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This theoretical article revives a classical bridging construct, canalization, to describe a new model of a general factor of psychopathology. To achieve this, we have distinguished between two types of plasticity, an early one that we call 'TEMP' for 'Temperature or Entropy Mediated Plasticity', and another, we call 'canalization', which is close to Hebbian plasticity. These two forms of plasticity can be most easily distinguished by their relationship to 'precision' or inverse variance; TEMP relates to increased model variance or decreased precision, whereas the opposite is true for canalization. TEMP also subsumes increased learning rate, (Ising) temperature and entropy. Dictionary definitions of 'plasticity' describe it as the property of being easily shaped or molded; TEMP is the better match for this. Importantly, we propose that 'pathological' phenotypes develop via mechanisms of canalization or increased model precision, as a defensive response to adversity and associated distress or dysphoria. Our model states that canalization entrenches in psychopathology, narrowing the phenotypic state-space as the agent develops expertise in their pathology. We suggest that TEMP - combined with gently guiding psychological support - can counter canalization. We address questions of whether and when canalization is adaptive versus maladaptive, furnish our model with references to basic and human neuroscience, and offer concrete experiments and measures to test its main hypotheses and implications. This article is part of the Special Issue on "National Institutes of Health Psilocybin Research Speaker Series"., Competing Interests: Declaration of competing interest RCH, DE, AG, DJN report being a scientific advisor to a number of new companies and not-for-profits that are seeking to develop psychedelic therapy and bring it to market. RCH is grateful to Meg Spriggs for comments on an earlier draft of this manuscript, Courtney Gallen for guidance on referencing brain network modularity findings, Rayyan Zafar for references on dopamine, stimulants and Hebbian mechanisms, Lindsay Cameron for references on environmental enrichment and neuroplasticity, and Max Wolff for the connection to the ideas of Klaus Grawe., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Psychedelic therapy is perhaps the most exciting new development in psychiatry. Not only does it offer a radical new approach to treatment where mainstream approaches have proven ineffective, but the growing evidence for transdiagnostic efficacy is eliciting a re-think of current diagnostic and symptom-specific approaches to psychiatry. This excitement has led to a massive investment in this field with many tens of new pharmaceutical companies being set up to research the effects of known psychedelics and develop new patentable molecules. Whilst this enthusiasm is to be welcomed, it is important that new research is properly grounded in established facts and reflects current knowledge. In this commentary we lay out the knowledge framework that should be taken into account by all innovative researchers in this field., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A range of medications target different aspects of the GABA system; understanding their effects is important to inform further drug development. Effects on the waking EEG comparing these mechanisms have not been reported; in this study we compare the effects on resting MEG spectra of the benzodiazepine receptor agonist zolpidem, the delta sub-unit selective agonist gaboxadol (also known as THIP) and the GABA reuptake inhibitor tiagabine. These were two randomised, single-blind, placebo-controlled, crossover studies in healthy volunteers, one using zolpidem 10 mg, gaboxadol 15 mg and placebo, and the other tiagabine 15 mg and placebo. Whole head MEG recordings and individual MEG spectra were divided into frequency bands. Baseline spectra were subtracted from each post-intervention spectra and then differences between intervention and placebo compared. After zolpidem there were significant increases in beta frequencies and reduction in alpha frequency power; after gaboxadol and tiagabine there were significant increases in power at all frequencies up to beta. Enhancement of tonic inhibition via extrasynaptic receptors by gaboxadol gives rise to a very different MEG signature from the synaptic action of zolpidem. Tiagabine theoretically can affect both types of receptor; from these MEG results it is likely that the latter is the more prominent effect here., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

