Journal of Psychopharmacology

Our 1992 paper, ‘The neural substrates of sensorimotor gating of the startle reflex: a review of recent findings and their implications’, reviewed a series of (then) new and preliminary findings from cross-species studies of prepulse inhibition of the startle reflex, and commented on their implications. At the time that the report was composed, PubMed listed about 40 citations for studies using the search term ‘prepulse inhibition’. In the ensuing 25 years, the field has added about 2700 such reports, reflecting the substantial growth in interest in prepulse inhibition and its utility across a number of different experimental applications. The 30th anniversary of the Journal of Psychopharmacology provides an opportunity to comment briefly on what was described in that 1992 report, how the field has progressed in the subsequent decades, and the paths forward for studies of prepulse inhibition and its use as an operational measure of sensorimotor gating. Among these future paths, we highlight the use of prepulse inhibition as: an endophenotype for genomic studies, and a biomarker for healthy brain circuitry, which may predict sensitivity to psychotherapeutics. Our 1992 report was highly speculative and based on paper-thin empirical data, yet viewed in a certain light, it appears to have contained a basic roadmap for a journey spanning the next 25 years of prepulse inhibition research… and ‘what a long, strange trip it’s been’.

The significance of investigating effects of deprivation of social experience in rodents is reviewed in the context of the review by Robbins et al. (1996) in the Journal of Psychopharmacology (10: 39-47). The early development of the paradigm by which rats were reared post-weaning in social isolation is described and compared with other early experience manipulations. The specification of the neural and behavioural phenotype of the isolate is brought up-to-date, focusing on changes in motivation and cognitive function, as well as on contrasting changes in the dopamine and serotonin systems, and in cortical (including hippocampal) structure and function. The relevance of the isolate for animal models of psychiatric disorders such as attention deficit hyperactivity disorder and schizophrenia is reviewed, and it is considered that the paradigm best exemplifies a manipulation that can be applied to test effects of certain forms of social adversity during adolescence on brain development and behaviour.

In 1997, neuropsychological and neuroimaging evidence supported the involvement of the frontal lobes and indeed the brain in depression. This was a challenge to conventional phenomenology and linked with the imperative to use neuroscience to understand major mental illness. Since that time, we are seeing ever more convincing evidence for the genetic basis of mental illness (including depression), relevant abnormality in grey and white matter and neuropsychological analysis of brain function. It has proved more difficult to pin down structural abnormality in major depression at the cellular level, but a focus on glial cells is increasingly justified by the evidence. Neuroscience continues to be a buttress against anti-scientific impulses in psychiatry and can help attract young people to enter it as a profession.

In 1998 we published a perspective review describing how drug-induced neuroadaptations might serve towards understanding drug craving. We proposed experimental perspectives to help discern data relevant to long-lasting brain changes, and to distinguish dopamine-related changes that were largely pharmacological from glutamatergic changes that were based on drug–environment associations. These perspectives are embedded in drug abuse research, and the last 18 years has witnessed marked development in understanding addiction-associated corticostriatal glutamate plasticity. Here we propose three new perspectives on how the field might approach integrating and using the emerging data on glutamatergic adaptations. (1) Consider adaptations produced in kind across drug classes as most useful towards understanding shared characteristics of addiction, such as relapse. (2) Consider how drug-induced changes in glia and the extracellular matrix may contribute to synaptic alterations. (3) Make measurements not only at late withdrawal, but also during drug seeking events to capture transient changes that mediate active drug seeking that are shared across drug classes.

The highly-interconnected and neurochemically-rich frontal cortex plays a crucial role in the regulation of mood and cognition, domains disrupted in depression and other central nervous system disorders, and it is an important site of action for their therapeutic control. For improving our understanding of the function and dysfunction of the frontal cortex, and for identifying improved treatments, quantification of extracellular pools of neuromodulators by microdialysis in freely-moving rodents has proven indispensable. This approach has revealed a complex mesh of autoreceptor and heteroceptor interactions amongst monoaminergic pathways, and led from selective 5-HT reuptake inhibitors to novel classes of multi-target drugs for treating depression like the mixed α₂-adrenoceptor/5-HT reuptake inhibitor, S35966, and the clinically-launched vortioxetine and vilazodone. Moreover, integration of non-monoaminergic actions resulted in the discovery and development of the innovative melatonin receptor agonist/5-HT_2C receptor antagonist, Agomelatine. Melatonin levels, like those of corticosterone and the “social hormone”, oxytocin, can now be quantified by microdialysis over the full 24 h daily cycle. Further, the introduction of procedures for measuring extracellular histamine and acetylcholine has provided insights into strategies for improving cognition by, for example, blockade of 5-HT₆ and/or dopamine D₃ receptors. The challenge of concurrently determining extracellular levels of GABA, glutamate, d-serine, glycine, kynurenate and other amino acids, and of clarifying their interactions with monoamines, has also been resolved. This has proven important for characterizing the actions of glycine reuptake inhibitors that indirectly augment transmission at N-methyl-d-aspartate receptors, and of “glutamatergic antidepressants” like ketamine, mGluR5 antagonists and positive modulators of AMPA receptors (including S47445). Most recently, quantification of the neurotoxic proteins Aβ42 and Tau has extended microdialysis studies to the pathogenesis of neurodegenerative disorders, and another frontier currently being broached is microRNAs. The present article discusses the above themes, focusses on recent advances, highlights opportunities for clinical “translation”, and suggests avenues for further progress.

