Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders

Hippocampal output is increased in affective disorders and is mediated by increased glutamatergic input via N-methyl-D-aspartate (NMDA) receptor and moderated by antidepressant treatment. Activation of NMDA receptors by glutamate evokes the release of nitric oxide (NO) by the activation of neuronal nitric oxide synthase (nNOS). The human hippocampus contains a high density of NMDA receptors and nNOS-expressing neurons suggesting the existence of an NMDA-NO transduction pathway which can be involved in the pathogenesis of affective disorders. We tested the hypothesis that nNOS expression is increased in the human hippocampus from affectively ill patients. Immunocytochemistry was used to demonstrate nNOS-expressing neurons in sections obtained from the Stanley Consortium postmortem brain collection from patients with major depression (MD, N = 15), bipolar disorder (BD, N = 15), and schizophrenia (N = 15) and from controls (N = 15). nNOS-immunoreactive (nNOS-IR) and Nissl-stained neurons were counted in entorhinal cortex, hippocampal CA1, CA2, CA3, and CA4 subfields, and subiculum. The numbers of Nissl-stained neurons were very similar in different diagnostic groups and correlated significantly with the number of nNOS-IR neurons. Both the MD and the BD groups had greater number of nNOS-IR neurons/400 µm² in CA1 (mean ± SEM: MD = 9.2 ± 0.6 and BD = 8.4 ± 0.6) and subiculum (BD = 6.7 ± 0.4) when compared to control group (6.6 ± 0.5) and this was significantly more marked in samples from the right hemisphere. These changes were specific to affective disorders since no changes were seen in the schizophrenic group (6.7 ± 0.8). The results support the current view of the NMDA-NO pathway as a target for the pathophysiology of affective disorders and antidepressant drug development.Stanley FoundationCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES

Effect of escitalopram on the processing of emotional faces

Serotonin has been implicated in the neurobiology of depressive and anxiety disorders, but little is known about its role in the modulation of basic emotional processing. The aim of this study was to determine the effect of the selective serotonin reuptake inhibitor, escitalopram, on the perception of facial emotional expressions. Twelve healthy male volunteers completed two experimental sessions each, in a randomized, balanced order, double-blind design. A single oral dose of escitalopram (10 mg) or placebo was administered 3 h before the task. Participants were presented to a task composed of six basic emotions (anger, disgust, fear, happiness, sadness, and surprise) that were morphed between neutral and each standard emotion in 10% steps. Escitalopram facilitated the recognition of sadness and inhibited the recognition of happiness in male, but not female faces. No drug effect on subjective measures was detected. These results confirm that serotonin modulates the recognition of emotional faces, and suggest that the gender of the face can have a role in this modulation. Further studies including female volunteers are needed

Involvement of the periaqueductal grey matter and spinal 5-hydroxytryptaminergic pathways in morphine analgesia: Effects of lesions and 5-hydroxytryptamine depletion

1 Electrolytic lesions of the periaqueductal grey matter (PAG) were made in rats. The analgesia produced by intraperitoneal injection of morphine (10 and 20 mg/kg), tested by the tail flick and hot plate methods, was substantially reduced in the lesioned rats. Baseline pain thresholds were unaffected by the lesions. 2 The lesion effects were not due to damage to the dorsal raphé nucleus. The extent of histologically determined damage to the dorsal raphé and the resulting decrease in striatal 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations did not correlate with the reduction in morphine analgesia produced by the lesion. Furthermore, microinjections of 5, 6-dihydroxytryptamine (5,6-DHT) into the dorsal raphé nucleus produced a similar fall in 5-HIAA levels but had no effect on morphine analgesia. 3 Selective destruction of the periventricular catecholamine system produced by microinjection of 6-hydroxydopamine (6-OHDA) caused a slight decrease in morphine analgesia, thus raising the possibility that catecholamines may be involved in the action of morphine in the PAG. 4 5,7-Dihydroxytryptamine-induced lesions of the spinal cord 5-hydroxytryptaminergic pathways reduced cord 5-HT concentration by 70% and markedly attenuated morphine analgesia as determined by the tail flick test. 5 These experiments provide additional evidence that the PAG is a major site of action of opiates in producing analgesia. Furthermore, they have demonstrated the probable involvement of spinal 5-hydroxytryptaminergic pathways in the mediation of opiate analgesic effects

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×drug picture location×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

The neural basis of maternal responsiveness to infants: an fMRI study

Using fMRI, we examined the neural correlates of maternal responsiveness. Ten healthy mothers viewed alternating blocks of video: (i) 40 s of their own infant; (ii) 20 s of a neutral video; (iii) 40 s of an unknown infant and (iv) 20 s of neutral video, repeated 4 times. Predominant BOLD signal change to the contrast of infants minus neutral stimulus occurred in bilateral visual processing regions BA minus neutral stimulus occurred in bilateral visual processing regions (BA 38), left amygdala and visual cortex (BA 19), and to the unknown infant minus own infant contrast in bilateral orbitofrontal cortex (BA 10,47) and medial prefrontal cortex (BA 8). These findings suggest that amygdala and temporal pole may be key sites in mediating a mother's response to her infant and reaffirms their importance in face emotion processing and social behaviour