Changes In Receptor Sensitivity Research Articles

Role of allopregnanolone-mediated γ-aminobutyric acid A receptor sensitivity in the pathogenesis of premenstrual dysphoric disorder: Toward precise targets for translational medicine and drug development.

Premenstrual dysphoric disorder (PMDD) can be conceptualized as a disorder of suboptimal sensitivity to neuroactive steroid hormones. Its core symptoms (emotional instability, irritability, depression, and anxiety) are related to the increase of stress sensitivity due to the fluctuation of hormone level in luteal phase of the menstrual cycle. In this review, we describe the emotional regulatory effect of allopregnanolone (ALLO), and summarize the relationship between ALLO and γ-aminobutyric acid A (GABAA) receptor subunits based on rodent experiments and clinical observations. A rapid decrease in ALLO reduces the sensitivity of GABAA receptor, and reduces the chloride influx, hindered the inhibitory effect of GABAergic neurons on pyramidal neurons, and then increased the excitability of pyramidal neurons, resulting in PMDD-like behavior. Finally, we discuss in depth the treatment of PMDD with targeted GABAA receptors, hoping to find a precise target for drug development and subsequent clinical application. In conclusion, PMDD pathophysiology is rooted in GABAA receptor sensitivity changes caused by rapid changes in ALLO levels. Targeting GABAA receptors may alleviate the occurrence of PMDD.

Genetic variation in the human olfactory receptor OR5AN1 associates with the perception of musks.

Humans have significant individual variations in odor perception, derived from their experience or sometimes from differences in the olfactory receptor (OR) gene repertoire. In several cases, the genetic variation of a single OR affects the perception of its cognate odor ligand. Musks are widely used for fragrance and are known to demonstrate specific anosmia. It, however, remains to be elucidated whether the OR polymorphism contributes to individual variations in musk odor perception. Previous studies reported that responses of the human musk receptor OR5AN1 to a variety of musks in vitro correlated well with perceptual sensitivity to those odors in humans and that the mouse ortholog, Olfr1440 (MOR215-1), plays a critical role in muscone perception. Here, we took advantage of genetic variation in OR5AN1 to examine how changes in receptor sensitivity are associated with human musk perception. We investigated the functional differences between OR5AN1 variants in an in vitro assay and measured both perceived intensity and detection threshold in human subjects with different OR5AN1 genotypes. Human subjects homozygous for the more sensitive L289F allele had a lower detection threshold for muscone and found macrocyclic musks to be more intense than subjects homozygous for the reference allele. These results demonstrate that the genetic variation in OR5AN1 contributes to perceptual differences for some musks. In addition, we found that the more functional variant of OR5A1, a receptor involved in β-ionone perception, is associated with the less functional variant of OR5AN1, suggesting that the perceived intensities of macrocyclic musks and β-ionone are inversely correlated.

Depressive-like state sensitizes 5-HT1A and 5-HT1B auto-receptors in the dorsal raphe nucleus sub-system

Dorsal raphe (DR) and median raphe (MR) 5-HT neurons are two distinct sub-systems known to be regulated by 5-HT1A and 5-HT1B auto-receptors. Whether the auto-receptors in each sub-system are functionally altered in depressive-like state remains unknown. The present study is aimed to study a specific circuit (DR-ventral hippocampus and MR-dorsal hippocampus) within each sub-system to investigate changes in receptor sensitivity in the pathogenesis of depression. A mouse model of depression was developed through the social defeat paradigm, and was then treated with fluoxetine (FLX). 5-HT1A auto-receptor in the neuronal cell body (DR or MR) and 5-HT1B auto-receptor in the axonal terminal (ventral or dorsal hippocampus) were directly targeted by local perfusion of antagonists (5-HT1A: WAY100635; 5-HT1B: GR127935) through reverse microdialysis. Time courses of dialysate 5-HT measured at the axonal terminal were subsequently determined for each circuit. At baseline, 5-HT1A and 5-HT1B antagonists dose-dependently increased dialysate 5-HT, with sub-circuit specificity. In the depressive-like state, greater increases in dialysate 5-HT were observed only in the DR-ventral hippocampus circuit following local delivery of both antagonists, which were then fully restored following the FLX treatment. In contrast, no changes were observed in the MR-dorsal hippocampus circuit. Our results demonstrate differential changes in sensitivities of 5-HT1A and 5-HT1B auto-receptors in the DR-ventral hippocampus and MR-dorsal hippocampus circuits. 5-HT1A and 5-HT1B auto-receptors in the DR-ventral hippocampus circuit are sensitized in the depressive-like state. Taken together, these results suggest that the DR sub-system maybe the neural substrate mediating depressive phenotypes.

