Functional Neuroanatomy of Morphine-Induced Abstinence, Tolerance, and Sensitisation

The investigation into the relationship between neural plasticity in the rat forebrain associated with opiate-induced behaviours yielded two major results. The major finding of the functional neuroanatomy of acute morphine dependence was that doses of naloxone that induced hyperalgesia following a brief exposure to morphine, in previously drug-naïve rats, caused a specific induction of the inducible transcription factor (itf) proteins c-Fos and zif268 in the extended amygdala. Moreover, doses of naloxone that caused a simple reversal in morphine analgesia failed to induce itf proteins in these same brain regions. This increase in itf proteins was specific to regions of the extended amygdala that receive and process nociceptive information relayed via the spino-parabrachio-amygdaloid pathway and was not observed in other regions that are involved in supraspinal pain modulation such as the rostral ventromedial medulla and the periaqueductal gray. We also found that acute morphine increased c-Fos protein in the basolateral amygdala and the major output nucleus of the central amygdala the medial subdivision. Acute morphine also up-regulated c-Fos protein in striatal, midbrain, and hypothalamic nuclei. A unique finding of the current study was that prolonged exposure to morphine was required to induce c-Fos in these brain regions, as the subsequent administration of naloxone 30-minutes after morphine either reversed or blocked this induction. These results indicate the potential role of the amygdala in analgesia following systemic morphine and in pain facilitation during acute morphine abstinence. Investigation into the neurons and circuitry that undergo long-term neuroplasticity in response to repeated morphine exposure revealed that network-level changes in the distribution of Fos protein in the nucleus accumbens and striatum predicted both tolerance to catalepsy and psychomotor sensitisation. Drug-naïve rats became profoundly cataleptic following morphine, an effect that rats with a drug-history became tolerant. Rats with a history of morphine exposure showed an increase in stereotyped behaviours compared to drug-naïve rats. The major finding of this study was that a shift in the induction of c-Fos protein from a matrix predominance in drug-naïve rats toward a patch predominance in drug-sensitised rats in the accumbens core predicted both tolerance to catalepsy and sensitisation of oral stereotyped behaviours. Acute injection of morphine in a drug-naïve rat induced catalepsy and increased the number of c-Fos-positive neurons in matrix striatopallidal projection neurons of the rostral accumbens core. An increase in activity of striatopallidal projection neurons, which give rise to the indirect pathway, could potentially increase inhibitory drive to the pedunculopontine nucleus (PPN). The PPN, long known as a site of termination for basal ganglia output, is thought to direct the outflow of incentive-motivational and sensorimotor information from the nucleus accumbens to pons, medullary, and spinal cord nuclei translating the incentive impact of the stimuli into appropriate motor, autonomic and emotive responses (Winn et al., 1997). Inhibition of this nucleus would cause the animal to be unable to initiate a movement and in effect lock up, which is precisely what cataleptic postures look like. In contrast c-Fos-positive neurons were decreased in the rostral matrix and increased in patch striatonigral projection neurons along the rostro-caudal extent of the accumbens core when morphine was administered to drug-sensitised rats. Striatonigral neurons located in the patch give rise to the direct pathway innervating the dopaminergic neurons in both substantia pars compacta and the dopamine rich islands in the substantia nigra pars reticulata (Berendse et al., 1992; Gerfen, 1992; Furuta et al., 2002). Activity of this pathway is thought to be involved in the initiation of movement (Gerfen, 1992; Gerfen and Wilson, 1996), however, when this pathway is overstimulated as is the case when morphine is injected in drug-sensitised rats this could potentially cause increased activity of PPN neurons leading to repetitive psychomotor behaviours or stereotypy. This data adds to the growing body of evidence that suggests that long-term neuroadaptations induced by drugs of abuse including morphine that lead to behavioural sensitisation involves the circuitry that includes the nucleus accumbens

Functional Neuroanatomy of Morphine-Induced Abstinence, Tolerance, and Sensitisation

