Jolanta Opacka-Juffry

Long-term effects of early life deprivation on brain glia in fischer rats

Both clinical and experimental studies have indicated that depression and depression-like animal conditions are associated with disruption of the intrinsic plasticity of the brain, resulting in neuronal atrophy. However, little is known about the brain glia in these conditions. Early life stress in the form of infant abuse or neglect constitutes a risk factor in the aetiology of major depressive disorder in later life. It is possible to model this relation between early life stress and depression in the rat through maternal deprivation; in adulthood, this postnatal manipulation is known to lead to depression-like behaviour. In the stress-hyperresponsive Fischer strain, P1-14 pups were isolated for 4 h/day (early deprivation, ED, n=6) or were nonhandled (NH, n=6); they were left undisturbed until adulthood. Postmortem quantitative analysis of regional astroglial distribution and morphology based on glial fibrillary acidic protein (GFAP) immunohistochemistry indicated a significant effect of ED on the density of GFAP-reactive astrocytes in brain areas implicated in stress-related behaviour. A moderate (10-22%) but consistent reduction in GFAP-reactive astrocyte density was seen in dorsal dentate gyrus, prefrontal cortex, ventral hippocampal CA1, cingulate cortex, dorsal hippocampal CA1 and basolateral amygdala. The ED-related reduction in GFAP-immunoreactive astrocyte density was more marked than the reduction in total cell density, which suggests that GFAP immunoreactivity, rather than the number of astrocytes, was reduced. This study provides evidence that early life stress leads to long-term changes in the density of astroglia in the brain regions involved in stress responses in the rat.

Early deprivation leads to long-term reductions in motivation for reward and 5-HT1A binding and both effects are reversed by fluoxetine

Early life stress is a risk factor in aetiology of depression. In rats, early life stress can lead to pro-depressive biomarkers in adulthood. The present study in male Wistar rats investigated the effects of early life deprivation and fluoxetine on motivation for reward, activity in the forced swim test, and brain monoamine receptors, in adulthood. P1-14 pups were isolated for 4 h/day (early deprivation, ED) or were handled for 1 min (CON). They were weaned at PND21 and left undisturbed until 4-6 months old. The ED and CON groups were halved to receive either vehicle or fluoxetine (FLX, 10 mg/kg, 31 days). Thus, four treatment groups were studied: CON-VEH, CON-FLX, ED-VEH and ED-FLX, n = 8 each. On a progressive ratio schedule, ED-VEH animals showed significantly reduced motivation to obtain sucrose versus CON-VEH, and this reward-motivation deficit was reversed by FLX. Activity in the forced swim test was unaffected by ED and increased by FLX. Quantitative autoradiography was used to determine 5-HT1A and 5-HT2C receptor binding with [O-methyl-(3)H]WAY 100635 and [(3)H]mesulergine (added spiperone and 8-OH-DPAT), respectively. In ED-VEH versus CON-VEH, 5-HT1A receptor binding was significantly reduced in anterior cingulate, motor cortex, ventral hippocampal CA1 and dorsal raphé; this was reversed by chronic FLX. Concomitant ED-dependent reductions observed in 5-HT2C (motor and frontal cortices, ventral CA1 and dorsal raphé) and D2 (dorsolateral striatum and accumbens) binding were not reversed by FLX. Because chronic FLX treatment reversed the ED-induced behavioural and 5-HT1A binding deficits, the 5-HT1A receptor is implicated as a selective therapeutic target.

Experience of stress in childhood negatively correlates with plasma oxytocin concentration in adult men

Early life experience is known to affect responses to stress in adulthood. Adverse experience in childhood and/or adolescence sensitises to life events that precipitate depression in later life. Published evidence suggests a relationship between depression and oxytocin (OT), but the extent to which early life experience influences OT disposition in adulthood deserves further exploration. This study hypothesised that early life stress (ELS) has a long-term negative effect on OT system activity. The study was performed on 90 male volunteers (18–56 years; mean ± standard deviation = 27.7 ± 7.09 years). Several questionnaires were used to assess: health, early life stressful experiences in childhood (ELS-C, up to 12 years) and early life stressful adolescence (13–18 years), recent stressful life events, depressive symptoms, state–trait anxiety and social desirability. Plasma OT concentration was estimated by means of a competitive enzyme immunoassay. Lower OT concentrations were significantly associated with higher levels of ELS-C (p < 0.01), and with depressive symptoms and trait anxiety (both p < 0.05). The interaction between ELS-C and trait anxiety was significant (p < 0.05), indicating that the link between ELS-C and plasma OT concentration is moderated by trait anxiety. These results contribute to the evidence that early life adverse experience is negatively associated with OT system activity in adulthood, and offer further insight into mediator and moderator effects on this link.

