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Biomedical subjects

J F Deakin

Publications and source records attributed to J F Deakin.

At least 19 recordsLinked to original sources
PubMed2001

The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics?

Increasing attention is being directed towards the role of the serotonergic system in the neurochemistry of schizophrenia and antipsychotic drug treatment. This review considers the 5-HT1A receptor in this context. In patients with schizophrenia, the majority of post-mortem studies have reported increases in 5-HT1A receptor density in the prefrontal cortex in the approximate range 15-80%. Although the pathophysiological significance of this finding is unclear, given the location of a major proportion of these receptors on pyramidal cells, it may reflect an abnormal glutamatergic network. In terms of drug treatment, 5-HT1A agonists clearly display anticataleptic activity in rats. In addition, 5-HT1A agonists consistently increase dopamine release in the prefrontal cortex in rodents, which is an effect that might be predicted to improve negative symptoms. 5-HT1A agonists augment classical neuroleptics in some rat models of antipsychotic action and may be capable of modulating the glutamatergic network therapeutically. Despite the encouraging preclinical data, there is a paucity of clinical studies of 5-HT1A agonist augmentation of neuroleptics in the treatment of schizophrenia. However, the clinical relevance may be clarified by the atypical antipsychotic drugs clozapine, quetiapine and ziprasidone which combine D2 receptor antagonism and 5-HT1A agonism. In conclusion, given the increased prefrontal 5-HT1A receptor density in the illness, and the anticataleptic activity of 5-HT1A agonists combined with their ability to evoke prefrontal dopamine release, there is now a sufficient rationale to examine thoroughly the role of the 5-HT1A receptor in schizophrenia and antipsychotic drug treatment.

Animals↗
PubMed2001

Relationship between 5-HT function and impulsivity and aggression in male offenders with personality disorders.

BACKGROUND: Reduced serotonergic (5-HT) function and elevated testosterone have been reported in aggressive populations. AIMS: To investigate relationships between impulsivity, aggression, 5-HT function and testosterone in male offenders with personality disorders. METHOD: Sixty male offenders with DSM-III-R personality disorders and 27 healthy staff controls were assessed using the Special Hospital Assessment of Personality and Socialisation (SHAPS), impulsivity and aggression ratings, d-fenfluramine challenge and plasma hormone concentrations. RESULTS: The SHAPS non-psychopaths and those with schizoid personality disorders had enhanced 5-HT function (prolactin response to d-fenfluramine). Reduced 5-HT function was found in offenders with DSM-III-R borderline personality disorders and those with a history of repeated self-harm or alcohol misuse. The 5-HT function was inversely correlated more strongly with impulsivity than with aggression. Plasma testosterone correlated positively with aggressive acts. The SHAPS primary psychopaths had lower initial cortisol and higher testosterone concentrations than controls. CONCLUSIONS: Future studies are needed to investigate regional brain 5-HT function.

Adult↗
PubMed2000

Expression of neuronal nitric oxide synthase mRNA in stress-related brain areas after restraint in rats.

The objective of the present study was to investigate the expression of neuronal nitric oxide synthase (nNOS) mRNA in stress-related areas after restraint. Male Wistar rats (n=4-6/group) submitted to 2 h of restraint during one (acute) or seven (chronic) days were sacrificed 24 h after the last restraint period. In situ hybridisation was performed with oligonucleotide probes radiolabeled with (35)S. Acute restraint induced a significant increase in nNOS mRNA in the paraventricular hypothalamic nucleus (PVN), medial parvocellular part, dorsolateral periaqueductal grey (DLPAG) and medial amygdaloid nucleus, but not in the hippocampal formation. This effect persisted after chronic restraint in the PVN and DLPAG. These results suggest that restraint stress induces changes in gene expression of nNOS in areas related to stress reactions.

Amygdala↗
PubMed2000

Attentional bias for drug cues in opiate dependence.

