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At least 1,423 records · Page 79Linked to original sources
PubMed1998

Dopamine receptors and dopamine transporter in brain function and addictive behaviors: insights from targeted mouse mutants.

Recent advances in molecular biology have resulted in a number of genetically manipulated mice with defined changes at dopamine receptor and the dopamine transporter (DAT) loci. Mice with targeted mutations at the D1 receptor (D1R) are growth-retarded and show downregulated expression of dynorphin and substance P. Behavioral assessment indicates that mutants have deficiencies in spatial learning and initiating movement, as well as in responding to novel stimuli. D1R mutants do not become locomotor activated with cocaine or show upregulated immediate early gene (IEG) expression, but D2 receptor-dependent IEG changes are intact. Acute cocaine administration increases substance P levels, suggesting that striatal expression of this neuropeptide can be modulated by D1R-independent processes. Failure of locomotor activation is also seen with repeated amphetamine treatment. Surprisingly, D1R-deficient mice retain cocaine-conditioned place preference. In contrast, D2 receptor knockout mice are bradykinetic, show increased striatal enkephalin expression and an absence of opiate rewarding effects. D3 receptor mutants are hyperactive when assessed in an exploratory assay and display reduced anxiety-associated behavior in an elevated plus maze test. The recently described D4 receptor homozygous mutants exhibit a reduction in baseline locomotor activity and were shown to be supersensitive to the locomotor activating effects of alcohol and psychostimulant drugs. As expected, DAT knockout mice are hyperactive and do not respond to cocaine or amphetamine. The observation that D2 and D4 dopamine receptor and DAT mutants show compensatory effects, together with the complicating issue of their hybrid genetic background may temper conclusions regarding the direct effects of the targeted mutation on phenotype.

Animals↗
PubMed1998

Glutamate receptors: brain function and signal transduction.

Glutamate receptors are important in neural plasticity, neural development and neurodegeneration. N-methyl-d-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors act as glutamate-gated cation channels, whereas metabotropic receptors (mGluRs) modulate the production of second messengers via G proteins. Molecular studies from our and other laboratories indicated that NMDA receptors and mGluRs exist as multiple subunits (NMDAR1 and NMDAR2A-2D) and multiple subtypes (mGluR1-mGluR8). In light of the molecular diversity of glutamate receptors, we explored the function and intracellular signaling mechanisms of different members of glutamate receptors. In the visual system, retinal bipolar cells receive glutamate transmission from photoreceptors and contribute to segregating visual signals into ON and OFF pathways. The molecularly cloned mGluR6 is restrictedly expressed at the postsynaptic site of ON-bipolar cells in both rod and cone systems. Gene targeting of mGluR6 results in a loss of ON responses without changing OFF responses and severely impairs detecting visual contrasts. Since AMPA receptors mediate OFF responses in OFF-bipolar cells, two distinct types of glutamate receptors effectively operate for ON and OFF responses. mGluR1 and mGluR5 are both coupled to inositol triphosphate (IP3)/calcium signal transduction with an identical agonist selectivity. Single-cell intracellular calcium ([Ca2+]i) recordings indicated that glutamate evokes a non-oscillatory and oscillatory [Ca2+]i response in mGluR1-expressing and mGluR5-expressing cells, respectively. This difference results from a single amino acid substitution, aspartate of mGluR1 or threonine of mGluR5, at the G protein-interacting carboxy-terminal domains. Protein kinase C phosphorylation of the threonine of mGluR5 is responsible for inducing [Ca2+]i oscillations in mGluR5-expressing cells and cultured glial cells. Thus, the two closely related mGluR subtypes mediate diverging intracellular signaling in glutamate transmission.

Animals↗
PubMed1996

Dopamine receptors and brain function.

In the central nervous system (CNS), dopamine is involved in the control of locomotion, cognition, affect and neuroendocrine secretion. These actions of dopamine are mediated by five different receptor subtypes, which are members of the large G-protein coupled receptor superfamily. The dopamine receptor subtypes are divided into two major subclasses: the D1-like and D2-like receptors, which typically couple to Gs and Gj mediated transduction systems. In the CNS, the various receptor subtypes display specific anatomical distributions, with D1-like receptors being mainly post-synaptic and D2-like receptors being both pre- and post-synaptic. D1 and D2 dopamine receptors, the most abundant subtypes in the CNS, appear to be expressed largely in distinct neurons. Substance P and dynorphin, which are expressed in D1 receptor-containing neurons, as well as pre-proenkephalin in D2 receptor-containing neurons, have been used as monitors of dopaminergic activity in the CNS. Expression of immediate early genes, in particular fos, has also been found to correlate with dopaminergic transmission. Dopamine released from the hypothalamus controls the synthesis and secretion of prolactin from the anterior pituitary via D2 dopamine receptors. As yet none of the dopamine receptor subtypes have been associated with the etiology of psychotic disorders, such as schizophrenia. However, the recent characterization of D3 and D4 receptors which are, interestingly, expressed in areas of the CNS mediating cognition and affect or showing increased affinity for certain neuroleptics, have renewed the interest and hope of finding effective neuroleptics devoid of side effects. Finally, the recent production of genetically-derived animals lacking several of these receptor genes should help elucidate which specific physiological paradigms the receptors mediate.