The effects of benzofury (5-APB) on the dopamine transporter and 5-HT2-dependent vasoconstriction in the rat

5-APB, commonly marketed as benzofury is a new psychoactive substance and erstwhile legal high which has been implicated in 10 recent drug-related deaths in the UK. This drug was available on the internet and in head shops and was one of the most commonly sold legal highs up until its recent UK temporary ban (UK Home Office). Despite its prominence, very little is known about its pharmacology. This study was undertaken to examine the pharmacology of 5-APB in vitro. We hypothesised that 5-APB would activate the dopamine and 5-HT systems which may underlie its putative stimulant and hallucinogenic effects. Autoradiographic studies showed that 5-APB displaced both [(125)I] RTI-121 and [(3)H] ketanserin from rat brain tissue suggesting affinity at the dopamine transporter and 5-HT2 receptor sites respectively. Voltammetric studies in rat accumbens brain slices revealed that 5-APB slowed dopamine reuptake, and at high concentrations caused reverse transport of dopamine. 5-APB also caused vasoconstriction of rat aorta, an effect antagonised by the 5-HT2A receptor antagonist ketanserin, and caused contraction of rat stomach fundus, which was reversed by the 5-HT2B receptor antagonist RS-127445. These data show that 5-APB interacts with the dopamine transporter and is an agonist at the 5-HT2A and 5-HT2B receptors in the rat. Thus 5-APBs pharmacology is consistent with it having both stimulant and hallucinogenic properties. In addition, 5-APBs activity at the 5-HT2B receptor may cause cardiotoxicity.

Behavioural and biochemical responses to morphine associated with its motivational properties are altered in adenosine A2A receptor knockout mice

The purinergic system through the A2A adenosine receptor regulates addiction induced by different drugs of abuse. The aim of the present study was to investigate the specific role of A2A adenosine receptors (A2ARs) in the behavioural and neurochemical responses to morphine associated with its motivational properties.

Psychometric and neurobiological assessment of resilience in a non-clinical sample of adults.

BACKGROUNDnResilient individuals are capable of adjusting and coping successfully in the face of adversity. Efforts to assess resilience and its biomarkers have focused on individuals with a history of trauma and related disorders.nnnOBJECTIVEnTo psychologically assess resilience in a non-clinical community population through questionnaires, and analyse the associations between the psychological parameters and salivary cortisol and dehydroepiandrosterone sulphate (DHEA-S) as putative biomarkers of resilience.nnnMETHODnAn opportunistic sample (n=196) completed a cross-sectional survey assessing resilience, self-reported depressive symptoms and anxiety, and possible correlates. A sub-sample (n=32) selected in order to maximise variation of mental health, provided saliva samples for enzyme-linked immunoassay (ELISA) detection of cortisol and DHEA-S.nnnRESULTSnResilience correlated negatively with depressive symptoms, trait anxiety and early life stress, and positively with self-efficacy, optimism, social support and wellbeing (all r>0.40; all p-values ≤0.001 except for early life stress: r=-0.20; p≤0.05). Resilience and DHEA-S concentrations correlated significantly (r=0.35; p≤0.05); this relationship remained stable after adjustment for demographics. Gender differences were observed for DHEA-S and cortisol (p≤0.05).nnnCONCLUSIONnResilience is associated with positive aspects of psychological health and salivary DHEA-S, suggesting the latter can be treated as a biomarker of resilience in a non-clinical sample of adults.