Altered CNS Serotonin Signaling and Social Deficits Elicited by Blast‐Induced Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, accounting for approximately 2.8 million emergency room visits and an economic burden of nearly $30 billion annually. The lack of any FDA approved medications to treat the acute or chronic effects of TBI contributes greatly to the societal and economic costs. The most common enduring comorbidity of mild to moderate TBI is the generation of neuropsychiatric disorders including major depressive disorder (MDD), anxiety, and aberrant behaviors such as social withdrawal. These disorders/behaviors are linked to altered serotonin (5‐HT) signaling within the CNS. However, the effects of neurotrauma on the normal, physiologic function of the serotonergic system are currently not well defined. We hypothesize that TBI results in specific alterations of 5‐HT signaling, ultimately impacting mood and behavioral states mediated by 5‐HT signaling. To test this hypothesis, adult, wild type C57Bl/6J mice were subjected to either a single, moderate blast‐induced TBI or sham treatment. Ten days post‐injury (dpi) or sham treatments, high performance liquid chromatography (HPLC) revealed a significant increase in total 5‐HT and 5‐HIAA levels within the raphe nucleus of TBI subjects compared to their sham counterparts, an effect not found in the prefrontal cortex (PFC) or somatosensory cortex (SSC), areas of high 5‐HT innervation. TBI subjects (10 dpi) exhibited a significant potentiation in head twitch response (HTR) elicited by administration of the 5‐HT precursor, 5‐hydroxytryptophan (5‐HTP, 100 mg/kg, i.p.) as compared to their sham counterparts, an effect mediated by the activation of cortical 5‐HT2A receptors. To ascertain 5‐HT2A or 5‐HT1A receptor sensitivity changes elicited by TBI, DOI‐induced head twitch assays and 8‐OH‐DPAT‐induced hypothermia assays were utilized, respectively. No changes in 5‐HT1A receptor sensitivity were detected in TBI subjects following administration of the 5‐HT1A agonist 8‐OH‐DPAT (0.1 mg/kg, s.c., 10 dpi), however administration of the 5‐HT2A agonist DOI (1 mg/kg, i.p., 3 and 10 dpi) resulted in a significant potentiation of HTR in TBI subjects as compared to their sham counterparts, indicative of increased 5‐HT2A receptor sensitivity. As 5‐HT signaling is a major determinant of complex social behavior, we hypothesized that TBI‐induced changes in homeostatic 5‐HT signaling would coincide with behaviors reminiscent of social withdrawal. Using the Crawley Three Chamber Sociability Assay, significant social deficits were found in TBI subjects (10 dpi) as compared to their sham counterparts. Collectively, our studies suggest that TBI acts to alter specific aspects of 5‐HT signaling within the CNS, effects that may drive TBI‐induced changes in behavior and the generation of neuropsychiatric disorders. A greater understanding of how various forms of neurotrauma causes altered 5‐HT signaling may lead to the discovery of pharmacotherapies aimed at ameliorating the chronic neuropsychiatric complications of TBI.Support or Funding InformationThis work was supported in part by the Brain and Behavioral Research Foundation (Grant No. 25230).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease.

