John O’Connor

Pro-inflammatory cytokines and their effects in the dentate gyrus

The older notion of a central nervous system existing in essential isolation from the immune system has changed dramatically in recent years as the body of evidence relating to the interactions between these two systems has grown. Here we address the role of a particular subset of immune modulatory molecules, the pro-inflammatory cytokines, in regulating neuronal function and viability in the dentate gyrus of the hippocampus. These inflammatory mediators are known to be elevated in many neuropathological conditions, such as Alzheimers disease, Parkinsons disease and ischaemic injury that follows stroke. Pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1beta) and interleukin 18 (IL-18), have been shown to regulate neurotoxicity; although, due to the complexity of the cytokine action in neurons and glia, the effect may be either facilitatory or protective, depending on the circumstances. As well as their role in neurotoxicity and neuroprotection, the pro-inflammatory cytokines have also been shown to be potent regulators of synaptic function. In particular, TNF-alpha, IL-1beta and IL-18 have all been shown to inhibit long-term potentiation, a form of neuronal plasticity widely believed to underlie learning and memory, both in the early p38 mitogen activated protein kinase-dependant phase and the later protein synthesis-dependant phase. In this article we address the mechanisms underlying these cytokine effects in the dentate gyrus of the hippocampus.

Interleukin-18 mediated inhibition of LTP in the rat dentate gyrus is attenuated in the presence of mGluR antagonists

Pro-inflammatory cytokines are known to be elevated in several neuropathological states that are associated with learning and memory impairments. We have previously demonstrated the inhibition of long-term potentiation (LTP), a recognised model for memory, in the dentate gyrus region of the rat hippocampus, by interleukin-18. We have also previously shown that the inhibitory effect of TNF-alpha on LTP can be attenuated by inhibitors of metabotropic glutamate receptors (mGluRs). We therefore went on to investigate the effects of the mGluR antagonists MPEP and MTPG on the effect of IL-18 on LTP in the rat dentate gyrus in vitro. Recordings of field excitatory post-synaptic potentials (EPSPs) were made from the medial perforant path of rat hippocampal slices. IL-18 (100 ng/ml) applied for 20 min before-HFS had no significant effect on baseline EPSPs but significantly impaired LTP (IL-18 LTP 116+/-9%, versus control LTP 163+/-6% 1h post-tetanus, P<0.001, n=5). Perfusion of the mGluR5 specific antagonist MPEP (5 microM) for 40 min prior to application of IL-18 had no significant effect on baseline EPSPs but significantly attenuated the inhibitory effect of IL-18 on LTP at 30 min but not 1h (177+/-2% and 138+/-8%, respectively, compared to controls; n=5). Perfusion of the group II mGluR antagonist MTPG (50 microM) for 40 min prior to application of IL-18 had no significant effect on baseline EPSPs but was found to significantly reverse the inhibitory effect of IL-18 on LTP at 1h (164+/-6% compared to IL-18 alone, n=5). This study provides novel evidence of the involvement of mGluRs in the IL-18 mediated inhibition of LTP.

CX3CL1 is up-regulated in the rat hippocampus during memory-associated synaptic plasticity

Several cytokines and chemokines are now known to play normal physiological roles in the brain where they act as key regulators of communication between neurons, glia, and microglia. In particular, cytokines and chemokines can affect cardinal cellular and molecular processes of hippocampal-dependent long-term memory consolidation including synaptic plasticity, synaptic scaling and neurogenesis. The chemokine, CX3CL1 (fractalkine), has been shown to modulate synaptic transmission and long-term potentiation (LTP) in the CA1 pyramidal cell layer of the hippocampus. Here, we confirm widespread expression of CX3CL1 on mature neurons in the adult rat hippocampus. We report an up-regulation in CX3CL1 protein expression in the CA1, CA3 and dentate gyrus (DG) of the rat hippocampus 2 h after spatial learning in the water maze task. Moreover, the same temporal increase in CX3CL1 was evident following LTP-inducing theta-burst stimulation in the DG. At physiologically relevant concentrations, CX3CL1 inhibited LTP maintenance in the DG. This attenuation in dentate LTP was lost in the presence of GABAA receptor/chloride channel antagonism. CX3CL1 also had opposing actions on glutamate-mediated rise in intracellular calcium in hippocampal organotypic slice cultures in the presence and absence of GABAA receptor/chloride channel blockade. Using primary dissociated hippocampal cultures, we established that CX3CL1 reduces glutamate-mediated intracellular calcium rises in both neurons and glia in a dose dependent manner. In conclusion, CX3CL1 is up-regulated in the hippocampus during a brief temporal window following spatial learning the purpose of which may be to regulate glutamate-mediated neurotransmission tone. Our data supports a possible role for this chemokine in the protective plasticity process of synaptic scaling.

