); AM281, a CB1 selective antagonist (2,5 mg/kg, i.p.) was administered during abstinence. Immunohistochemical analysis …

Vulnerability to alcohol operant-drinking behaviour: implications of environmental stim

Environmental stimuli, occurring early in life, shape the drinking trajectories and the psychopathological outcome of alcohol consumption in adult life. In particular, early perinatal procedures can permanently alter various patterns of drug use and behaviour in rat adulthood (Pryce CR, 2001). Early handling (EH) apparently is responsible for neurochemical and behavioural changes in adulthood, due to boosts in maternal care after daily reunion. It has been suggested that fostered maternal care, in the form of licking and grooming, is a key feature in determining neural changes and offspring fear responses and alter the reward/reinforcement pathway through epigenetic mechanisms that likely u…

Pregnenolone sulphate enhances spatial orientation and object discrimination in adult male rats: Evidence from a behavioural and electrophysiological study

Abstract Neurosteroids can alter neuronal excitability interacting with specific neurotransmitter receptors, thus affecting several functions such as cognition and emotionality. In this study we investigated, in adult male rats, the effects of the acute administration of pregnenolone-sulfate (PREGS) (10 mg/kg, s.c.) on cognitive processes using the Can test, a non aversive spatial/visual task which allows the assessment of both spatial orientation–acquisition and object discrimination in a simple and in a complex version of the visual task. Electrophysiological recordings were also performed in vivo , after acute PREGS systemic administration in order to investigate on the neuronal activati…

Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase.

Summary: Glutamate has been implicated in a wide range of brain pathologies and is thought to be metabolized via the astrocyte-specific enzyme glutamine synthetase (GS). We show here that oligodendrocytes, the myelinating glia of the central nervous system, also express high levels of GS in caudal regions like the midbrain and the spinal cord. Selective removal of oligodendrocyte GS in mice led to reduced brain glutamate and glutamine levels and impaired glutamatergic synaptic transmission without disrupting myelination. Furthermore, animals lacking oligodendrocyte GS displayed deficits in cocaine-induced locomotor sensitization, a behavior that is dependent on glutamatergic signaling in th…

Effect of Acetaldehyde Intoxication and Withdrawal on NPY Expression: Focus on Endocannabinoidergic System Involvement

Acetaldehyde (ACD), the first alcohol metabolite, plays a pivotal role in the rewarding, motivational and addictive properties of the parental compound. Many studies have investigated the role of ACD in mediating neurochemical and behavioral effects induced by alcohol administration, but very little is known about the modulation of neuropeptide systems following ACD intoxication and withdrawal. Indeed the neuropeptide Y (NPY) system is altered during alcohol withdrawal in key regions for cerebrocortical excitability and neuroplasticity. The primary goal of this research was to investigate the effects of ACD intoxication and withdrawal by recording rat behavior and by measuring neuropeptide …

Involvement of Dopamine D2 Receptors in Addictive-Like Behaviour for Acetaldehyde

Acetaldehyde, the first metabolite of ethanol, is active in the central nervous system, where it exerts motivational properties. Acetaldehyde is able to induce drinking behaviour in operant-conflict paradigms that resemble the core features of the addictive phenotype: drug-intake acquisition and maintenance, drug-seeking, relapse and drug use despite negative consequences. Since acetaldehyde directly stimulates dopamine neuronal firing in the mesolimbic system, the aim of this study was the investigation of dopamine D2-receptors' role in the onset of the operant drinking behaviour for acetaldehyde in different functional stages, by the administration of two different D2-receptor agonists, q…

Early handling effect on female rat spatial and non-spatial learning and memory

This study aims at providing an insight into early handling procedures on learning and memory performance in adult female rats. Early handling procedures were started on post-natal day 2 until 21, and consisted in 15 min, daily separations of the dams from their litters. Assessment of declarative memory was carried out in the novel-object recognition task; spatial learning, reference- and working memory were evaluated in the Morris water maze (MWM). Our results indicate that early handling induced an enhancement in: (1) declarative memory, in the object recognition task, both at 1h and 24h intervals; (2) reference memory in the probe test and working memory and behavioral flexibility in the…

Dopamine involvement in Acetaldehyde drinking behaviour: role of Ropinirole on.

Rats self-administer acetaldehyde(ACD), ethanol's first metabolite, directly into cerebral ventricles (1), and multiple ICV infusions of ACD produce conditioned place preference (2). ACD, such as alcohol and other substances of abuse, interacts with dopaminergic reward system (3) and its reinforcing and addictive properties have been assessed through an operant-conflict conditioning procedure (4). Since dopamine D2receptor over-expression in the Nacc attenuates alcohol intake (5), this study aims at exploring the effects of ropinirole administration during abstinence, on ACD relapse. The protocol has been scheduled into 3 different periods: training ( animals have been trained to self-admin…