BACKGROUND: In a number of theories of compulsive drug use conditioned responses to stimuli associated with drug taking play a pivotal role. For example, according to incentive-sensitization theory (Robinson & Berridge, 1993), drug-related stimuli selectively capture attention, and the neural mechanisms underlying this attentional bias play a key role in the development and maintenance of drug dependence, and in relapse. However, there has been little work that assesses attentional biases in addiction. METHODS: We used a pictorial probe detection task to investigate whether there is an attentional bias to stimuli associated with drug use in opiate dependence. Stimuli presented included pairs of drug-related and matched neutral pictures. Methadone-maintained opiate addicts (N = 16) were compared with age-matched controls (N = 16). RESULTS: A mixed design analysis of variance of response times to probes revealed a significant three-way interaction of group x drug picture location x probe location. Opiate addicts had relatively faster reaction times to probes that replaced drug pictures rather than neutral pictures, consistent with the predicted attentional bias to drug-related stimuli. CONCLUSIONS: These results support the idea that an attentional bias for drug-related stimuli occurs in opiate dependence. This is consistent with the concept of a central role for such salient stimuli in compulsive drug use.

Adult↗
PubMed2000

Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines. British Association for Psychopharmacology.

A revision of the British Association for Psychopharmacology guidelines for treating depressive disorders with antidepressants was undertaken in order to specify the scope and target of the guidelines and to update the recommendations based explicitly on the available evidence. A consensus meeting, involving experts in depressive disorders and their treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from participants and interested parties. A literature review is given which identifies the quality of evidence followed by recommendations, the strength of which are based on the level of evidence. The guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing, management when initial treatment fails, continuation treatment, maintenance treatment to prevent recurrence and stopping treatment.

Antidepressive Agents↗
PubMed2000

Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk. Focal dysfunction and distributed disconnectivity reappraised.

BACKGROUND: PET studies of verbal fluency in schizophrenia report a failure of 'deactivation' of left superior temporal gyrus (STG) in the presence of activation of left dorsolateral prefrontal cortex (DLPFC), which deficit has been attributed to underlying 'functional disconnectivity'. AIM: To test whether these findings provide trait-markers for schizophrenia. METHOD: We used H2(15)O PET to examine verbal fluency in 10 obligate carriers of the predisposition to schizophrenia, 10 stable patients and 10 normal controls. RESULTS: We found no evidence of a failure of left STG deactivation in carriers or patients. Instead, patients failed to deactivate the precuneus relative to other groups. We found no differences in functional connectivity between left DLPFC and left STG but patients exhibited significant disconnectivity between left DLPFC and anterior cingulate cortex. CONCLUSIONS: Failure of left STG 'deactivation' and left fronto-temporal disconnectivity are not consistent findings in schizophrenia; neither are they trait-markers for genetic risk. Prefrontal functional disconnectivity here may characterise the schizophrenic phenotype.

Heterozygote↗
PubMed2000

Effect of acute tryptophan depletion on CO2-induced anxiety in patients with panic disorder and normal volunteers.

BACKGROUND: Uncertainties remain about the role of serotonin in the aetiology and treatment of panic disorder. AIMS: To investigate the effect of reducing brain serotonin function on anxiety at rest, and following 5% CO2 provocation in normal controls and patients with panic disorder. METHOD: Twenty drug-free patients with DSM-III-R panic disorder and 19 controls received a tryptophan-free amino acid drink on one occasion and a control drink on the other in a double-blind, balanced protocol. 5% CO2 was given as a panic challenge after 270 minutes. RESULTS: Plasma tryptophan fell by more than 80% both patients and controls after the tryptophan-free drink. Tryptophan depletion did not alter resting anxiety. In patients alone, tryptophan depletion caused a greater anxiogenic response and an increased rate of panic attacks (9 v. 2, P < 0.05) after 5% CO2 challenge. No normal volunteers panicked. CONCLUSIONS: Serotonin may directly modulate panic anxiety in patients with panic disorder. This may underlie the efficacy of serotonergic antidepressants in treating panic disorder.

Adolescent↗
PubMed1999

NR2B-containing NMDA receptors are up-regulated in temporal cortex in schizophrenia.