GABA (gamma-amino-butyric-acid) is the primary inhibitory neurotransmitter in the human brain. It has been proposed that the symptoms of autism spectrum disorders (ASDs) are the result of deficient GABA neurotransmission, possibly including reduced expression of GABAA receptors. However, this hypothesis has not been directly tested in living adults with ASD. In this preliminary investigation, we used Positron Emission Tomography (PET) with the benzodiazepine receptor PET ligand [(11)C]Ro15-4513 to measure α1 and α5 subtypes of the GABAA receptor levels in the brain of three adult males with well-characterized high-functioning ASD compared with three healthy matched volunteers. We found significantly lower [(11)C]Ro15-4513 binding throughout the brain of participants with ASD (p < 0.0001) compared with controls. Planned region of interest analyses also revealed significant reductions in two limbic brain regions, namely the amygdala and nucleus accumbens bilaterally. Further analysis suggested that these results were driven by lower levels of the GABAA α5 subtype. These results provide initial evidence of a GABAA α5 deficit in ASD and support further investigations of the GABA system in this disorder. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

5-Isothiocyanato-2-benzofuranyl-2-imidazoline (BU99006) is an irreversible ligand based on the highly selective I(2) binding site ligand 2BFI. In competition binding assays it has been shown to have high affinity and selectivity for the I(2) binding site and to irreversibly inhibit the binding of [(3)H]2BFI. In this present study we have sought to confirm and expand on these findings both in vitro and in vivo. In vitro pre-incubation of rat whole brain membranes with BU99006 (10 microM) was shown to reduce the specific binding of [(3)H]2BFI to 10% of the control values, an effect not seen using 2BFI or BU224. Pre-treatment of rat whole brain membranes by BU99006, or by the alpha(2)-adrenoceptor antagonists RX821002 or rauwolscine had no effect on the specific binding of [(3)H]RX821002. In vivo pre-treatment of rats with BU99006 (15 mg x kg(-1), i.v.) caused a substantial loss of [(3)H]2BFI specific binding in subsequent in vitro saturation analysis and autoradiography; this loss was shown to be dose dependent. These data indicate that BU99006 is selectively and irreversibly affecting I(2) binding sites both in vitro and in vivo and that it represents an invaluable tool in the further understanding of the I(2) binding site.

The aim of this study was to investigate imidazoline(2) (I(2)) binding site- and alpha(2)-adrenoceptor-mediated control of central noradrenergic and HPA axis activity in control rats and chronically stressed rats with adjuvant-induced arthritis (AA). Basal levels of extracellular nonadrenaline (NA) in the region of the hypothalamic paraventricular nucleus (PVN) of AA rats were significantly greater than controls. Both the I(2) binding site selective ligand BU224 (10 mg kg(-1) i.p.) and the alpha(2)-adrenoceptor antagonist RX821002 (2.5 mg kg(-1) i.p.) significantly elevated extracellular levels of NA in the PVN region and plasma corticosterone (CORT) in a rapid and transient manner in both control and AA rats. The noradrenergic response of AA rats to BU224 was significantly enhanced compared with drug treated controls. There was a significant correlation between extracellular NA in the PVN region and plasma CORT following BU224 and RX821002. In conclusion, central noradrenergic and HPA axis activity in control and chronically stressed AA rats appear to be under the control of both I(2) binding sites and alpha(2)-adrenoceptors. Increased basal levels of extracellular NA in the PVN region of AA rats suggests increased noradrenergic activity in these animals which is modulated to a greater extent by I(2) binding sites than by alpha(2)-adrenoceptors.

The polymorphism of a variable number tandem repeat (VNTR) region of the serotonin transporter gene consists of three alleles containing, respectively, 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. The frequencies of the three alleles in 384 individuals presenting after deliberate self harm were the same as a group of 346 controls. However, ratings of anxiety (and state anger) were higher in those patients with genotypes including the shorter repetitive elements. The findings support the hypothesis that, in this group of patients with low rates of severe psychiatric disorder, allelic variation in the serotonin transporter gene may contribute to the expression of anxiety symptoms.

Thermoregulatory and plasma corticosterone responses to peripheral LPS and TNF alpha were compared and correlated with brain FOS protein expression. TNF alpha mimicked the corticosterone response evoked by LPS and the increase in FOS expression in the hypothalamic PVN. TNF alpha also mimicked LPS-activation of central noradrenergic and adrenergic neurones. TNF alpha did not induce a hypothermia which might reflect its failure to activate the vasopressin neurones of the BNST.