The investigation into the relationship between neural plasticity in the rat forebrain associated with opiate-induced behaviours yielded two major results. The major finding of the functional neuroanatomy of acute morphine dependence was that doses of naloxone that induced hyperalgesia following a brief exposure to morphine, in previously drug-naïve rats, caused a specific induction of the inducible transcription factor (itf) proteins c-Fos and zif268 in the extended amygdala. Moreover, doses of naloxone that caused a simple reversal in morphine analgesia failed to induce itf proteins in these same brain regions. This increase in itf proteins was specific to regions of the extended amygdala that receive and process nociceptive information relayed via the spino-parabrachio-amygdaloid pathway and was not observed in other regions that are involved in supraspinal pain modulation such as the rostral ventromedial medulla and the periaqueductal gray. We also found that acute morphine increased c-Fos protein in the basolateral amygdala and the major output nucleus of the central amygdala the medial subdivision. Acute morphine also up-regulated c-Fos protein in striatal, midbrain, and hypothalamic nuclei. A unique finding of the current study was that prolonged exposure to morphine was required to induce c-Fos in these brain regions, as the subsequent administration of naloxone 30-minutes after morphine either reversed or blocked this induction. These results indicate the potential role of the amygdala in analgesia following systemic morphine and in pain facilitation during acute morphine abstinence. Investigation into the neurons and circuitry that undergo long-term neuroplasticity in response to repeated morphine exposure revealed that network-level changes in the distribution of Fos protein in the nucleus accumbens and striatum predicted both tolerance to catalepsy and psychomotor sensitisation. Drug-naïve rats became profoundly cataleptic following morphine, an effect that rats with a drug-history became tolerant. Rats with a history of morphine exposure showed an increase in stereotyped behaviours compared to drug-naïve rats. The major finding of this study was that a shift in the induction of c-Fos protein from a matrix predominance in drug-naïve rats toward a patch predominance in drug-sensitised rats in the accumbens core predicted both tolerance to catalepsy and sensitisation of oral stereotyped behaviours. Acute injection of morphine in a drug-naïve rat induced catalepsy and increased the number of c-Fos-positive neurons in matrix striatopallidal projection neurons of the rostral accumbens core. An increase in activity of striatopallidal projection neurons, which give rise to the indirect pathway, could potentially increase inhibitory drive to the pedunculopontine nucleus (PPN). The PPN, long known as a site of termination for basal ganglia output, is thought to direct the outflow of incentive-motivational and sensorimotor information from the nucleus accumbens to pons, medullary, and spinal cord nuclei translating the incentive impact of the stimuli into appropriate motor, autonomic and emotive responses (Winn et al., 1997). Inhibition of this nucleus would cause the animal to be unable to initiate a movement and in effect lock up, which is precisely what cataleptic postures look like. In contrast c-Fos-positive neurons were decreased in the rostral matrix and increased in patch striatonigral projection neurons along the rostro-caudal extent of the accumbens core when morphine was administered to drug-sensitised rats. Striatonigral neurons located in the patch give rise to the direct pathway innervating the dopaminergic neurons in both substantia pars compacta and the dopamine rich islands in the substantia nigra pars reticulata (Berendse et al., 1992; Gerfen, 1992; Furuta et al., 2002). Activity of this pathway is thought to be involved in the initiation of movement (Gerfen, 1992; Gerfen and Wilson, 1996), however, when this pathway is overstimulated as is the case when morphine is injected in drug-sensitised rats this could potentially cause increased activity of PPN neurons leading to repetitive psychomotor behaviours or stereotypy. This data adds to the growing body of evidence that suggests that long-term neuroadaptations induced by drugs of abuse including morphine that lead to behavioural sensitisation involves the circuitry that includes the nucleus accumbens

Use of SMS texts for facilitating access to online alcohol interventions: a feasibility study

A41 Use of SMS texts for facilitating access to online alcohol interventions: a feasibility study In: Addiction Science & Clinical Practice 2017, 12(Suppl 1): A4

Individual Responses to Organisational Change: An Interoceptive Predictive Processing Account