ObjectiveTo investigate the kinetics and metabolism of caffeine in serum from patients with Parkinson disease (PD) and controls using liquid chromatography–mass spectrometry.MethodsLevels of caffeine and its 11 metabolites in serum from 108 patients with PD and 31 age-matched healthy controls were examined by liquid chromatography–mass spectrometry. Mutations in caffeine-associated genes were screened by direct sequencing.ResultsSerum levels of caffeine and 9 of its downstream metabolites were significantly decreased even in patients with early PD, unrelated to total caffeine intake or disease severity. No significant genetic variations in CYP1A2 or CYP2E1, encoding cytochrome P450 enzymes primarily involved in metabolizing caffeine in humans, were detected compared with controls. Likewise, caffeine concentrations in patients with PD with motor complications were significantly decreased compared with those without motor complications. No associations between disease severity and single nucleotide variants of the ADORA2A gene encoding adenosine 2A receptor were detected, implying a dissociation of receptor sensitivity changes and phenotype. The profile of serum caffeine and metabolite levels was identified as a potential diagnostic biomarker by receiver operating characteristic curve analysis.ConclusionAbsolute lower levels of caffeine and caffeine metabolite profiles are promising diagnostic biomarkers for early PD. This is consistent with the neuroprotective effect of caffeine previously revealed by epidemiologic and experimental studies.Classification of evidenceThis study provides Class III evidence that decreased serum levels of caffeine and its metabolites identify patients with PD.

TLR and RLR Signaling Are Reprogrammed in Opposite Directions after Detection of Viral Infection

Innate immune recognition of RNA is key for the initiation of immunity in response to viral infection. Although the factors controlling the detection of viral RNA by innate immune receptors in host cells are increasingly well understood, little is known about the dynamic changes in signaling after the initial triggering of these receptors. In this study, we report that preconditioning with the synthetic dsRNA polyinosinic-polycytidylic acid [poly(I:C)], a mimetic of viral RNA, rapidly reprograms murine APCs by simultaneously augmenting sensitivity of endosomal TLRs and inhibiting activation of RIG-I-like receptors (RLRs) in an IFN-β-dependent manner. These changes in receptor sensitivity were also seen in vivo after treatment of mice with poly(I:C). Mechanistically, the increased sensitivity of the TLR pathway was associated with elevated MAPK and NF-κB activity. The RLR response was inhibited downstream of TANK-binding kinase-1, resulting in decreased IFN regulatory factor 3 phosphorylation. Reprogramming of pattern-recognition receptor signaling also occurred after viral infection, because infection of host cells with Sendai virus or their exposure to supernatant from virus-infected cells induced the same changes in TLR and RLR sensitivity as poly(I:C). Thus, innate recognition of viral infection critically modifies responses to pattern-recognition receptor stimulation. These dynamic adaptations to infection may reinforce antiviral immunity and at the same time serve to limit pathological inflammation.

Respiratory vulnerability to vehicle buffeting

Buffeting in a jerky ride in a bus or ambulance normally provokes a sustained tachypnoea driven by vibration and sensory mechanisms including vestibular signals. Tachypnoea reinforces the torso against mechanical shocks but results in overbreathing, causing a mild fall in CO(2). However, normal CO(2) is rapidly restored by a reduction in depth of breathing. We test the hypothesis that vulnerable subjects, exemplified by elderly individuals and patients with vestibular disorders, may fail to adapt to buffeting. Respiratory and cardiovascular functions were recorded from five elderly subjects, two patients with bilateral loss of vestibular function and five patients with 'BPPV,' while being exposed to 15-min buffeting in a flight simulator which simulated transport in an ambulance over rough pavement. Results were compared with published norms. Some subjects sustained overbreathing during motion, through either tachypnoea or deep breathing, causing a marked reduction in CO(2) levels (3/5, 2/2 avestibular, 4/5 elderly, 4/5 BPPV). Others failed to raise breathing frequency which would render them susceptible to mechanical shock (4/5 elderly, 1/2 avestibular). Overbreathing was particularly evident in three anxious subjects. Overbreathing during buffeting could be caused by (1) resetting of CO(2) rest levels lower; (2) change in receptor sensitivity; (3) adjustment of central drive to breathing; and (4) stiffening of posture because of motion discomfort reduced the ability to modulate breathing. The buffeting experienced was moderately violent. More profound hypocapnia and mechanical shock are likely to result in vulnerable individuals failing to adapt to severe buffeting in transport on unpaved roads, in war zones or by sea ambulance.