To date, the study of the relationship between drug occupancy and action in the brain has had to rely on the use of either animal models or of indirect kinetic measures in man, e.g. serum concentrations of unbound drug (as a measure of "free" drug in brain). We describe the first set of experiments which directly measure agonist-induced changes in both pharmacodynamic effects and pharmacokinetic parameters simultaneously and which demonstrate the feasibility of these studies in man. Five healthy volunteers each had two PET scans using [11C]flumazenil (a radiolabelled benzodiazepine site antagonist) as part of a study investigating kinetic models and the relationship between occupancy and effect of benzodiazepine site ligands. In both studies the [11C]flumazenil was displaced from the brain by infusion of midazolam administered i.v. 30 min into the scan. In one study a higher dose of midazolam was administered than in the other (range 12.5-50 micrograms/kg). Time-activity curves of the concentration of radioligand were derived in 17 different brain regions using a stereotactic automatic method of region selection. We demonstrated that there are significant differences in an index of occupancy, induced by the two different doses of midazolam, both across brain regions and within subjects. There was a significant correlation between measured occupancy index change and pharmacodynamic effects as measured by the peak change in beta 1 spectral power on EEG. There was no significant correlation between dose administered and EEG changes; plasma concentrations of midazolam were correlated with the occupancy index and with the EEG measures. In addition, we have demonstrated that a non-regional total index of brain occupancy can be obtained by analysing the non-tomographic data obtained with the PET scanner (total radioactivity counts head curve) and that this index shows significant correlations both with the dose administered and with the pharmacodynamic measure. This last finding validates the use of other non-tomographic counting techniques (Malizia et al., 1995a) where an index of displacement can be obtained after the administration of less than 1% of the dose of radiation needed for a PET study. These studies are likely to be useful in human psychopharmacology, in particular in the assessment of tolerance and of putative changes in benzodiazepine sensitivity in anxiety disorders. The same principles can be applied to other ligand studies and will be useful to validate current PK/PD models.

The autoradiographic [14C]2-deoxyglucose procedure was used to map function-related alterations in local cerebral glucose use following acute administration of the alpha 2-adrenoceptor antagonist, idazoxan (0.3-3 mg kg-1 s.c.). The most prominent feature of the results obtained was the significant reduction in glucose use in certain locus coeruleus projection areas. Thus, in various cortical, hippocampal and thalamic regions, as well as structures involved in auditory and visual function, idazoxan administration was associated with a 13-20% decrease in glucose use. In a complementary microdialysis study, the effect of idazoxan on extracellular noradrenaline levels in the frontal cortex of rats, manipulated in the same fashion as during the [14C]2-deoxyglucose procedure (i.e. following the application of surgery and partial restraint), was examined. Both surgery and restraint were associated with a modest but significant increase in basal noradrenaline release (+31% and +26%, respectively). Subsequent administration of idazoxan (3 mg kg-1 s.c.) evoked a further increase in noradrenaline release, the magnitude of which was the same as that observed following its administration to freely-moving rats (+113%). These combined data suggest that idazoxan-induced reductions in cerebral glucose use, at least in the frontal cortex, may occur as a consequence of the increase in noradrenaline release. In addition, it appears that surgery and partial restraint do not alter alpha 2-adrenoceptor tone in the frontal cortex.

Idazoxan (10 mg/kg, i.p.) produces an unexpected increase in food intake in freely-feeding rats which has been linked to its high affinity for non-adrenoceptor idazoxan binding sites. In this study, a dose-related antagonism of idazoxan-induced food intake by the beta-adrenoceptor antagonist (-)-propranolol (5-20 mg/kg, i.p.), which also blocks 5-HT1 (5-hydroxytryptamine1) receptors has been demonstrated. (+)-Propranolol (10, 20 mg/kg, i.p.) did not attenuate idazoxan-induced feeding. (-)-Propranolol (10 mg/kg, i.p.) but not the (+)-enantiomer (10 mg/kg, i.p.) also significantly inhibited the food intake, induced by the 5-HT1A agonist 8-OH-DPAT (0.25 mg/kg, i.p.). Idazoxan-induced feeding was not altered by the selective beta-adrenoceptor antagonists betaxolol (beta 1; 5 mg/kg, i.p.) and ICI 118,551 (beta 2; 5 mg/kg, i.p.) but was potentiated by the 5-HT receptor antagonist metergoline (5 mg/kg, i.p.). The anomalous findings with metergoline may reflect its action at different sub-types of 5-HT receptor. The water intake induced by idazoxan and the peripherally-active alpha 2-adrenoceptor antagonist L-659,066 was also blocked in a stereoselective manner by propranolol (10 mg/kg) but not significantly by either metergoline (5 mg/kg, i.p.), the beta 1-adrenoceptor antagonist betaxolol (5 mg/kg, i.p.) nor by the beta 2-adrenoceptor antagonist ICI 118,551 (5 mg/kg, i.p.). These results suggest that the food intake induced by idazoxan (and perhaps mediated by non-adrenoceptor idazoxan binding sites) may involve the 5-HT system, although further studies, using antagonists acting selectively at the different sub-types of 5-HT receptor, are required to confirm this.(ABSTRACT TRUNCATED AT 250 WORDS)