Animals↗
PubMed2001

Acute effect of 3-(4-acetamido)-butyrril-lorazepam (DDS2700) on brain function assessed by PET at rest and during attentive tasks.

The aim of this study was to assess, by positron emission tomography (PET), the effect on cerebral functional activity of a new lorazepam-gamma-aminobutyric acid (GABA) conjugate [3-(4-acetamido)-butyrril lorazepam (DDS2700)]. Ten healthy volunteers were studied by PET and [18F]fluoro-deoxy-D-glucose ([18F]FDG) under baseline conditions and following the administration of DDS2700. Regional cerebral blood flow (rCBF) was measured by PET and 15O-water in three additional participants while they performed attentive tasks, before and after drug administration. DDS2700 induced a decrease in the regional cerebral metabolic rate of glucose (rCMRglu) in the thalamus (-17%), cerebellum (-11%) and caudate nucleus (-8%). The observed effects on glucose metabolism were probably related to the subjective sedation and tiredness reported by the participants. During the attentive tasks, rCBF increased in frontal and temporal regions associated with attentional processing of auditory material. These circuits were no longer active after DDS2700 administration, while rCBF increased in cingulate cortex, occipitoparietal regions, pons and cerebellum. These drug-induced activations might be directly related to intervening sleepiness and to the consequent effort in keeping attention focused on the tasks. The effects of DDS2700 on glucose metabolism at rest, and on rCBF during activation conditions, indicate a drug action on cerebral networks involved in alertness, vigilance and attention maintenance. PET assessment by [18F]FDG and water may provide complementary information in pharmacodynamic studies.

Adult↗
PubMed1984

Brain function in psychiatric disorders. II. Regional cerebral blood flow in medicated unipolar depressives.

Regional cerebral blood flow was measured during resting baseline and the performance of a verbal and a spatial task in 14 medicated depressives and 25 matched controls. Overall resting flows did not differ, nor were there hemispheric or anteroposterior differences between patients and controls for resting flows. Differences between patients and controls were evident during cognitive activity, and the effects were different for male and female patients. Depressed female patients had higher than normal flows in all conditions, whereas depressed male patients had lower than normal resting flows, which increased to normal during cognitive activity. Their anterior flows increased for the verbal task but not for the spatial task.

Adult↗
PubMed1985

Brain function in psychiatric disorders. III. Regional cerebral blood flow in unmedicated schizophrenics.

Regional cerebral blood flow (rCBF) was measured during resting baseline and the performance of a verbal and a spatial task in 19 unmedicated schizophrenics and 19 matched controls. Abnormalities in rCBF were evident in schizophrenics both for resting and activated measures. Resting flows were higher in the left hemisphere for schizophrenics, supporting the hypothesis of left hemispheric overactivation. This effect was stronger in the more severely disturbed patients. The pattern of rCBF changes during activation with the verbal and spatial tasks was also different in schizophrenics. Laterality of flow changes further supported the hypothesis of left hemispheric overactivation. Furthermore, whereas normals had greater increase in flow for the spatial than the verbal task, schizophrenics showed the reverse pattern. This effect also was more pronounced in the severely disturbed patients. Comparison with an earlier sample of medicated schizophrenics suggested that neuroleptics restore symmetry of resting flows before they produce symptomatic relief. Medication did not affect the abnormalities in pattern of rCBF changes during activation with cognitive tasks.

Adolescent↗
PubMed1998

Functional brain electrical activity mapping in boys with attention-deficit/hyperactivity disorder.

BACKGROUND: Symptoms of attention-deficit/hyperactivity disorder (ADHD) have been associated with frontal lobe deficits. We used a novel brain electrical imaging method to investigate rapid and continuous changes in brain activity during the continuous performance task (CPT) in normal boys and in boys with ADHD. The amplitude and latency topography of the steady-state visually evoked potential (SSVEP) were examined while subjects performed the "X" version of the CPT (CPT-X; the reference task) and the "A-X" version of the CPT (CPT-AX). METHODS: Seventeen boys meeting DSM-III-R criteria for ADHD and 17 age-matched controls participated in the study. Brain electrical activity was recorded from 64 scalp sites. During the reference task, subjects pressed a microswitch on the unpredictable appearance of the letter X. During the CPT-AX, subjects were required to press the microswitch on the appearance of the letter X only if an A had preceded it. RESULTS: In the interval between the appearances of the A and the X of the correct trials of the CPT-AX, control boys showed transient reductions in SSVEP latency at right prefrontal sites. By contrast, boys with ADHD showed no change or an increase in prefrontal SSVEP latency at right prefrontal sites. CONCLUSION: Our results suggest increased speed of prefrontal neural processing in children without ADHD following a priming stimulus, and a deficit in such processes in children with ADHD.