Our article in this journal some 15 years ago focussed on the role of serotonin (5-HT) autoreceptors in the mechanism of action of antidepressant drugs. Specifically in this regard, the results were summarised of rat microdialysis studies carried out to examine: (a) the relative importance of 5-HT_1A and 5-HT_1B autoreceptors, including (b) possible regional variation, and (c) potential changes in autoreceptor responsiveness following chronic selective serotonin reuptake inhibitor administration. In the present reflection piece, I recap some of the key findings against a brief background and provide an account of their bearing within the context of subsequent endeavours in the antidepressant drug research and development field. I conclude by shortly commenting on selected topics relevant to novel, interesting advances and avenues for future research.

The 2002 paper “Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine” by Bell and colleagues – reprinted in this issue of the Journal – reports on a study undertaken in the halcyon days of David Nutt’s Psychopharmacology Unit at the University of Bristol, England. In this invited commentary authors of the original work discuss the impact of this paper on the field of acute tryptophan depletion research (especially in the field of clinical anxiety disorders) and the development of disorder-specific anxiogenic provocations over the past decade.

Here, Reynolds and Neill describe the studies that preceded and followed publication of this paper, which reported a deficit in parvalbumin (PV), a calcium-binding protein found in GABA interneurons known to be reduced in schizophrenia patients, in conjunction with a deficit in reversal learning in an animal model for schizophrenia. This publication resulted from common research interests: Reynolds in the neurotransmitter pathology of schizophrenia, and Neill in developing animal models for schizophrenia symptomatology. The animal model, using a sub-chronic dosing regimen (sc) with the non-competitive NMDA receptor antagonist PCP (phencyclidine), evolved from previous work in rats (for PCP) and primates (for cognition). The hypothesis of a PV deficit came from emerging evidence for a GABAergic dysfunction in schizophrenia, in particular a deficit in PV-containing GABA interneurons. Since this original publication, a PV deficit has been identified in other animal models for schizophrenia, and the PV field has expanded considerably. This includes mechanistic work attempting to identify the link between oxidative stress and GABAergic dysfunction using this scPCP model, and assessment of the potential of the PV neuron as a target for new antipsychotic drugs. The latter has included development of a molecule targeting KV3.1 channels located on PV-containing GABA interneurons which can restore both PV expression and cognitive deficits in the scPCP model.

In 2007, we proposed an explanation of delusion formation as aberrant prediction error-driven associative learning. Further, we argued that the NMDA receptor antagonist ketamine provided a good model for this process. Subsequently, we validated the model in patients with psychosis, relating aberrant prediction error signals to delusion severity. During the ensuing period, we have developed these ideas, drawing on the simple principle that brains build a model of the world and refine it by minimising prediction errors, as well as using it to guide perceptual inferences. While previously we focused on the prediction error signal per se, an updated view takes into account its precision, as well as the precision of prior expectations. With this expanded perspective, we see several possible routes to psychotic symptoms – which may explain the heterogeneity of psychotic illness, as well as the fact that other drugs, with different pharmacological actions, can produce psychotomimetic effects. In this article, we review the basic principles of this model and highlight specific ways in which prediction errors can be perturbed, in particular considering the reliability and uncertainty of predictions. The expanded model explains hallucinations as perturbations of the uncertainty mediated balance between expectation and prediction error. Here, expectations dominate and create perceptions by suppressing or ignoring actual inputs. Negative symptoms may arise due to poor reliability of predictions in service of action. By mapping from biology to belief and perception, the account proffers new explanations of psychosis. However, challenges remain. We attempt to address some of these concerns and suggest future directions, incorporating other symptoms into the model, building towards better understanding of psychosis.

Since the observation that oxytocin has key effects on social decision making, research on this exciting neuropeptide has doubled in volume: hundreds of studies have pursued the promise of a specific oxytocin action on high-level cognition and social function with wide potential translational implications (from autism to social anxiety to dementia). Here we review the evidence on whether the complex behavioural effects observed in humans after exogenous oxytocin administration build on changes in basic emotional information processing, in particular emotional facial expressions recognition, and attention and memory for emotionally-valenced stimuli.

We observe that recent studies confirm a facilitatory effect of oxytocin to more accurate emotion processing, irrespective of emotion type. However, it remains unclear whether this action precedes, is independent of or even secondary to the neuropeptide promoting a greater salience of social stimuli. Overall, this growing research area has shown that oxytocin produces behavioural and neurofunctional outcomes that are highly dependent on the experimental context and on individual differences (gender, personality, life experiences). This poses an exciting challenge for future experimental medicine designs to address and unpack complex interactions between individual and context characteristic, which is needed for the development of more precise clinical applications.