In this study it has been shown that the unexpected increase in food consumption, produced by the alpha 2-adrenoceptor antagonist idazoxan (10 mg/kg, i.p.) in rats, was significantly attenuated by small doses of the opioid antagonist (-)-naloxone (0.1, 1 mg/kg, i.p.) and totally inhibited by a small dose of naltrexone (1 mg/kg, i.p.). On the other hand, idazoxan-induced feeding was not affected by (+)-naloxone (0.1, 1 mg/kg, i.p.), which is inactive at opioid receptors. In addition, idazoxan-induced food consumption was not blocked by the delta-opioid antagonist, naltrindole (0.1, 1 mg/kg, i.p.) nor by the mu/delta-antagonist, RX8008M (16-methyl cyprenorphine; 0.1, 1 mg/kg, i.p.), which clearly discriminates between mu/delta- and kappa-opioid receptor function in vivo. These findings suggest that idazoxan may lead to the release of endogenous opioid peptides, which subsequently stimulate feeding by activation of kappa-, as opposed to mu- or delta-opioid receptors. This response is unlikely to be due to alpha 2-adrenoceptor blockade, since other highly selective alpha 2-adrenoceptor antagonists do not increase food intake and, instead may reflect the high affinity of idazoxan for non-adrenoceptor idazoxan binding sites.

This study shows that the selective GABAB antagonist CGP 35348 had no effect on body temperature in mice in doses up to 300 mg/kg i.p. However, the highest dose abolished the hypothermia induced by the GABAB agonist baclofen (10 mg/kg i.p.) but not that produced by the GABA-mimetic progabide (200 mg/kg i.p.); the benzodiazepine agonist loprazolam (3 mg/kg i.p.); the alpha 2-agonist UK 14,304 (1 mg/kg i.p.) nor the mu-opioid agonist morphine (30 mg/kg i.p.). These findings, showing selective antagonism of GABAB receptors by CGP 35348, confirm that this compound may be a valuable tool for exploration of GABAB receptor function in vivo.

It has recently been demonstrated that kindling occurs with repeated administration of the benzodiazepine "inverse agonist" FG 7142. The present study was an investigation of the effects of other ligands for the benzodiazepine receptor in mice kindled with FG 7142. It was shown that over a range of doses the lowering effects of FG 7142 on the seizure threshold were greater in kindled animals than in control. In contrast, the hypothermic effect of FG 7142 was unaltered. The effects of the partial inverse agonist CGS 8216 were unaltered. The effects of the full inverse agonist DMCM were unchanged except for an enhancement of its convulsant effect when infused at a concentration of 100 mu gm 1-1. Studies with the full agonist benzodiazepine, flurazepam and the full agonist beta-carboline, ZK 93423, showed small but significant reductions in their hypothermic effects. The sedative and anticonvulsant effects of flurazepam were unaltered, whereas the anticonvulsant effects of ZK 93423 were decreased in animals kindled with FG 7142. There was a pronounced reduction in the anticonvulsant and hypothermic effects of the partial agonist beta-carboline, ZK 91296. These data do not fit any simple explanation of kindling being due to a change in the function of benzodiazepine receptors, although they may offer some support for the idea that kindling with FG 7142 produces a change in the effects of all beta-carboline compounds which act at the benzodiazepine receptor.

