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PubMed1999

Cell migration from the ganglionic eminence to the neocortex investigated by labeling nuclei with UV irradiation via a fiber-optic cable.

Recent studies have shown that the ganglionic eminence is one of the sources of tangentially migrating cells in the developing neocortex. Since the migration of the DiI-labeled cells from the ganglionic eminence to the neocortex was not monitored by videomicroscopy in these reports, we devised a novel method to study cell migration in vitro and in vivo. The new method involves ultraviolet (UV) irradiation of the cells through a fiber-optic cable and subsequent identification of the irradiated cells on the basis of the formation of thymine dimers in the nuclei. First, we tested the new method (UV-thymine dimer-labeling method) by applying it to monitor the cell migration of neuronal precursor cells in the rostral migratory stream in the neonatal rat telencephalon. In vitro, UV irradiation for 1 s through the fiber-optic cable resulted in the formation of sufficient thymine dimers as to allow immunohistochemical detection after 6 h of incubation; a significant proportion of the irradiated cells continued to migrate in the same direction and at the same speed as those before irradiation. There was no significant difference in the cell migration distance over 6 h between cells exposed and not exposed to the UV irradiation in vitro. In vivo, this method revealed that three times as many cells in the subventricular zone of the olfactory bulb migrated rostrally as caudally. The new method also allowed us to measure the speed of cell migration, which was estimated to be about 70 microm/h at the maximum in the rostral direction. After these examinations of reliability of the method, we applied it to the rat embryo brain. One day after UV irradiation of the ganglionic eminence, labeled migrating cells were found in the striatum, in the internal capsule, and in the intermediate zone of the neocortex. The observation period of cell migration to the neocortex was extended by the use of a xeroderma pigmentosum group A gene mutant mouse, which lacked an ability to remove thymine dimer from the UV-irradiated nuclei. Two days after the UV irradiation, labeled migrating cells from the ganglionic eminence of the mutant mouse embryos were found both in the cortical plate and in the intermediate zone of the neocortex.

Animals↗
PubMed1997

Effects of combined ventral forebrain grafts to neocortex and amygdala on behavior of rats with damage to the nucleus basalis magnocellularis.

In rats with damage to the nucleus basalis magnocellularis, transplantation of the embryonic ventral forebrain to the neocortex improves behavioral performance in some behavioral tasks. The present investigation focuses on improvement of behavioral performance by combined graft placement to both neocortex and amygdala. Male rats received unilateral microinjections of quisqualate to the nucleus basalis magnocellularis to produce cell damage. Embryonic ventral forebrain cell suspensions were placed in one group of rats in the frontal and parietal neocortex, in a second group in the amygdala, and in a third group in the frontal and parietal neocortex and in the amygdala. These groups were compared to a group of nonoperated rats and a group of rats with damage but with no grafts. Quisqualate-induced damage to the nucleus basalis magnocellularis reduced cholinergic innervation in the ipsilateral cortical hemisphere, impaired performance in the one-trial training version of passive avoidance, an increased motility and time spent in the open arms of the elevated plus maze. Combined graft placement to neocortex and amygdala normalized performance of passive avoidance and restored the normal time spent in the open arms of an elevated plus maze. These results suggest that after damage to the nucleus basalis magnocellularis, modulation of function in multiple brain regions may be necessary for optimization of adaptive behavior in situations involving induction of fear.

Amygdala↗
PubMed1998

Gyri of the human neocortex: an MRI-based analysis of volume and variance.

This magnetic resonance imaging (MRI)-based morphometric analysis of cortical topography in the human brain is based upon the segmentation and parcellation of volumetric T1-weighted MRI data for a set of 20 young adult brains including 10 males and 10 females. For the most part, each parcellation unit (PU) of the neocortex corresponds to a single or a portion of a single gyrus. The volumes of each PU were computed for each brain. Subsets of PUs were also grouped so as to represent the neocortex for the frontal, temporal, parietal and occipital lobes. The coefficient of variation of the mean volume of total neocortex and that of the neocortex assigned to individual lobes cluster around 10%, whereas that of neocortex assigned to the individual gyri (PU) is more than twice that value. Approximately 80% of the total variance in gyral volume arises from determinants interactive for individual and specific gyri, while only approximately 10% of the total variance appears to be a reflection of uniform scaling to total neocortical volume. Sexual dimorphism contributes a pervasive though relatively small component of this variance. These results have implications for the study of structure-function correlation, and the proper statistical methods of handling volumetric data in morphometric studies. In addition, the nature of the covariance structure of the data will lead to future hypotheses regarding the relationships between the various potential genetic and epigenetic gyral influencing factors.