Differential effects of chronic partial sleep deprivation and stress on serotonin‐1A and muscarinic acetylcholine receptor sensitivity

Disrupted sleep and stress are often linked to each other, and considered as predisposing factors for psychopathologies such as depression. The depressed brain is associated with reduced serotonergic and enhanced cholinergic neurotransmission. In an earlier study, we showed that chronic sleep restriction by forced locomotion caused a gradual decrease in postsynaptic serotonin-1A receptor sensitivity, whilst chronic forced activity alone, with sufficient sleep time, did not affect receptor sensitivity. The first aim of the present study was to examine whether the sleep loss-induced change in receptor sensitivity is mediated by adrenal stress hormones. The results show that the serotonin-1A receptor desensitization is independent of adrenal hormones as it still occurs in adrenalectomized rats. The second aim of the study was to establish the effects of sleep restriction on cholinergic muscarinic receptor sensitivity. While sleep restriction affected muscarinic receptor sensitivity only slightly, forced activity significantly hypersensitized the muscarinic receptors. This hypersensitization is because of the stressful nature of the forced activity protocol as it did not occur in adrenalectomized rats. Taken together, these data confirm that sleep restriction may desensitize the serotonin-1A receptor system. This is not a generalized effect as sleep restriction did not affect the sensitivity of the muscarinic cholinergic receptor system, but the latter was hypersensitized by stress. Thus, chronic stress and sleep loss may, partly via different pathways, change the brain into a direction as it is seen in mood disorders.

The effect of brain-derived neurotrophic factor on sensory and autonomic function after lingual nerve repair

Brain-derived neurotrophic factor (BDNF) is important in the response to peripheral nerve injury and may enhance regeneration. We have assessed its role in the functional recovery of sensory afferents and autonomic efferents after repair of the chorda tympani and lingual nerves in the cat. Six months after entubulation repair, with or without the incorporation of BDNF at the repair site, the recovery of secretomotor and vasomotor efferents was determined by recording salivary flow from the submandibular gland and temperature changes on the tongue surface, each evoked by stimulation of the repaired nerve. Electrophysiological recordings from the lingual and chorda tympani nerves proximal to the repair were undertaken to characterise mechanosensitive, thermosensitive, and gustatory afferents. When compared with data from uninjured control animals, both repair groups showed changes in receptor sensitivity and spontaneous discharge, and persistent reductions in conduction velocity, proportion of gustatory and thermosensitive units, rate of salivary secretion, and vasomotor responses. Comparisons between the outcome of repair with or without BDNF revealed few differences. In the BDNF group, fewer units in the chorda tympani responded to gustatory or thermal stimuli and the sensitivity of the gustatory units was lower. The conduction velocity of afferents in the lingual nerve was also lower, but the mechanoreceptive field size was higher. Thus, despite its known trophic role in the gustatory system, BDNF had not enhanced recovery of these or other fibre populations. We conclude that the application of BDNF to a site of lingual nerve repair has a negative effect on the long-term outcome.

Time Course of Habituation After Repeated Ice-Bath Immersion of the Ankle

Context:Cryotherapy is initially uncomfortable, but habituation is thought to occur during treatment.Objective:To examine pain habituation to ice-bath immersion over 5 consecutive days.Design:Mean Borg ratings were analyzed by ANOVA.Setting:Athletic training laboratory.Intervention:Ankle immersion in a 1 °C ice bath for 20 min.Participants:28 healthy individuals.Main Outcome Measure:Level of discomfort was rated at immersion; during treatment at 1, 3, 5, 8, 11, 14, 17, and 20 min; and 1 min posttreatment.Results:Analysis revealed significant main effects for day and time and a Day × Time interaction. Day 1 had higher pain ratings than days 4 and 5. From min 1 to 11 there was a progressive decline in pain rating; after that there was no significant decline.Conclusions:Discomfort was greatest during the first 5 min, and perception of discomfort at initial immersion was consistent across 5 days. In addition, after 3 days of treatments habituation occurred. Taken together, this suggests that treatment habituation is not the result of change in receptor sensitivity.

The use of antidepressant and antipsychotic drugs in elderly epilepsy patients.

