Dissociable dopaminergic and pavlovian influences in goal-trackers and sign-trackers on a model of compulsive checking in OCD.

RATIONALE: Checking is a functional behaviour that provides information to guide behaviour. However, in obsessive-compulsive disorder (OCD), checking may escalate to dysfunctional levels. The processes underpinning the transition from functional to dysfunctional checking are unclear but may be associated with individual differences that support the development of maladaptive behaviour. We examined one such predisposition, sign-tracking to a pavlovian conditioned stimulus, which we previously found associated with dysfunctional checking. How sign-tracking interacts with another treatment with emerging translational validity for OCD-like checking, chronic administration of the dopamine D2 receptor agonist quinpirole, is unknown. OBJECTIVES: We tested how functional and dysfunctional checking in the rat observing response task (ORT) was affected by chronic quinpirole administration in non-autoshaped controls and autoshaped animals classified as sign-trackers or goal-trackers. METHODS: Sign-trackers or goal-trackers were trained on the ORT before the effects of chronic quinpirole administration on checking were assessed. Subsequently, the effects on checking of different behavioural challenges, including reward omission and the use of unpredictable reinforcement schedules, were tested. RESULTS: Prior autoshaping increased checking. Sign-trackers and goal-trackers responded differently to quinpirole sensitization, reward omission and reinforcement uncertainty. Sign-trackers showed greater elevations in dysfunctional checking, particularly during uncertainty. By contrast, goal-trackers predominantly increased functional checking responses, possibly in response to reduced discrimination accuracy in the absence of cues signalling which lever was currently active. CONCLUSIONS: The results are discussed in terms of how pavlovian associations influence behaviour that becomes compulsive in OCD and how this may be dependent on striatal dopamine D2 receptors.

Complex trauma, PTSD and complex PTSD in African refugees.

Background: The introduction of the diagnosis of complex posttraumatic stress disorder (CPTSD) by ICD-11 is a turning point in the field of traumatic stress studies. It's therefore important to examine the validity of CPTSD in refugee groups exposed to complex trauma (CT) defined as a repeated, prolonged, interpersonal traumatic event. Objective: The objective of this study was to compare DSM-5 and ICD-11 post-traumatic stress disorder diagnoses and to evaluate the discriminant validity of ICD-11 PTSD and CPTSD constructs in a sample of treatment-seeking refugees living in Italy. Method: The study sample included 120 treatment-seeking African refugees living in Italy. All participants were survivors of at least one CT. PTSD and CPTSD diagnoses were assessed according to both DSM-5 and ICD-11 criteria. Results: Findings revealed that 79% of the participants met the DSM-5 criteria for PTSD, 38% for ICD-11 PTSD and 30% for ICD-11 CPTSD. Generally, ICD-11 CPTSD items evidenced strong sensitivity and negative predictive power, low specificity and positive predictive power. Latent class analysis results identified two distinct groups: (1) a PTSD class, (2) a CPTSD class. None of the demographic and trauma-related variables analysed was significantly associated with diagnostic group. On the other hand, the months spent in Italy were significantly associated with PCL-5 score. Conclusions: Findings extend the current evidence base to support the discriminant validity of PTSD and CPTSD amongst refugees exposed to torture and other gross violations of human rights. The results suggest also that, in the post-traumatic phase, the time spent in a 'safe place' condition contributes to improve the severity of post-traumatic symptomatology, but neither this variable nor other socio-demographic factors seem to contribute to the emergence of complex PTSD. Further investigations are needed to clarify which specific vulnerability factors influence the development of PTSD or CPTSD in refugees exposed to complex trauma.