Adult↗
PubMed1989

Timing of expression of tau and its encoding mRNAs in the developing cerebral neocortex and cerebellum of the mouse.

The expression of tau mRNA and of the corresponding encoded protein variants was studied during postnatal development in two brain regions differing in their timing of differentiation: the cerebral neocortex and the cerebellum. (a) The expression of tau mRNA was different in the two regions. Maximal contents were found at early stages in the cerebral neocortex, with a 10-fold decrease at later stages. In the cerebellum, two peaks of tau mRNA were observed soon after birth and in adulthood, with minimal values at postnatal day 6. (b) The expression of total tau proteins was similar to that of their encoding mRNAs in the cerebral neocortex, i.e., high concentrations after birth and low contents at later stages. In contrast, two peaks of tau proteins were observed in the cerebellum: the first perinatally and the second with a maximum at postnatal day 15. (c) Both in the cerebral neocortex and especially in the cerebellum, increasing concentrations of mature tau variants were expressed at late developmental stages, i.e., when total tau protein contents were decreased. In conclusion, the fluctuations in expression of tau and of its encoding mRNA seen in the cerebellum seem to reflect differences in the timing of differentiation of the various cell types, i.e., the macroneurons and the interneurons, present in this brain region. The adult tau variants appear in both the neocortex and the cerebellum only at late developmental stages, i.e., when most of the circuitry has been established, although these two regions markedly differ in their timing of differentiation.

Animals↗
PubMed1991

Homology and evolutionary origins of the 'neocortex'.

The telencephalon of mammals is characterized by the presence of a hexalaminated structure on its external surface, with specific auditory, visual, somatosensory and motor regions. Due to its seeming unique presence in mammals, it is frequently designated as the neocortex. The evolutionary origins of the so-called neocortex have long puzzled comparative neuroanatomists, in view of the seeming absence of a neocortical-like anlage in nonmammalian amniotes. The resolution of this puzzle requires analysis of both adult and embryonic brains. Experimental neuroanatomical, physiological and behavioral methods applied to adult avian and reptilian brains have finally clarified several fundamental questions regarding the origins of 'neocortex' and have indicated that these origins can be viewed as consequent to two separate events: (1) The elaboration of constituent neuronal populations and their associated connections that are common to the telencephalae of both nonmammalian and mammalian amniotes. In mammals these populations are found within the so-called neocortex. In birds and reptiles, most of these neurons are found within the dorsal and dorsolateral ventricular ridges (DVR and DLVR). (2) In mammals, the components of the DVR and DLVR are incorporated into the thin overlying pallium to form a laminated 'neocortex'. Analysis of development in domestic chicks suggests that the DVR is one of several prosencephalic neuromeres ('Prosomeres') that contribute to the ontogeny of comparable structures in birds. Perhaps in mammals, as well, cortical development is consequent to incorporation of these several prosomeres into proliferative ependyma of the pallial mantle.

Animals↗
PubMed1987

Regional heterogeneity in the distribution of somatostatin-28- and somatostatin-28(1-12)-immunoreactive profiles in monkey neocortex.

The distribution of the prosomatostatin-derived peptides (PSDP), somatostatin-28 and somatostatin-28(1-12), in the cynomolgus monkey (Macaca fascicularis) neocortex was characterized in quantitative immunohistochemical studies of 3 visual areas (V1, primary visual cortex; V2, the adjacent visual association area; and AIT, a visual association area in anterior inferior temporal cortex), 2 auditory areas (AI, primary auditory cortex; and T1, an adjacent auditory association area) and anterior cingulate cortex (Area 24). The results of similar quantitative analyses in 3 homologous areas in rat neocortex (primary visual, primary auditory, and anterior cingulate) are also presented. Primate cortical areas differed significantly in both density and laminar distribution of PSDP-immunoreactive profiles. Area 24, the most densely labeled area, had nearly 6 times as many PSDP-immunoreactive neurons as V1. Both auditory areas contained approximately two-thirds the number of PSDP-immunoreactive neurons found in Area 24; however, both had nearly 4 times as many immunoreactive neurons as V1. The 3 visual areas showed incremental increases in the number of PSDP-immunoreactive neurons; V2 contained nearly twice and AIT nearly 3 times the number of immunoreactive neurons present in V1. Both the supra- and infragranular layers were densely labeled in Area 24 and Area T1, however, in AI, V1, V2, and AIT the infragranular layers were relatively sparsely labeled. In contrast to the regional heterogeneity found in the primate neocortex, the distribution of immunoreactive neurons was quite uniform across the 3 rat cortical areas. The rat cortical areas contained substantially fewer immunoreactive neurons than most of the monkey cortical areas, and a majority of these immunoreactive neurons were located in the infragranular layers. These findings suggest that the regional specialization of primate neocortex involves the selective distribution of PSDP-immunoreactive neurons. They also suggest that chemically specified intrinsic organization of neocortex is not likely to be uniform across species or across cortical areas in the primate. The distinctive regional distribution patterns of PSDP-immunoreactive profiles appear to parallel that of the long corticocortical projections (contralateral and distant ipsilateral projections), suggesting an association between these presumed inhibitory interneurons and this important extrinsic system.

