Comparison of effects of haloperidol administration on amphetamine-stimulated dopamine release in the rat medial prefrontal cortex and dorsal striatum.
Research has shown that there are important neurochemical differences between the mesocortical and mesostriatal dopamine systems. The work reported in this paper has sought to compare the regulation of dopamine release in the medial prefrontal cortex and the anterior caudate-putamen. In vivo microdialysis was used to recover dialysate fluid for subsequent assay for dopamine concentrations. The responses to D2 antagonist (haloperidol) administration, which has been shown to increase impulse-dependent dopamine release, were compared. Results demonstrated a diminished effect of systemic haloperidol administration on dopamine efflux in the prefrontal cortex. The responses to systemic administration of a nonimpulse-dependent, transporter-mediated, dopamine releaser (d-amphetamine) were also contrasted. Results again demonstrated a diminished pharmacological effect in the cortex. The potential interaction of stimulation of these two types of dopamine release was examined by coadministration of these compounds. Haloperidol pretreatment dramatically potentiated the dopamine-releasing effect of amphetamine administration. This effect was observed in both the cortex and the striatum. Subsequent work demonstrated that this effect of haloperidol was mediated by D2-like receptors in the prefrontal cortex. These results are discussed in relation to other neurochemical and neuroanatomical studies demonstrating sparse densities of dopamine transporter sites and dopamine D2 receptors in the cortex compared with the striatum. They demonstrate a functional correlate to the recently reported, largely extrasynaptic localization of dopamine transporter sites in the prefrontal cortex. Furthermore, they demonstrate the existence of cortical D2-like autoreceptors that may normally be "silent" under basal conditions. (+info)
Lateralized effects of medial prefrontal cortex lesions on neuroendocrine and autonomic stress responses in rats.
The medial prefrontal cortex (mPFC) is highly activated by stress and modulates neuroendocrine and autonomic function. Dopaminergic inputs to mPFC facilitate coping ability and demonstrate considerable hemispheric functional lateralization. The present study investigated the potentially lateralized regulation of stress responses at the level of mPFC output neurons, using ibotenic acid lesions. Neuroendocrine function was assessed by plasma corticosterone increases in response to acute or repeated 20 min restraint stress. The primary index of autonomic activation was gastric ulcer development during a separate cold restraint stress. Restraint-induced defecation was also monitored. Plasma corticosterone levels were markedly lower in response to repeated versus acute restraint stress. In acutely restrained animals, right or bilateral, but not left mPFC lesions, decreased prestress corticosterone levels, whereas in repeatedly restrained rats, the same lesions significantly reduced the peak stress-induced corticosterone response. Stress ulcer development (after a single cold restraint stress) was greatly reduced by either right or bilateral mPFC lesions but was unaffected by left lesions. Restraint-induced defecation was elevated in animals with left mPFC lesions. Finally, a left-biased asymmetry in adrenal gland weights was observed across animals, which was unaffected by mPFC lesions. The results suggest that mPFC output neurons demonstrate an intrinsic right brain specialization in both neuroendocrine and autonomic activation. Such findings may be particularly relevant to clinical depression which is associated with both disturbances in stress regulatory systems and hemispheric imbalances in prefrontal function. (+info)
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. (+info)
A PET study of sequential finger movements of varying length in patients with Parkinson's disease.
To study the difficulty that patients with Parkinson's disease have in performing long sequential movements, we used H2(15)O PET to assess the regional cerebral blood flow (rCBF) associated with the performance of simple repetitive movements, well-learned sequential finger movements of varying length and self-selected movements. Sequential finger movements in the Parkinson's disease patients were associated with an activation pattern similar to that found in normal subjects, but Parkinson's disease patients showed relative overactivity in the precuneus, premotor and parietal cortices. Increasing the complexity of movements resulted in increased rCBF in the premotor and parietal cortices of normal subjects; the Parkinson's disease patients showed greater increases in these same regions and had additional significant increases in the anterior supplementary motor area (SMA)/cingulate. Performance of self-selected movements induced significant activation of the anterior SMA/cingulate in normal subjects but not in Parkinson's disease patients. We conclude that in Parkinson's disease patients more cortical areas are recruited to perform sequential finger movements; this may be the result of increasing corticocortical activity to compensate for striatal dysfunction. (+info)
Electrophysiological examination of the effects of sustained flibanserin administration on serotonin receptors in rat brain.