Saturation analyses of [3H]L-689,560, [3H]CGP 39653 and NMDA-specific [3H]ifenprodil binding revealed an equivalent increase (0.7 pmol/mg) in the number of [3H]L-689,560 and [3H]ifenprodil binding sites in superior temporal cortex (BA22) from drug-treated chronic schizophrenic patients and control subjects. No differences were observed between control and schizophrenic subjects for [3H]CGP 39653 binding in BA22, or for any of the radioligands binding to pre-motor cortex (BA6). Since [3H]L-689,560, [3H]CGP 39653 and [3H]ifenprodil label the glycine, glutamate and ifenprodil sites of the NMDA receptor complex, which are associated with NR1, NR1/NR2A and NR1/NR2B subunits respectively, our findings suggest that NR2B-containing receptors are selectively up-regulated in superior temporal cortex in schizophrenia.

2-Amino-5-phosphonovalerate↗
PubMed1999

Tryptophan depletion impairs stimulus-reward learning while methylphenidate disrupts attentional control in healthy young adults: implications for the monoaminergic basis of impulsive behaviour.

RATIONALE: Altered serotonergic and dopaminergic function have been widely implicated in behavioural disorders associated with impulsivity and risk-taking. However, little research has addressed the specific cognitive consequences of changed monoaminergic function that might contribute to the production of impulsive behaviour. OBJECTIVES AND METHODS: We compared the effects of rapid plasma tryptophan depletion, acute doses of the mixed indirect catecholamine agonist, methylphenidate (40 mg), and acute doses of the alpha(1)/alpha(2 )agonist, clonidine (1.5 microg/kg), on aspects of visual discrimination learning involving either acquisition of altered stimulus-reward associations (i.e. updating the affective valence of exteroceptive stimuli) or the control of attention towards relevant as opposed to irrelevant stimulus dimensions. RESULTS: Relative to subjects who received placebo, subjects with reduced tryptophan exhibited a deficit in the ability to learn changed stimulus-reward associations, but were still able to shift an acquired attentional set away from a now-irrelevant stimulus dimension towards a newly relevant dimension. By contrast, subjects who received methylphenidate were able to learn effectively about changing stimulus-reward associations, but showed an enhanced ability to shift an attentional bias, in combination with slowed response times. Subjects who received clonidine showed neither of these changes. CONCLUSIONS: These results suggest that reduction in central serotonin leads to altered neuromodulation of the cortical and subcortical regions (e.g. orbitofrontal cortex, striatum and anterior temporal structures) that mediate important aspects of associative learning whereby exteroceptive stimuli acquire altered incentive motivational value. On the other hand, facilitation of catecholamine neurotransmitters may disrupt the allocation of attention between relevant and irrelevant features of the environment, perhaps through altered modulation of the dorsolateral prefrontal cortex. The implications of these results for understanding the differential neuromodulation of cognitive functions are discussed.

Adolescent↗
PubMed1999

Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: evidence for monoaminergic mechanisms.

We used a novel computerized decision-making task to compare the decision-making behavior of chronic amphetamine abusers, chronic opiate abusers, and patients with focal lesions of orbital prefrontal cortex (PFC) or dorsolateral/medial PFC. We also assessed the effects of reducing central 5-hydroxytryptamine (5-HT) activity using a tryptophan-depleting amino acid drink in normal volunteers. Chronic amphetamine abusers showed suboptimal decisions (correlated with years of abuse), and deliberated for significantly longer before making their choices. The opiate abusers exhibited only the second of these behavioral changes. Importantly, both sub-optimal choices and increased deliberation times were evident in the patients with damage to orbitofrontal PFC but not other sectors of PFC. Qualitatively, the performance of the subjects with lowered plasma tryptophan was similar to that associated with amphetamine abuse, consistent with recent reports of depleted 5-HT in the orbital regions of PFC of methamphetamine abusers. Overall, these data suggest that chronic amphetamine abusers show similar decision-making deficits to those seen after focal damage to orbitofrontal PFC. These deficits may reflect altered neuromodulation of the orbitofrontal PFC and interconnected limbic-striatal systems by both the ascending 5-HT and mesocortical dopamine (DA) projections.

Adult↗
PubMed1999

Comparison of buspirone with diazepam and fluvoxamine on aversive classical conditioning in humans.