Adolescent↗
PubMed1999

Assessment of trigeminal small-fiber function: brain and reflex responses evoked by CO2-laser stimulation.

Laser pulses selectively excite mechano-thermal nociceptors and evoke brain potentials that may reveal small-fiber dysfunction. We applied CO2-laser pulses to the perioral and supraorbital regions and recorded the scalp laser-evoked potentials (LEPs) and reflex responses in the orbicularis oculi, masticatory, and neck muscles in 30 controls and 10 patients with facial sensory disturbances. Low-intensity pulses readily evoked scalp potentials consisting of a negative component with a latency of 165 ms followed by a positive component at 250 ms. In vertex recordings, the amplitude of LEPs exceeded 30 microV. Although only high-intensity pulses evoked reflex responses, some subjects showed--even to low-intensity pulses--an orbicularis oculi (blink-like) response that markedly contaminated the scalp recording. Scalp LEPs were abnormal in patients with hypalgesia and normal trigeminal reflexes and normal in patients with normal pain sensitivity and abnormal trigeminal reflexes. Possibly because of the high receptor density in this area and the short conduction distance, laser stimulation of the trigeminal territory yields low-threshold and large LEPs, which are useful for detecting dysfunction in peripheral and central pain pathways.

Adult↗
PubMed1996

Antisocial personality disorder, childhood delinquency, and frontal brain functioning: EEG and neuropsychological findings.

This experiment examined the ability of EEG activity and neuropsychological testing to predict both antisocial personality disorder (ASP) and retrospective self-ratings of early childhood problem behaviors (CPB). Regression analyses found that increased frontal left-hemisphere EEG activation was associated with a decreased likelihood of the diagnosis of ASP or CPB. An association was also found between several motor tests of the Luria-Nebraska and Porteus Maze Test scores and CPB/ASP. The current findings suggest that ASP and CPB are associated with variations in frontal lobe functioning. They further suggest that disturbances in prefrontal functioning may be a common biological ground that links ASP, substance abuse, and biological mechanisms of reinforcement.

Adult↗
PubMed1990

Localization of epileptic foci using a large-area magnetometer and functional brain anatomy.

We used a large-area, 7-channel, first-order superconducting quantum interference device (SQUID) gradiometer to preoperatively determine the sites of epileptic foci in 2 patients with intractable temporal lobe seizures. The equivalent dipoles for the epileptic spikes were located with respect to external landmarks of the skull and in relation to the generation sites of magnetic auditory evoked responses. It was also possible, for the first time, to determine the location of the equivalent source using simultaneously measured data from seven locations only. The sites of the equivalent dipoles, in the right temporal lobe, agreed with the electrocorticographic and depth electrode recordings made during the operation.

Adult↗
PubMed1995

On functional brain asymmetries in perceptual priming.

Brain asymmetries in implicit memory were studied using a perceptual identification priming paradigm. At the study phase, Subjects rated either the readability or the likeability of words. At the test phase, perceptual priming for these words was measured by presenting stimuli briefly either in the left or in the right visual hemifield. The typeface of the words was varied between the study and test. The orientation task manipulation at the study phase did not influence priming, although it had a powerful effect on a test of explicit memory. Priming effects were form-specific: words which were studied in the same typeface as they were tested were primed more strongly than words which were studied in a different typeface. No hemispheric asymmetries were observed in form-specific priming, but in general, priming was greater in the right hemifield/left hemisphere. These findings suggest that the hemispheres are equally effective in analysing and storing form-specific information at the early stages of word recognition process. Asymmetries favoring the left hemisphere may develop at a higher, more abstract level of presemantic visual word form processing.

Adult↗
PubMed2001

Functional brain mapping of monkey tool use.

When using a tool, we can perceive a psychological association between the tool and the body parts-the tool is incorporated into our "body-image." During tool use, visual response properties of bimodal (tactile and visual) neurons in the intraparietal area of the monkey's cerebral cortex were modified to include the hand-held tool. Visual properties of the monkey intraparietal neurons may represent the body-image in the brain. We explored tool use-induced activation within the intraparietal area and elsewhere in alert monkey brain using positron emission tomography (PET). Tool use-related activities compared with the control condition (simple-stick manipulation) revealed a significant increase in cerebral blood flow in the corresponding intraparietal region, basal ganglia, presupplementary motor area, premotor cortex, and cerebellum. These tool use-specific areas may participate in maintaining and updating the body-image for the precise guidance of a hand-held rake onto a distant reward.

Animals↗