D2 receptor‐mediated inhibition of dopamine release in the rat striatum in vitro is modulated by CB1 receptors: studies using fast cyclic voltammetry

Cannabinoid CB1 receptors are highly expressed in the striatum where they are known to be co‐localized with dopamine D2 receptors. There is now strong evidence that cannabinoids modulate dopamine release in the brain. Using fast cyclic voltammetry, single pulse stimulation (0.1 ms; 10 V) was applied every 5 min and peak dopamine release was measured with a carbon fibre microelectrode. Application of the D2 receptor agonist, quinpirole, inhibited single pulse dopamine overflow in a concentration‐dependent manner (IC50: 3.25 × 10−8 M). The CB1 receptor agonist WIN55212‐2 (WIN; 1 μM) had no effect on single pulse dopamine release (93.9 ± 6.6% at 60 min, n = 5) but attenuated the inhibitory effect of quinpirole (30 nM; quinpirole 39.0 ± 4.2% vs. quinpirole + WIN, 48.2 ± 3.7%, n = 5, p < 0.05). This affect was antagonized by the CB1 receptor anatgonist [N‐(Piperidin‐1‐yl)‐5‐(4‐iodophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide] (AM‐251, 1 μM). Dopamine release evoked by four pulses delivered at 1 Hz (4P1Hz) and 10 pulses delivered at 5 Hz (10P5Hz) was significantly inhibited by WIN [72.3 ± 7.9% control (peak 4 to 1 ratio measurement) and 66.9 ± 3.8% control (area under the curve measurement), respectively, p < 0.05; n = 6 for both]. Prior perfusion of WIN significantly attenuated the effects of quinpirole on multiple pulse‐evoked dopamine release (4P1Hz: quinpirole, 28.4 ± 4.8% vs. WIN + quinpirole, 52.3 ± 1.2%; 10P5Hz: quinpirole, 29.5 ± 1.3% vs. WIN + quinpirole, 59.4 ±7.1%; p < 0.05 for both; n = 6). These effects were also antagonized by AM‐251 (1 μM). This is the first report demonstrating a functional, antagonistic interaction between CB1 receptors and D2 autoreceptors in regulating rat striatal dopamine release.

Homelessness and the problem of containment

Homelessness is a problem that is hardly spared to any society in our modern world. Usually discussed by people concerned with social policy, sociology, public health and politics, homelessness has only quite recently begun to command the attention of professionals concerned with psychological and psychotherapeutic processes. Following from the authors experience of working therapeutically with homeless people, as well as in discussions with homeless services, the paper follows a line of thinking around homelessness that is explicitly psychodynamic in orientation. The central argument here is that homelessness is an experience that is, so to speak, waiting to happen. Homelessness is portrayed as a natural extension of an underlying experience of the sister states of uncontainment and alienation. I argue that the homeless person not only experienced a lack of containment in his earliest interactions, but has grown through life with significant difficulties in this area. Homelessness then is an extreme response to a deeper psychological reality that projects into a part of the persons life the agonies associated with uncontainment. Homelessness is the realization of an internal situation –a shifting of a personal struggle into a new and more visible stage. This view of homelessness is designed to provide an amendment to current views that privilege the roles of poverty and social exclusion in the origins of homelessness rather than as an alternative account of the origins of homelessness.