The effects of buspirone, fluvoxamine and diazepam were investigated, using healthy volunteers, in an aversive conditioning paradigm, a putative model for conditioned anxiety. The main prediction was that buspirone, an anxiolytic agent which reduces activity in serotonin (5-hydroxytryptophan, 5-HT) neurones, would attenuate aversively conditioned skin conductance responses. Skin conductance responses were recorded to 10 neutral tones (habituation phase). Tone 11 was immediately followed by a 1-s 90-dB aversive white noise (unconditioned stimulus). The conditioning trial reinstated responding to a second presentation of the tones (extinction phase). Skin conductance response amplitude, inter-response level and spontaneous fluctuations were recorded. There were five treatment groups comprising five men and five women. One control group took placebo, another control group received nothing; there was no effect of placebo on any measure. Diazepam (2 mg, p.o.), a positive comparator, markedly reduced the amplitude of skin conductance responses at all phases of the experiment, but only in women. Buspirone (5 mg, p.o.) had the predicted effect of accelerating extinction but also of unexpectedly accelerated habituation of skin conductance responses. There was a trend to reduce spontaneous fluctuations and no effect on skin conductance level. The effects of buspirone were thus specific to responses to stimuli. Fluvoxamine (25 mg, p.o.) had similar effects to buspirone and diazepam in women. An action common to buspirone, fluvoxamine and diazepam, which may account for their shared effect on conditioned autonomic responses, is the suppression of neural activity in the dorsal raphe nucleus. It is argued that enhanced habituation must involve a different mechanism, such as enhanced 5-HT1A function in the terminal fields of the median raphe nucleus.

Acoustic Stimulation↗
PubMed1998

Comparison of glutamate and gamma-aminobutyric acid uptake binding sites in frontal and temporal lobes in schizophrenia.

BACKGROUND: Theories of schizophrenia proposing deficiencies of amino acid [glutamate, gamma-aminobutyric acid (GABA)] neurons are in accord with the observed temporal lobe pathology of the disease rather than with the newer theory of glutamate hyperinnervation and hyperfunction in areas of prefrontal cortex. This study addresses the issue by measuring specific uptake sites as indices of glutamatergic and GABAergic neuron densities in frontal and temporal lobes. METHODS: Frontal cortex (six areas) and temporal lobe (six areas of cortex, amygdala, and hippocampus) were dissected from 19 control autopsy brains and 12 brains from neuroleptic drug-treated schizophrenic patients. Groups had similar ages, postmortem intervals, and storage times. Membranes, prepared from tissue homogenates, were incubated with D-[3H]aspartate to measure neuronal and glial glutamate uptake site binding in 14 areas and with [3H]nipecotic acid to measure neuronal GABA uptake site binding in 11 areas. RESULTS: Glutamate and GABA uptake sites were not reduced in prefrontal and temporal areas. Instead, we found small increases in glutamate uptake sites in prefrontal areas. Some tendency toward increased GABA uptake sites were not disease-related. CONCLUSIONS: Our findings concur with other studies that propose locally overabundant glutamate systems in prefrontal cortex in schizophrenia. Losses of amino acid neurons do not accompany the temporal lobe pathology.

Aged↗
PubMed1998

Absence of basal ganglia amino acid neuron deficits in schizophrenia in three collections of brains.

Amino acid (glutamatergic, GABAergic) neuron deficiency theories of schizophrenia offer plausible explanations of pathogenesis. However, reports of disease-related reductions in amino acid synthesizing enzymes in post-mortem brains are contradictory. We measured neuronal uptake sites for gamma-aminobutyric acid (GABA; [3H]nipecotic acid binding) and nerve terminal/glial uptake sites for L-glutamate (D-[3H aspartate binding) in three independent groups of post-mortem brains from patients with schizophrenia and control subjects. Measurements were also made of the phencyclidine site of the glutamate N-methyl-D-aspartate (NMDA) receptor. Samples from patients showed no reductions in the binding of [3H]nipecotic acid or D-[3H]aspartate in caudate, putamen or globus pallidus. On the contrary, some increased binding of both ligands was observed in patients in many comparisons with controls. There were no clear-cut changes in NMDA receptor binding. The most consistent change in the brain sets was increased [3H]nipecotic acid binding in caudate-putamen. This could be due to neuroleptic treatment. The findings produce no evidence that schizophrenia involves major loss of GABA neuron terminals in the basal ganglia or losses of corticostriatal glutamatergic projections.