Organisational change is a ubiquitous phenomenon within contemporary workplaces, yet it is consistently reported that over 70% of organisational change attempts fail. Organisational change is characterised by uncertainty and conflict and is associated with decrements in health and well-being for employees and a reduction in organisational performance. The neurophysiological mechanisms underlying individual responses to organisational change have not been widely researched. The current study sought to apply the interoceptive predictive processing framework to examine how the central and peripheral nervous system is impacted by organisational change. An integrated electroencephalogram (EEG) and electrocardiogram (ECG) study was carried out in an organisation undergoing change. Fortyeight English speaking employees volunteered to participate in the study. EEG and electrocardiogram (ECG) recordings were taken as employees undertook an affective face word Stroop (AFWS) task, which pairs an affectively expressive face with either a congruent or incongruent emotion word to produce emotional interference and adaptation effects similar to those reported for the colour-word Stroop paradigm. EEG results showed left hemisphere dominant control related cortical activation in regions associated with cognitive, perceptual, and executive processes which were functionally connected to right pre-supplementary and supplementary motor areas. These findings indicate that organisational change is positively correlated with cognitive control when faced with conflicting affective challenges. ECG results showed that allostatic (cardiac) responses were negatively correlated with organisational change. The interoceptive predictive processing model provided a unitary framework for describing both seemingly paradoxical results. The novel findings have practical implications for organisations undergoing change and add to the nascent field of organisational neuroscience

Sex differences in the expression of estrogen receptor alpha within noradrenergic neurons in the sheep brain stem

In female sheep, high levels of estrogen exert a positive feedback action on gonadotropin releasing hormone (GnRH) secretion to stimulate a surge in luteinizing hormone (LH) secretion. Part of this action appears to be via brain stem noradrenergic neurons. By contrast, estrogen action in male sheep has a negative feedback action to inhibit GnRH and LH secretion. To investigate whether part of this sex difference is due to differences in estrogen action in the brain stem, we tested the hypothesis that the distribution of estrogen receptor α (ERα) within noradrenergic neurons in the brain stem differs between rams and ewes. To determine the distribution of ERα, we used double-label fluorescence immunohistochemistry for dopamine β-Hydroxylase, as a marker for noradrenergic and adrenergic cells, and ERα. In the ventrolateral medulla (A1 region), most ERα-immunoreactive (-ir) cells were located in the caudal part of the nucleus. Overall, there were more ERα-ir cells in rams than ewes, but the proportion of double-labeled cells was did not differ between sexes. Much greater numbers of ERα-ir cells were found in the nucleus of the solitary tract (A2 region), bu

Drying at high temperature for a short time maximizes the recovery of olive leaf biophenols

In the current study, recovery of phenolic compounds from fresh, air-dried, freeze-dried and oven-dried (at 60°C and 105°C) olive leaves was investigated. The phenol content and antioxidant activity were assessed by gross quantitative methods such as total phenol content (Folin-Ciocalteu's method), total flavonoid content, total o-diphenol content and total antioxidant capacity using ABTS+° and DPPH° scavenging assays. In addition, the phenolic composition of extracts was determined by high performance liquid chromatography (HPLC) equipped with diode array detection (DAD) with tandem mass (MS/MS) and the contribution of individual phenolic components to the antioxidant activity of extracts were evaluted by online ABTS scavenging assay. Extracts obtained from oven-dried leaves at 105°C showed the highest phenol recoveries and antioxidant activities, whereas extracts obtained from oven-dried leaves at 60°C had the lowest values. Oven drying of olive leaves at 105°C for three hours increased oleuropein recovery up to 38 fold as compared with fresh olive leaves. Our results stress the paramount importance of sample pre-treatment in the preparation and analysis of herbal medicines. Furthermore, we highlight the limitations of sole dependence on gross assessment of total phenolic composition and total antioxidant activity in studying plant samples

The protective role of plant biophenols in mechanisms of Alzheimer's disease

Self-assembly of amyloid beta peptide (Aβ) into the neurotoxic oligomers followed by fibrillar aggregates is a defining characteristic of Alzheimer's disease (AD). Several lines of proposed hypotheses have suggested the mechanism of AD pathology, though the exact pathophysiological mechanism is not yet elucidated. The poor understanding of AD and multitude of adverse responses reported from the current synthetic drugs are the leading cause of failure in the drug development to treat or halt the progression of AD and mandate the search for safer and more efficient alternatives. A number of natural compounds have shown the ability to prevent the formation of the toxic oligomers and disrupt the aggregates, thus attracted much attention. Referable to the abundancy and multitude of pharmacological activities of the plant active constituents, biophenols that distinguish them from the other phytochemicals as a natural weapon against the neurodegenerative disorders. This review provides a critical assessment of the current literature on in vitro and in vivo mechanistic activities of biophenols associated with the prevention and treatment of AD. We have contended the need for more comprehensive approaches to evaluate the anti-AD activity of biophenols at various pathologic levels and to assess the current evidences. Consequently, we highlighted the various problems and challenges confronting the AD research, and offer recommendations for future research