Desflurane, compared to halothane, augments phenylephrine-induced contraction in isolated rat aorta smooth muscle.

Purpose: The mechanism responsible for the mediation of hypertension in response to increased desflurane levels is unclear. This study compared the effect of desflurane and halothane on phenylephrine (PE)-induced contraction in rat aorta ring and the effect of desflurane in the presence and absence of nitric oxide (NO) synthase activity.Methods: Endothelium-free rat aorta rings were exposed serially to 10−7M, 10−6M and 10−5M PE alone and subsequently in the presence of 2 MAC desflurane and halothane. Secondly, endothelium-free preparations were exposed to 10−6M PE serially in the presence of 0, 1, 2 and 3 MAC desflurane and halothane. Thirdly, using an endothelium-intact preparation, the effect of desflurane on PE-induced contraction was examined, in the presence or absence of NG-nitrol-L-argine (L-NNA), an inhibitor of constitutive and inducible NO synthase.Results: Contraction amplitudes secondary to 10−6 and 10−5M PE in endothelium-free preparations were increased by 74% and 36% respectively (P<0.05) in the presence of 2 MAC desflurane compared to controls. In endothelium- free preparations, contraction amplitudes secondary to 10−6M PE were increased in the presence of 1 and 2 MAC desflurane by 32% and 18% respectively (P <0.05) and reduced by 16% in the presence of 3 MAC halothane (P <0.05). In endothelium-intact preparations an expected absolute increase in contraction amplitude occurred in the presence of L-NNA but the desflurane effect was detectable both in the presence and absence of L-NNA.Conclusion: Our results suggest that desflurane may have a local vasoconstrictive effect independent of endothelium and NO synthase activity. The mechanism remains to be determined.RésuméObjectif: Le mécanisme responsable de la médiation de l’hypertension en réponse à l’augmentation de desflurane n’est pas encore connu. La présente étude a comparé l’effet du desflurane et de l’halothane sur les contractions induites par la phényléphrine (PE). dans des anneaux d’aorte de rat, et l’effet du desflurane avec et sans actimité de la synthétase de l’oxyde nitrique (NO).Méthode: Des anneaux d’aorte de rat sans exdothélium ont été exposés par série à de la PE de 10−7M, 10−6M et 10−5M et, par la suite, à du desflurane et à de l’halothane à 2 CAM. Les préparations sans endothélium ont été ensuite exposées par série à de la PE a 10−6M en présence de desflurane et d’halothane à 0, 1, 2 et 3 CAM, Enfin, en utilisant une préparation dont l’endothélium a été conservé intact, l’effet du desflurane sur la contraction induite par la PE a été examiné, en présence et en l’absence de NG-nitro-L-arginine (L-NNA), un inhibiteur de la synthétase de NO constitutive et inductible.Résultats: L’amplitude des contractions secondaires à la présence de PE à 10−6 et à 10−5 dans des préparations sans endothélium a augmenté de 74 % et 36 %, respectivement (P<0,05) avec du desflurane à 2 CAM, en comparalson avec les témoins. Dans les préparations sans endothélium, l’amplitude des contractions liées à de la PE à 10−6 s’est élevée en présence de desflurane à 1 et 2 CAM, de 32 % et de 18 %, respectivement (P<0,05) et s’est abaissée de 16 % en présence d’halothane à 3 CAMP (P<0,05). Dans les préparations à l’endothélium intact, une augmentation absolute présumée de l’amplitude des contractions est survenue en présence de L-NNA, mais l’effet du desflurane a été détectable en présence et en l’absence de L-NNA.Conclusion: Nos résultats suggèrent que le desflurane pourrait avoir un effet vasoconstricteur local indépendant de l’endothélium et de l’activité de la synthétase de NO. Le mécanisme reste à déterminer.