The effects on body temperature of the benzodiazepine contragonists FG 7142 (N-methyl-beta-carboline-3-carboxamide) and DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), the benzodiazepine antagonist Ro 15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-7-oxo-4H-imidazo-(1,5-a)(1,4)benzod iazepin e -3-carboxylate) and the benzodiazepine agonist, flurazepam, were investigated in mice. Both of the contragonists and flurazepam reduced the body temperature. The antagonist Ro 15-1788 did not alter body temperature alone but significantly antagonised the effects of FG 7142 and of flurazepam. The effects of the latter two drugs on locomotor activity in animals in a familiar environment were also investigated. Flurazepam reduced the activity counts in these circumstances but FG 7142 did not cause a significant change, at doses which considerably reduced body temperature. The drug FG 7142 also reduced the body temperature in rats. The effects on body temperature of the benzodiazepine contragonists and flurazepam were unusual in that they were changes in the same direction, both antagonised by Ro 15-1788. However, they differed in that while the effects of flurazepam on locomotor activity might contribute to its hypothermic effect this did not appear to be the case for FG 7142.

Until recently the only pharmacological probes for delta-receptors have been peptide enkephalin analogues. These suffer from a number of limitations including high cost, partial agonist effects and a propensity for neurotoxicity. A stable non-peptide antagonist, naltrindole, has recently become available. We have explored its intrinsic actions and found that it attenuated swim stress-induced antinociception, a model for endogenous delta-receptor activation. Naltrindole may therefore be a useful alternative to presently available delta-receptor antagonists.

Two benzodiazepine antagonists were tested in an animal model of anxiety, the social interaction test. Ethyl beta-carboline-3-carboxylate (1 and 2 mg/kg) had a potent anxiogenic action; the imidazodiazepine RO 15-1788 (4-10 mg/kg) had a weak anxiogenic effect that with a larger dose (20 mg/kg) disappeared and RO 15-1788 (10 mg/kg) significantly counteracted the anxiogenic effect of the beta-carboline (1 mg/kg). The implications of these results for the understanding of the pharmacological basis of anxiety and for the existence and nature of an endogenous ligand for the benzodiazepine binding site are discussed.

A schedule of treatment with the benzodiazepine, flurazepam, in mice for 7 days caused a significant enhancement of the convulsive effects of the partial inverse agonist FG7142. Full convulsions were seen with FG7142 after the chronic administration of flurazepam, although this compound does not cause convulsions in normal mice of the strain used. The change appeared to be maximal at 24 hr after the last dose of flurazepam and lasted for up to a week. The chronic treatment with flurazepam caused tolerance to the effects of flurazepam, but the tolerance was of shorter duration than the increase in the effects of FG7142. When the benzodiazepine antagonist, Ro 15-1788, was given with the flurazepam, the incidence of convulsions induced by FG7142 was no longer significant. Repeated administration of midazolam also slightly increased the effects of FG7142. Single doses of flurazepam or midazolam did not significantly alter the effects of FG7142, although some convulsions were seen.

Groups of hypophysectomised rats were given either an electroconvulsive shock (ECS; 125V, 1 sec) once daily for 10 days or a sham-shock. Twenty-four hours after the final treatment both groups were tested for their responses to the dopamine agonist, apomorphine, the 5-hydroxytryptamine agonist, quipazine, and the alpha 2-adrenoceptor agonist, clonidine. Repeated electroconvulsive shock enhanced the locomotor activity produced by either quipazine (25 mg/kg i.p.) or apomorphine (0.2 mg/kg s.c.) compared to sham-shocked controls. This treatment also attenuated the hypoactivity produced by clonidine (0.5 mg/kg i.p.). These changes are identical to those produced in normal rats by repeated electroconvulsive shock. Hypophysectomy, therefore, did not abolish the increased 5-hydroxytryptaminergic and dopaminergic behavioural responses neither did it prevent the decreased functional activity of central alpha 2-adrenoceptors, which may be presynaptic. These data suggest that although electroconvulsive shock has been reported to stimulate the secretion of various pituitary hormones, this process is not essential for the development of the enhanced monoamine-mediated behavioural responses studied.