Developmental evidence for enhanced theory of mind for competitive versus cooperative contexts

There is a debate regarding the function of theory of mind (ToM), the capacity to infer, attribute, and reason about mental states. On the one hand are evolutionary and psychological work suggesting that ToM is greater for competition than cooperation. On the other hand are findings and theories promoting greater ToM for cooperation than competition. We investigate the question of whether ToM is greater for competition than cooperation or vice versa by examining the period of development during which explicit ToM comes online. In two studies, we examined preschool children’s abilities to explicitly express an understanding of false beliefs—a key marker of ToM—and ability to apply that understanding in first-person social interactions in competitive and cooperative contexts. Our findings reveal that preschool children are better at understanding false beliefs and applying that understanding in competitive contexts than in cooperative contexts

Olive Biophenols Reduces Alzheimer's Pathology in SH-SY5Y Cells and APPswe Mice

Alzheimer's disease (AD) is a major neurodegenerative disease, associated with the hallmark proteinacious constituent called amyloid beta (Aβ) of senile plaques. Moreover, it is already established that metals (particularly copper, zinc and iron) have a key role in the pathogenesis of AD. In order to reduce the Aβ plaque burden and overcome the side effects from the synthetic inhibitors, the current study was designed to focus on direct inhibition of with or without metal-induced Aβ fibril formation and aggregation by using olive biophenols. Exposure of neuroblastoma (SH-SY5Y) cells with Aβ42 resulted in decrease of cell viability and morphological changes might be due to severe increase in the reactive oxygen species (ROS). The pre-treated SH-SY5Y cells with olive biophenols were able to attenuate cell death caused by Aβ42, copper- Aβ42, and [laevodihydroxyphenylalanine (l-DOPA)] l-DOPA-Aβ42-induced toxicity after 24 h of treatment. Oleuropein, verbascoside and rutin were the major anti-amyloidogenic compounds. Transgenic mice (APPswe/PS1dE9) received 50 mg/kg of oleuropein containing olive leaf extracts (OLE) or control diet from 7 to 23 weeks of age. Treatment mice (OLE) were showed significantly reduced amyloid plaque deposition (

Olive Biophenols Reduces Alzheimer’s Pathology in SH-SY5Y Cells and APPswe Mice

Alzheimer’s disease (AD) is a major neurodegenerative disease, associated with the hallmark proteinacious constituent called amyloid beta (Aβ) of senile plaques. Moreover, it is already established that metals (particularly copper, zinc and iron) have a key role in the pathogenesis of AD. In order to reduce the Aβ plaque burden and overcome the side effects from the synthetic inhibitors, the current study was designed to focus on direct inhibition of with or without metal-induced Aβ fibril formation and aggregation by using olive biophenols. Exposure of neuroblastoma (SH-SY5Y) cells with Aβ42 resulted in decrease of cell viability and morphological changes might be due to severe increase in the reactive oxygen species (ROS). The pre-treated SH-SY5Y cells with olive biophenols were able to attenuate cell death caused by Aβ42, copper- Aβ42, and [laevodihydroxyphenylalanine (l-DOPA)] l-DOPA-Aβ42-induced toxicity after 24 h of treatment. Oleuropein, verbascoside and rutin were the major anti-amyloidogenic compounds. Transgenic mice (APPswe/PS1dE9) received 50 mg/kg of oleuropein containing olive leaf extracts (OLE) or control diet from 7 to 23 weeks of age. Treatment mice (OLE) were showed significantly reduced amyloid plaque deposition (p < 0.001) in cortex and hippocampus as compared to control mice. Our findings provide a basis for considering natural and low cost biophenols from olive as a promising candidate drug against AD. Further studies warrant to validate and determine the anti-amyloid mechanism, bioavailability as well as permeability of olive biophenols against blood brain barrier in AD