Stimulant mechanisms of cathinones — Effects of mephedrone and other cathinones on basal and electrically evoked dopamine efflux in rat accumbens brain slices

Mephedrone, an erstwhile legal high, and some non-abused cathinones (ethcathinone, diethylpropion and bupropion) were tested for stimulant effects in vitro, through assessing their abilities to increase basal and electrically evoked dopamine efflux in rat accumbens brain slices, and compared with cocaine and amphetamine. We also tested mephedrone against cocaine in a dopamine transporter binding study. Dopamine efflux was electrically evoked and recorded using voltammetry in the rat accumbens core. We constructed concentration response curves for these cathinones for effects on basal dopamine levels; peak efflux after local electrical stimulation and the time-constant of the dopamine decay phase, an index of dopamine reuptake. We also examined competition between mephedrone or cocaine and [(125)I]RTI121 at the dopamine transporter. Mephedrone was less potent than cocaine at displacing [(125)I]RTI121. Mephedrone and amphetamine increased basal levels of dopamine in the absence of electrical stimulation. Cocaine, bupropion, diethylpropion and ethcathinone all increased the peak dopamine efflux after electrical stimulation and slowed dopamine reuptake. Cocaine was more potent than bupropion and ethcathinone, while diethylpropion was least potent. Notably, cocaine had the fastest onset of action. These data suggest that, with respect to dopamine efflux, mephedrone is more similar to amphetamine than cocaine. These findings also show that cocaine was more potent than bupropion and ethcathinone while diethylpropion was least potent. Mephedrones binding to the dopamine transporter is consistent with stimulant effects but its potency was lower than that of cocaine. These findings confirm and further characterize stimulant properties of mephedrone and other cathinones in adolescent rat brain.

Emotional suppression explains the link between early life stress and plasma oxytocin

Early life stress (ELS) has been found to be associated with lower concentrations of plasma oxytocin (OT) in adulthood. It is not yet clear, however, what mechanisms underlie this association. The goal of the present study was to test the role of emotional suppression as an intervening variable between ELS in childhood and plasma OT. In a nonclinical sample of 90 men, ELS, emotional suppression, and plasma OT were assessed. Emotional suppression was positively associated with ELS (r = 0.37, p < 0.001) and negatively associated with plasma OT concentrations (r = −0.30, p < 0.01). In contrast, cognitive reappraisal – an alternative emotion regulation strategy – was not correlated with ELS or plasma OT concentrations. Cross-sectional regression analyses revealed that the ELS explained variance in plasma OT via emotional suppression. Moderation analyses revealed that the combination of high ELS and high emotional suppression was associated with the lowest concentrations of plasma oxytocin. These findings are consistent with the view that emotional suppression may be one pathway linking ELS and OT.

Chapter Four - Spicing Up Pharmacology: A Review of Synthetic Cannabinoids From Structure to Adverse Events

Recreational use of synthetic cannabinoids (SCB), a class of novel psychoactive substances is an increasing public health problem specifically in Western societies, with teenagers, young adults, and the prison population being the most affected. Some of these SCB are analogs of tetrahydrocannabinol, aminoalkylindoles, and other phytocannabinoid analogs have been detected in herbal preparations generically called Spice. Spice, K2 or fake cannabis is a general term used for variable herbal mixtures of unknown ingredients or chemical composition. SCB are highly potent CB1 cannabinoid receptor agonists falsely marketed and sold as safe and legal drugs. Here, we present an overview of the endocannabinoid system, CB, and SCB chemical structures and activity at CB receptors. Finally, we highlight the psychological effects of SCB, particularly on learning and memory, and adverse clinical effects including on the cardiovascular system, kidneys, and CNS, including psychosis. Taken together, it is clear that many SCB are extremely dangerous and a major public health problem.

In vivo dopaminergic and behavioral responses to acute cocaine are altered in adenosine A2A receptor knockout mice

Adenosine, acting on adenosine A2A receptors (A2ARs), regulates addictive processes induced by drugs of abuse. This study investigates the role of A2A adenosine receptors in neurochemical and behavioral responses to an acute cocaine challenge. Changes in the extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) of mice lacking A2A adenosine receptors and wild type (WT) littermates after an acute cocaine (20 mg/kg) administration were evaluated by in vivo microdialysis studies. Locomotor effects induced by cocaine were measured during the microdialysis procedure. Cocaine‐evoked increases in extracellular DA were not sustained in mice lacking A2ARs in comparison with wild‐type mice (P < 0.05). Cocaine administration significantly increased ambulatory activity in both genotypes. However, overall locomotor activity was further increased, whereas rest and small local movement measures were significantly attenuated in the A2AR knockout mice compared with WT littermates (P < 0.05). Our findings support an important role for adenosine A2AR in modulating the acute effects of cocaine, as demonstrated by the decrease in cocaine‐evoked dopaminergic transmission in the NAc. Furthermore, the results support an important antagonistic role of A2AR in vivo in regulating psychostimulant‐induced hyperlocomotion. Synapse, 2012.