The incidence of epilepsy is increasing among the el-derly, as was demonstrated by the results of the large-scale Rochester-based epidemiologic study by Hauser etal. (1) and confirmed by subsequent studies (2). Theincidence of epilepsy is now estimated to be 100/100,000in subjects older than 60 years and 160/100,000 in thoseaged 80–84 years, and its prevalence is seven of 1,000 insubjects aged 55–64 and 12 of 1,000 in those aged 85–94years (3,4).Epilepsy in the elderly is usually associated with otherorganic diseases, such as vascular, degenerative (Alzhei-mer disease) (4), and neoplastic diseases (5). Its inci-dence is higher (2.5% of recurrent seizures) amongpatients with hemorrhagic strokes than in those withother ischemic vascular diseases (6). The majority ofcases involve complex partial seizures (4), which arefrequently difficult to diagnose in the elderly, but gen-eralized tonic–clonic seizures also have been describedand are probably caused by degenerative diseases orcombinations of genetic and/or environmental factors.Recent studies have shown that cognitive deficits andtheir related disturbances also increase after a stroke (7),although the presence of deficits varies from subject tosubject (8).The prevalence of behavioral disturbances is higher inthe elderly than in the general population and may beassociated with depression (∼2–4%) or depressive symp-toms (10–25%) (9,10,11a). The male/female ratio is infavor of the second, as are the costs relating to psycho-pharmacologic treatment and the use of medical re-sources (11). It has been estimated that between 5 and50% of elderly subjects are depressed; the rate of suicideincreases with age, and seems be independent of, or sec-ondary to, stressful life events.The use of antipsychotic drugs is made particularlycomplex because many elderly people also are beingtreated for concomitant organic diseases, which givesrise to the possibility of pharmacologic interactions. In adescriptive analysis of 681 subjects with a mean age of86.9 years, which covered the period 1994–1996, Gironet al. (12) found that the nondemented subjects weretaking an average of 4.5 drugs (acting mainly on thecardiovascular system), and the demented subjects, anaverage of 4.8 drugs [acting mainly on the central ner-vous system (CNS)]. The use of drugs is therefore de-cidedly high in both demented and nondementedsubjects.Elderly patients are frequently prescribed psycho-tropic agents, although these are less well tolerated andgive rise to a higher incidence of adverse reactions thanin the young because of age-related pharmacodynamicand pharmacokinetic changes at the level of the neuro-chemical processes of the CNS. The pharmacodynamicphenomena associated with the increased sensitivity ofthe elderly to psychoactive drugs are related to neuro-morphologic modifications due to the process of agingitself. A progressive age-related loss in brain weight be-gins at the age 45–50 years and reaches a maximum atthe age of 86 years, when the brain weighs 11% less thanin young adults. There also are changes in receptor sen-sitivity: in comparison with the young, elderly subjectsrespond less to receptor agonists and -adrenergic block-ers (13) and more to benzodiazepine (BZD) sedatives,analgesics, and anticoagulants. This increased sensitivitymeans that the presence of 20–50% of the neurotrans-mitters involved is enough to obtain a response (14).Conversely, the elderly have fewer acetylcholine re-ceptors (acetylcholine is the quantitatively most wide-spread neurotransmitter in the CNS), which are involvedin learning, memory, motor skills, and sensation, as wellas more complex functions such as the affective func-tions. The age-related reduction in noradrenaline (NA)and dopamine (DA) may be as much as 50% (15,16),and there is a parallel decline in tyrosine hydroxylaseactivity (17).As antidepressants and antipsychotics modify theequilibrium of the cholinergic and monoaminergic sys-tems, they can give rise to clinically relevant centralanticholinergic toxicity. One example of this is the de-mentia syndrome, which consists of mood changes (fromeuphoria to depression), memory deficit, and neurologic

Neonatal exposure to a novel environment enhances the effects of corticosterone on neuronal excitability and plasticity in adult hippocampus

Electrophysiological studies have shown that activation of glucocorticoids receptors (GRs) influences neuronal excitability and activity dependent synaptic plasticity. In developmental studies, early life stimulation such as neonatal handling results in an up-regulation of glucocorticoid-receptor (GR) binding in the hippocampus that persists into adulthood. It is, therefore, hypothesized that early environment-induced changes in receptor sensitivity to corticosterone (CORT) might have functional effects on adult neuronal excitability and synaptic plasticity. To test this hypothesis, we exposed rats daily from post-natal days 1–21 to a non-home environment for 3 min. When the animals became adults, we studied the effects of glucocorticoid hormone corticosterone (CORT) on population spike (PS) amplitude and long-term potentiation of population spikes (PS-LTP) in vitro in the hippocampal CA1 region following activation of the Schaffer collateral fibers. Bath application of CORT reduced PS amplitude and subsequent induction of PS-LTP. This inhibitory effect of CORT was significantly greater in the slices from the novelty exposed rats (Novel) than the control rats that remained in their home cage (Home). Inhibition of population spike amplitude during CORT perfusion was 28.0±5.3% of baseline in Novel slices, and 9.1±4.4% in Home slices. CORT pre-exposure (20 min) also inhibited the subsequent induction of PS-LTP in Novel slices by 57.7±17.7% and by 7.5±12.1% in Home slices. These results provide electrophysiological evidence that neonatal novelty exposure results in functional increases in receptor sensitivity to CORT that enhances the inhibitory effects of CORT on field CA1 neuronal excitability and plasticity.