5-HT1A receptor agonists have proven to be effective antidepressant medications, however they suffer from a significant therapeutic lag before depressive symptoms abate. Flibanserin is a 5-HT1A receptor agonist and 5-HT2A receptor antagonist developed to possibly induce a more rapid onset of antidepressant action through its preferential postsynaptic 5-HT1A receptor agonism. Flibanserin antagonized the effect of microiontophoretically-applied DOI in the medial prefrontal cortex (mPFC) following 2 days of administration, indicating antagonism of postsynaptic 5-HT2A receptors. This reduction in the effect of locally-applied DOI was no longer present following 7-day flibanserin administration. Two-day flibanserin administration only marginally reduced the firing activity of dorsal raphe (DRN) 5-HT neurons. Following 7 days of administration, 5-HT neuronal firing activity had returned to normal and the somatodendritic 5-HT1A autoreceptors were desensitized. The responsiveness of postsynaptic 5-HT1A receptors located on CA3 hippocampus pyramidal neurons and mPFC neurons, examined using microiontophoretically-applied 5-HT and gepirone, was unchanged following a 7-day flibanserin treatment. As demonstrated by the ability of the 5-HT1A receptor antagonist WAY 100635 to selectively increase the firing of hippocampal neurons in 2- and 7-day treated rats, flibanserin enhanced the tonic activation of postsynaptic 5-HT1A receptors in this brain region. The results suggest that flibanserin could be a therapeutically useful compound putatively endowed with a more rapid onset of antidepressant action. (+info)
Clozapine preferentially increases dopamine release in the rhesus monkey prefrontal cortex compared with the caudate nucleus.
Despite substantial differences between species in the organization and elaboration of the cortical dopamine innervation, little is known about the pharmacological response of cortical or striatal sites to antipsychotic medications in nonhuman primates. To examine this issue, rhesus monkeys were chronically implanted with guide cannulae directed at the principal sulcus, medial prefrontal cortex, premotor cortex, and caudate nucleus. Alterations in dopamine release in these discrete brain regions were measured in response to administration of clozapine or haloperidol. Clozapine produced significant and long-lasting increases in dopamine release in the principal sulcus, and to a lesser extent, in the caudate nucleus. Haloperidol did not produce a consistent effect on dopamine release in the principal sulcus, although it increased dopamine release in the caudate. Clozapine's preferential augmentation of dopamine release in the dorsolateral prefrontal cortex supports the idea that clozapine exerts its therapeutic effects in part by increasing cortical dopamine neurotransmission. (+info)
Isodirectional tuning of adjacent interneurons and pyramidal cells during working memory: evidence for microcolumnar organization in PFC.
Studies on the cellular mechanisms of working memory demonstrated that neurons in dorsolateral prefrontal cortex (dPFC) exhibit directionally tuned activity during an oculomotor delayed response. To determine the particular contributions of pyramidal cells and interneurons to spatial tuning in dPFC, we examined both individually and in pairs the tuning properties of regular-spiking (RS) and fast-spiking (FS) units that represent putative pyramidal cells and interneurons, respectively. Our main finding is that FS units possess spatially tuned sensory, motor, and delay activity (i. e., "memory fields") similar to those found in RS units. Furthermore, when recorded simultaneously at the same site, the majority of neighboring neurons, whether FS or RS, displayed isodirectional tuning, i.e., they shared very similar tuning angles for the sensory and delay phases of the task. As the trial entered the response phase of the task, many FS units shifted their direction of tuning and became cross-directional to adjacent RS units by the end of the trial. These results establish that a large part of inhibition in prefrontal cortex is spatially oriented rather than being untuned and simply regulating the threshold response of pyramidal cell output. Moreover, the isodirectional tuning between adjacent neurons supports a functional microcolumnar organization in dPFC for spatial memory fields similar to that found in other areas of cortex for sensory receptive fields. (+info)
Impairment of EEG desynchronisation before and during movement and its relation to bradykinesia in Parkinson's disease.
OBJECTIVE: It has been suggested that the basal ganglia act to release cortical elements from idling (alpha) rhythms so that they may become coherent in the gamma range, thereby binding together those distributed activities necessary for the effective selection and execution of a motor act. This hypothesis was tested in 10 patients with idiopathic Parkinson's disease. METHODS: Surface EEG was recorded during self paced squeezing of the hand and elbow flexion performed separately, simultaneously, or sequentially. Recordings were made after overnight withdrawal of medication and, again, 1 hour after levodopa. The medication related improvement in EEG desynchronisation (in the 7.5-12.5 Hz band) over the 1 second before movement and during movement were separately correlated with the improvement in movement time for each electrode site. Correlation coefficients (r) > 0.632 were considered significant (p<0.05). RESULTS: Improvement in premovement desynchronisation correlated with reduction in bradykinesia over the contralateral sensorimotor cortex and supplementary motor area in flexion and squeeze, respectively. However, when both movements were combined either simultaneously or sequentially, this correlation shifted anteriorly, to areas overlying prefrontal cortex. Improvement in EEG desynchronisation during movement only correlated with reduction in bradykinesia in two tasks. Correlation was seen over the supplementary motor area during flexion, and central prefrontal and ipsilateral premotor areas during simultaneous flex and squeeze. CONCLUSIONS: The results are consistent with the idea that the basal ganglia liberate frontal cortex from idling rhythms, and that this effect is focused and specific in so far as it changes with the demands of the task. In particular, the effective selection and execution of more complex tasks is associated with changes over the prefrontal cortex. (+info)