A Flaw in the Fabric

There appears to be a broad impression that an explicitly psychoanalytic framework of obsessive–compulsive disorder (OCD) is outdated and obsolete. However, interpersonal dynamics and experiences within the family during childhood and their intrapersonal sequelae in particular, may have substantial bearing on the early stages of the development of OCD. The author presents a set of observations about obsessional thoughts based on case material from research projects, psychometric assessments and psychotherapy with these patients. Freud’s contributions to understanding the internal world of the patient are discussed, suggesting a need to extend beyond the crucible of emerging affects and their regulation and into the wider stage in which the most profound struggle exists around relating to the other. We place the individual’s experience of others at the centre of our theories of the aetiology of OCD. We need to expand our understanding of OCD, particularly in how we locate the individual’s internal struggles within the context of the social environment in, and perhaps out of, which they have emerged.

A Role for Adenosine A1 Receptors in GABA and NMDA-Receptor Mediated Modulation of Dopamine Release: Studies Using Fast Cyclic Voltammetry

In the striatum many neurotransmitters including GABA, glutamate, acetylcholine, dopamine, nitric oxide and adenosine interact to regulate synaptic transmission. Dopamine release in the striatum is regulated by a number of pre- and post-synaptic receptors including adenosine. We have recently shown using isolated rat striatal slices, and the technique of fast cyclic voltammetry, that adenosine A1 receptor-mediated inhibition of dopamine release is modulated by dopamine D1 receptors. In the present study we have investigated the influence of NMDA and GABA receptor activation on the modulation of electrically stimulated dopamine release by adenosine. Application of the adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA), concentration-dependently inhibited dopamine release to a maxiumum of 50%. Perfusion of the glutamate receptor agonist, NMDA, in low magnesium, caused a rapid and concentration-dependent inhibition of dopamine release. Prior perfusion with the adenosine A1 receptor antagonist, DPCPX, significantly reduced the effect of 5 μM and 10 μM NMDA on dopamine release. The GABAA receptor agonist, isoguvacine, had a significant concentration-dependent inhibitory effect on dopamine release which was reversed by prior application of the GABAA receptor antagonist, picrotoxin, but not DPCPX. Finally inhibition of dopamine release by CPA (1μM) was significantly enhanced by prior perfusion with picrotoxin. These data demonstrate an important role for GABA, NMDA and adenosine in the modulation of dopamine release.

Home remembered, relived and revised: a qualitative study exploring the experiences of home for homeless persons in supported accommodation

Abstract Psychological distress, trauma histories and intra-family conflict are strongly implicated in the pathways towards homelessness. For many also, homelessness in itself may constitute a trauma – extending, deepening and complicating the person’s existing distress. In the context of policy prioritising housing-led service provision, this study examines homeless individual’s lived experiences of home across their lives. Semi-structured interviews were conducted with 10 residents in a supported accommodation service for homeless individuals. Interview transcripts were analysed using interpretative phenomenological analysis (IPA). (Inserted:) Three super-ordinate themes emerged relating to the experience of the first home as a ‘non-home’, the continuing repeating of the past in the present and the desire for and attempts to bring about a new start in their lives. These themes and the links between them are discussed with particular reference to object relations and attachment theory and the concept of cumulative trauma.

To hold on or to let go? Loss and substitution in the process of hoarding

This paper explores and moves toward a way of understanding the emergence of hoarding in the context of unresolved, unprocessed loss. It is argued that hoarding represents in many instances the pain of loss and the pressing, often stubborn, reluctance to accept this, with the hoard being developed as a kind of bulwark against change, transience and parting with lost objects and lost states. The paper is framed within a psychodynamic–psychoanalytic framework, with hoarding considered as a kind of defensive and self-protective manoeuvre, the hoard in part symbolising the lost object and the capacity to hold onto things corresponding to an omnipotent claim to stop the passage of time and to hold at bay the reality of change. This paper specifically considers the theme of loss as it arises in the lives of people who compulsively hoard, considering how the painfully passive experience of loss can stimulate the active and compulsive process of gathering together that we see in hoarding. As well as a displacement of interest from the animate (the person) to the inanimate, we find in hoarding a part-reanimation in fantasy of the lost object in the midst of the hoard.