The association between risk factors for tardive dyskinesia and phenylalanine-induced abnormal movements in schizophrenia.

We examined whether an oral challenge dose of the amino acid phenylalanine (a dopamine precursor) exacerbates the abnormal movements of tardive dyskinesia (TD). We also examined age, gender, treatment duration, and baseline movement severity in relation to phenylalanine-induced changes in movements. Lastly, we assessed the influence of fasting amino acid levels on phenylalanine-induced movements. In a placebo-controlled fashion, the abnormal involuntary movement scale (AIMS) was obtained on 25 patients before and after a phenylalanine challenge drink. A general linear model determined the relative effects of age, gender, treatment duration, and fasting amino acid levels on the magnitude of induced movements. Age and treatment duration did not affect phenylalanine-induced movements. Lower fasting levels of phenylalanine were associated with greater movements after controlling for age, F = 11.89, p < 0.003. The severity of abnormal movements at baseline also predicted response to phenylalanine, F = 8.62, p = 0.0079. Brain amino acid and neurotransmitter pools are influenced by changes in dietary protein, which may have implications in the development and prevention of movement disorders. This study suggests that fasting amino acid levels may predict differences in vulnerability to movements during an influx of neurotransmitter precursors, perhaps due to long-term compensatory changes in receptor sensitivity. Copyright 2001 John Wiley & Sons, Ltd.

Acute opioid receptor desensitization and tolerance: is there a link?

1. Morphine, used long-term for the treatment of pain, results in drug tolerance. The therapeutic benefits, as well as side effects, of morphine are mediated predominantly via activation of mu-opioid receptors. Although the underlying mechanisms for opioid tolerance remains unclear, early adaptive processes, such as acute receptor desensitization and receptor downregulation, have been suggested to be crucial to the development of opioid tolerance. 2. Other neuroadaptations resulting from chronic opioid use include upregulation of the cAMP pathway, an increase in the cAMP response element-binding protein and Fos-related antigens. However, the connection between upregulation of these cellular elements and the mechanism behind the behavioural phenomenon remains unclear. 3. Acute receptor desensitization is thought to occur via uncoupling of the receptor and G-protein, which is followed by internalization of the receptor from the cell membrane. This process occurs after a few minutes of agonist exposure. Receptor-G-protein uncoupling is mediated via phosphorylation of putative sites on the intracellular loops of activated receptors. 4. Acute desensitization and downregulation of receptors both result in a reduction of agonist efficacy. These events occur early in the cascade of cellular adaptation; however, it is uncertain whether these processes contribute to the long-term changes in receptor sensitivity that occur after repeated exposure to opioids. 5. Acute desensitization may, in fact, be a protective mechanism whereby cells adapt to avoid the development of physiological drug tolerance by rapidly attenuating receptor-mediated signalling. Those drugs that do not cause receptor internalization, such as morphine, may have higher propensities to develop tolerance.

Effects of parkinsonian medication on sleep.