Antecedentes: La introducción del diagnóstico del trastorno de estrés postraumático complejo (TEPT-C) por la CIE-11 es un punto de inflexión en el campo de los estudios del estrés traumático. Por lo tanto, es importante examinar la validez del TEPT-C en los grupos de refugiados expuestos a un trauma complejo (TC) definido como un evento traumático interpersonal prolongado y repetido.Objetivo: El objetivo de este estudio fue comparar los diagnósticos de trastorno de estrés postraumático del DSM-5 y la CIE-11 y evaluar la validez discriminante de los constructos del TEPT y TEPT-C de la CIE-11 en una muestra de refugiados en busca de tratamiento que viven en Italia.Método: La muestra del estudio incluyó a 120 refugiados africanos que buscan tratamiento y que viven en Italia. Todos los participantes fueron sobrevivientes de al menos un TC. Los diagnósticos de TEPT y TEPT-C se evaluaron de acuerdo con los criterios del DSM-5 y de la CIE-11.Resultados: Los hallazgos muestran que el 79% de los participantes cumplieron con los criterios del DSM-5 para el TEPT, el 38% para el TEPT de la CIE-11 y el 30% para el TEPT-C de la CIE-11. En general, los ítems de TEPT-C de la CIE-11 evidenciaron una fuerte sensibilidad y poder predictivo negativo, baja especificidad y poder predictivo positivo. Los resultados del análisis de clase latente identificaron dos grupos distintos: (1) grupo de TEPT, (2) grupo de TEPT-C. Ninguna de las variables demográficas y relacionadas con el trauma analizadas se asoció significativamente con el grupo de diagnóstico. Por otro lado, los meses pasados en Italia se asociaron significativamente con la puntuación de PCL-5.Conclusiones: Los hallazgos amplían la base de evidencia actual para apoyar la validez discriminante del TEPT y el TEPT-C entre los refugiados expuestos a tortura y otras violaciones graves de los derechos humanos. Los resultados sugieren también que, en la fase postraumática, el tiempo pasado en una condición de "lugar seguro" contribuye a mejorar la gravedad de la sintomatología postraumática, pero ni esta variable ni otros factores sociodemográficos parecen contribuir a la aparición del TEPT-C. Se necesitan más investigaciones para aclarar qué factores de vulnerabilidad específicos influyen en el desarrollo de TEPT o TEPT-C en los refugiados expuestos a trauma complejo.

Electrophysiological and metabolic effects of CHF5074 in the hippocampus: protection against in vitro ischemia.

CHF5074 is a non-steroidal anti-inflammatory derivative holding disease-modifying potential for the treatment of Alzheimer's disease. The aim of the present study was to characterize the electrophysiological and metabolic profile of CHF5074 in the hippocampus. Electrophysiological recordings show that CHF5074 inhibits in a dose-dependent manner the current-evoked repetitive firing discharge in CA1 pyramidal neurons. This result is paralleled by a dose-dependent reduction of field excitatory post-synaptic potentials with no effect on the paired-pulse ratio. The effects of CHF5074 were not mediated by AMPA or NMDA receptors, since the inward currents induced by local applications of AMPA and NMDA remained constant in the presence of this compound. We also suggest a possible activity of CHF5074 on ASIC1a receptor since ASIC1a-mediated current, evoked by application of a pH 5.5 solution, is reduced by pretreatment with this compound. Moreover, we demonstrate that CHF5074 treatment is able to counteract in hippocampal slices the OGD-induced increase in alanine, lactate and acetate levels. Finally, CHF5074 significantly reduced the apoptosis in hippocampal neurons exposed to OGD, as revealed by cleaved-caspase-3 immunoreactivity and TUNEL staining. Overall, the present work identifies novel mechanisms for CHF5074 in reducing metabolic acidosis, rendering this compound potentially useful also in conditions of brain ischemia.

Pharmacological modulation of long-term potentiation in animal models of Alzheimer'’s disease.

The discovery of long-term potentiation (LTP) of hippocampal synaptic transmission, which represents a classical model for learning and memory at the cellular level, has stimulated over the past years substantial progress in the understanding of pathogenic mechanisms underlying cognitive disorders, such as Alzheimer’s disease (AD). Multiple lines of evidence indicate synaptic dysfunction not only as a core feature but also a leading cause of AD. Multiple pathways may play a significant role in the execution of synaptic dysfunction and neuronal death triggered by beta-amyloid (Abeta) in AD. Following intensive investigations into LTP in AD models, a variety of compounds have been found to rescue LTP impairment via numerous molecular mechanisms. Yet very few of these findings have been successfully translated into disease-modifying compounds in humans. This review recapitulates the emerging disease-modifying strategies utilized to modulate hippocampal synaptic plasticity with particular attention to approaches targeting ligand-gated ion channels, G-protein-coupled receptors (GPCRs), Receptor Tyrosine Kinases (RTKs) and epigenetic mechanisms. It is hoped that novel multi-targeted drugs capable of regulating spine plasticity might be effective to counteract the progression of AD and related cognitive syndromes.