ATP-Binding Cassette Transporters↗
PubMed1998

Abnormal persistence of cerebellar serotonin-1A receptors in schizophrenia suggests failure to regress in neonates.

This study investigated the neurodevelopmental basis of schizophrenia by examining an early transient population of serotonin-1A (5-HT1A) receptors using quantitative [3H]8-OH-DPAT autoradiography on sections of frozen postmortem cerebellum. Production of an ontogenetic map showed that human neonatal cerebellum acquired dense 5-HT1A receptors, most of which were eliminated by early childhood. Autoradiographic measurements on cerebellar vermis from 16 control adult subjects confirmed sparse 5-HT1A receptor binding. The data show a persistence of some vermal 5-HT1A receptors in brains from 19 adults with chronic schizophrenia in whom there may have been a slowed or arrested postnatal regression of vermal 5-HT1A receptors. Alternatively, some 5-HT1A receptors may have been re-expressed prior to, or subsequent to, the onset of the disease symptoms. The findings are not obviously explained by drug treatment and there are no data to explain how neuroleptics might promote expression of cerebellar 5-HT1A receptors. We propose that the study has identified a neurotransmitter receptor population which, in schizophrenia, undergoes misdirected reshaping during brain development. The findings support neurodevelopmental hypotheses of the disease.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

The role of serotonin in panic, anxiety and depression.

Anxiety and depressive disorders occur across a broad spectrum, and each different disorder may involve distinct genetic and neurobiologica/neurochemical mechanisms. Many classes of drug are available for the treatment of these disorders and, as might be expected, these drugs exhibit a variety of biochemical actions. Paradoxically, the single-action selective serotonin reuptake inhibitors are effective in a range of these disorders. However, the paradox may be resolved by an understanding of the distinct ways in which serotonin modifies the physiological coping mechanisms that become dysfunctional in these disorders.

Adaptation, Psychological↗
PubMed1997

Ritanserin facilitates anxiety in a simulated public-speaking paradigm.

The effects of ritanserin, a 5-HT2A/2C (5-hydroxytryptamine) antagonist, have been investigated in simulated public speaking with healthy volunteers. The aim was to investigate the role of 5-HT in subjective experimental anxiety. There were three experimental groups each comprising four or five males and 11 females. Subjects received placebo, ritanserin 2.5 or 10 mg, p.o. They rated themselves using the Spielberger State-Trait Anxiety Inventory and visual analogue scales factored into anxiety, sedation and discontentment scores. Autonomic measures included skin conductance and heart rate. Subjects were told, 75 min after drug or placebo ingestion, without prior warning, to prepare a 4-min speech. Measures were taken before, during and after the speech. Ritanserin prolonged the anxiety induced by the procedure on the subjective ratings but had minimal effect on autonomic responses to the procedure. The result contrasts with an anxiolytic-like effect of ritanserin on aversively conditioned autonomic responses. The present finding is compatible with animal behavioural evidence that 5-HT has distinct and opposing roles in modulating conditioned and unconditioned anxiety.

Adolescent↗
PubMed1996

Autoradiography with [3H]8-OH-DPAT reveals increases in 5-HT(1A) receptors in ventral prefrontal cortex in schizophrenia.

We previously reported increased glutamatergic innervation in orbital frontal cortex in schizophrenia. In view of the evidence that one serotonin (5-HT) receptor, the 5-HT(1A) subtype, is associated with cortical glutamatergic neurons, we have used quantitative receptor autoradiography to measure the specific binding of the 5-HT(1A) receptor ligand [3H]8-OH-DPAT (2 nM) in sections of orbital frontal cortex taken from 18 control and 12 schizophrenic postmortem brains. Schizophrenic patients, as compared with controls, had increased 5-HT(1A) receptor binding in the three orbital frontal regions examined. These effects were pronounced in the male subgroup, and were most apparent in the outer cortical laminae. These data are consistent with the hypothesis that schizophrenia is associated with an abnormal glutamatergic afferent innervation of orbital frontal cortex.

8-Hydroxy-2-(di-n-propylamino)tetralin↗