Patients suffering from Parkinson's disease (PD) often report about sleep disorders and excessive daytime sleepiness. To some extent, motor disabilities or neural degeneration of sleep modulating structures may be responsible for these effects. Depressive disorders also contribute to the occurrence of insomnia and daytime sleepiness. Nevertheless, dopaminergic, anticholinergic, and other drugs used in PD have a great impact on sleep/wakefulness mechanisms. They may indirectly improve or worsen sleep by changing motor symptoms such as akinesia, hyperkinesia, or tremor. Although their is only little information on the complex regulation of vigilance, it is well known that monoaminergic and cholinergic drugs could influence it directly. Data from animal experiments and clinical experiences led to the hypothesis of a biphasic influence on sleep by dopaminergic substances: small doses of L-Dopa e. g. appear to improve sleep whilst higher doses led to insomnia. Different dopaminergic receptor types or changes in receptor sensitivity may explain these phenomena. Dopaminergic and anticholinergic drugs suppress REM sleep. Recently, initial data on 'sleep attacks' after pramipexole or ropinirole treatment were published. Our preliminary results using 24 h polygraphic recordings showed excessive daytime sleepiness in patients taking ropinirole and L-Dopa which disappeared when changed to ropinirole monotherapy. Sleepiness did never appear as an irresistible attack. Current hypotheses on this topic are reviewed.

Remodelling colour contrast: implications for visual processing and colour representation

Colour contrast describes the influence of one colour on the perception of colours in neighbouring areas. This study addresses two issues: (i) the accurate representation of the colour changes; (ii) the underlying visual mechanisms. Observers viewed a haploscopic display in which a standard display was presented to one eye and a matching display to the other. The matches could be represented accurately using a diagram that is a logarithmic transformation of the MacLeod–Boynton ( r, b) (1979) chromaticity diagram. Since haploscopic presentation has been described as isolating retinal processes (Whittle, P., & Challands, P.D.C. (1969). The effect of background luminance on the brightness of flashes. Vision Research, 9, 1095–1110; Chichilnisky, E.J., & Wandell, B.A. (1995). Photoreceptor sensitivity changes explain color appearance shifts induced by large uniform backgrounds in dichoptic matching. Vision Research, 35, 239–254), the results are discussed in terms of receptor sensitivity changes and the ratio of receptor contrasts.

Neurobiological similarities in antidepressant sleep deprivation and psychostimulant use: a psychostimulant theory of antidepressant sleep deprivation.

This paper attempts to summarize the evidence for the hypothesis that psychostimulant-like neurotransmitter processes within certain regions of the limbic system induce the positive effects of antidepressant sleep deprivation (SD). Preclinical and human studies indicate similar neurobiological effects of psychostimulants such as amphetamines, cocaine and SD. In clinical use, SD and psychostimulants have similar characteristics and behavioral effects. Furthermore, acute psychostimulant challenge decreases limbic metabolism in imaging studies, and SD decreases elevated limbic metabolism in SD responders, indicating that psychostimulant-like neurotransmitter release could decrease limbic metabolism in SD responders. Most antidepressant pharmacotherapies change the reactivity of the dopamine system, and a decrease of presynaptic dopamine or postsynaptic availability can induce depression. Sleep is accompanied by a reduction of catecholamine release and those processes which are increased by psychostimulants. It is concluded that a proposed regional postsynaptic deficit in catecholaminergic neurotransmission can be overcome either acutely by enhanced release during SD or psychostimulant use, or chronically by changes in receptor sensitivity or gene expression due to antidepressant therapies. A postsynaptic deficit in these areas becomes evident if presynaptic release is reduced in conditions such as sleep. Therefore, sleep is depressiogenic for predisposed individuals and the reduction of sleep avoids understimulation of subsensitive postsynaptic processes, which are enhanced by psychostimulants.

Designing a new generation of antidepressant drugs.

Although longer-term adaptive changes in receptor sensitivity may better explain the delayed onset of action of antidepressants, the mechanism based on acutely elevated noradrenaline (NA) and serotonin (5-HT) synaptic levels remains the basis for new drug design. The dual action concept, which postulates that effects on both NA and 5-HT are more advantageous than a selective action on serotonin reuptake (SSRI), has been used to design new antidepressants such as venlafaxine and mirtazapine. Both drugs enhance NA and 5-HT neurotransmission with little affinity for receptors mediating tricyclic-like side effects. Mirtazapine, the prototype noradrenergic and specific serotonergic antidepressant (NaSSA), specifically enhances 5-HT1 neurotransmission and blocks 5-HT2 and 5-HT3 receptors, and in contrast to venlafaxine lacks SSRI-like and adverse cardiovascular side effects. The unique pharmacological action of mirtazapine is a result of implementation of two concepts: dual action as a basis of efficacy combined with receptor-specific action as a basis of tolerability.

O-18-267 - Transplantation of dopaminerglc neurons in a rat model of Parkinson’s disease: Long-term functional restauration of the nigrostriatal pathway

Extensive lesions of the fimbria-fornix pathways and the cingular bundle deprive the hippocampus of a substantial part of its cholinergic, noradrenergic and serotonergic afferents and, among several other behavioural alterations, induce lasting impairment of spatial learning and memory capabilities. After a brief presentation of the neuroanatomical organization of the hippocampus and the connections relevant to the topic of this article, studies which have contributed to characterize the neurochemical and behavioural aspects of the fimbria-fornix lesion “syndrome” with lesion techniques differing by the extent, the location or the specificity of the damage produced, are reviewed. Furthermore, several compensatory changes that may occur as a reaction to hippocampal denervation (sprouting, changes in receptor sensitivity and modifications of neurotransmitter turnover in spared fibres) are described and discussed in relation with their capacity (or incapacity) to foster recovery from the lesion-induced deficits. According to this background, experiments using intrahippocampal or “parahippocampal” grafts to substitute for missing cholinergic, noradrenergic or serotonergic afferents are considered according to whether the reported findings concern neurochemical and/or behavioural effects. Taken together, these experiments suggest that appropriately chosen fetal neurons (or other cells such as, for instance, genetically-modified fibroblasts) implanted into or close to the denervated hippocampus may substitute, at least partially, for missing hippocampal afferents with a neurochemical specificity that closely depends on the neurochemical identity of the grafted neurons. Thereby, such grafts are able not only to restore some functions as they can be detected locally, namely within the hippocampus, but also to attenuate some of the behavioural (and other types of) disturbances resulting from the lesions. In some respects, also these graft-induced behavioural effects might be considered as occurring with a neurochemically-defined specificity. Nevertheless, if a graft-induced recovery of neurochemical markers in the hippocampus seems to be a prerequisite for also behavioural recovery to be observed, this neurochemical recovery is neither the one and only condition for behavioural effects to be expressed, nor is it the one and only mechanism to account for the latter effects. © 1997 Elsevier Science Ltd. All Rights Reserved.

THE FIMBRIA-FORNIX/CINGULAR BUNDLE PATHWAYS: A REVIEW OF NEUROCHEMICAL AND BEHAVIOURAL APPROACHES USING LESIONS AND TRANSPLANTATION TECHNIQUES

Extensive lesions of the fimbria-fornix pathways and the cingular bundle deprive the hippocampus of a substantial part of its cholinergic, noradrenergic and serotonergic afferents and, among several other behavioural alterations, induce lasting impairment of spatial learning and memory capabilities. After a brief presentation of the neuroanatomical organization of the hippocampus and the connections relevant to the topic of this article, studies which have contributed to characterize the neurochemical and behavioural aspects of the fimbria-fornix lesion “syndrome” with lesion techniques differing by the extent, the location or the specificity of the damage produced, are reviewed. Furthermore, several compensatory changes that may occur as a reaction to hippocampal denervation (sprouting, changes in receptor sensitivity and modifications of neurotransmitter turnover in spared fibres) are described and discussed in relation with their capacity (or incapacity) to foster recovery from the lesion-induced deficits. According to this background, experiments using intrahippocampal or “parahippocampal” grafts to substitute for missing cholinergic, noradrenergic or serotonergic afferents are considered according to whether the reported findings concern neurochemical and/or behavioural effects. Taken together, these experiments suggest that appropriately chosen fetal neurons (or other cells such as, for instance, genetically-modified fibroblasts) implanted into or close to the denervated hippocampus may substitute, at least partially, for missing hippocampal afferents with a neurochemical specificity that closely depends on the neurochemical identity of the grafted neurons. Thereby, such grafts are able not only to restore some functions as they can be detected locally, namely within the hippocampus, but also to attenuate some of the behavioural (and other types of) disturbances resulting from the lesions. In some respects, also these graft-induced behavioural effects might be considered as occurring with a neurochemically-defined specificity. Nevertheless, if a graft-induced recovery of neurochemical markers in the hippocampus seems to be a prerequisite for also behavioural recovery to be observed, this neurochemical recovery is neither the one and only condition for behavioural effects to be expressed, nor is it the one and only mechanism to account for the latter effects. © 1997 Elsevier Science Ltd. All Rights Reserved.