Animals↗
PubMed1980

The brain of the mammal-like reptile Probainognathus jenseni (Therapsida, Cynodontia). A correlative paleo-neoneurological approach to the neocortex at the reptile-mammal transition.

A natural endocranial cast of the South American cynodont Probainognathus jenseni is studied, and an evaluation of the probable nature of the neocortex at the level of certain cynodonts of the Middle Triassic is made, based in the available paleo-neoneurological information. The endocast of Probainognathus shows well developed olfactory bulbs, long cerebral hemispheres, small anterior colliculi and well represented cerebellum and flooculi. The pineal gland may have been located between the caudal hemispheric poles. No parietal foramen exists. The dorsal surface of the cerebral hemispheres shows a slope at the level of the anterior edge of the caudal fourth part, which is interpreted as the posterior limit of the neocortical plate. At the level of the olfactory peduncles, it is visible a stem vessel; one of its branches distributes on the anterior part of the lateral border of the hemisphere. It is advanced the interpretation that this latter vessel could indicate the paleo-neocortical boundary. The analysis of the neoneurological information led the author to suppose that the neocortex of Probainognathus, and surely of other cynodonts of the Middle Triassic, has shown supplementary somatic sensory and motor, visual and auditory representations, and perhaps incipient primary somati sensory and motor ones, advancing a "polymodal cortex", as it is supposed had stem mammals. Moreover, the histostructure of the neocortex at this state of the evolution may have been in a proisocortical-isocortical stage, that is, in the beginnings of the true neocortex. The confrontation of the paleoneurologic with the neoneurologic information led the author to suppose that Triconodon and Ptilodus have had a neocortex, surely more developed than Probainognathus, but that it is not seen in the endocasts at present studied. The quantitative analysis of Probainognathus' endocast, as well as those of other cynodonts, suggest that certain cynodonts of the Middle Triassic were in an advanced state toward endothermy.

Animals↗
PubMed1997

TGF-beta receptor type II and fetuin in the developing sheep neocortex.

Fetuin shows a characteristic pattern of distribution in the developing neocortex in many mammalian species. Its expression is confined to early-appearing cortical-plate and later subplate neurons. A short 19 amino-acid sequence of fetuin shows a degree of homology to an 18 amino-acid sequence of the TGF-beta type II receptor (TbetaR-II) and in vitro fetuin binds to members of the TGF-beta family of cytokines. It has been suggested that fetuin is the biologically significant antagonist of these cytokines. We have compared, using immunocytochemistry, the distribution pattern of TbetaR-II and fetuin in the developing neocortex of foetal sheep. TbetaR-II immunoreactivity first appears at around 40 days of gestation in the fetal sheep (E40, term in sheep is 150 days from conception), localised in two discreet bands: one just outside the cortical plate in the inner part of the marginal zone and one deep in the cortical plate in what becomes the transient subplate zone. By E70-E80, TbetaR-II is prominent in a population of subplate cells, whereas, by E120 only small patches of TbetaR-II-positive cells are visible, principally in pyramidal cells in layer VI. The developmental sequence of the staining pattern for TbetaR-II in the neocortex is complementary to that for fetuin, rather than overlapping with it. Double-labelling of fetuin and TbetaR-II shows some cellular co-localisation, especially at E60, but most fetuin-positive cells are not immunoreactive for TbetaR-II. Thus, fetuin's proposed role as an antagonist of TGF-beta cytokines and mimic of TbetaR-II is not consistent with the observed distribution of these two molecules in the developing neocortex of the foetal sheep.

Animals↗
PubMed2005

Transplantation of GABAergic neurons into adult mouse neocortex.

GABAergic neurons in the neocortex contribute to various brain functions by regulating cortical pyramidal neurons. A deficiency of GABAergic neurons in the neocortex leads to the dysregulation of cortical neuronal circuits, but this can be overcome by cell transplantation, which provides a practical approach to repair damaged neuronal circuits. Here, we focused on the transplantation of committed neuronal progenitor cells. Because neuronal differentiation is considerably suppressed in the adult neocortex, we transfected proneural bHLH transcription factors into neural precursor cells to commit them to a neuronal lineage prior to the cell transplantation. We show that ventral neural stem cells transfected with Ngn1 are integrated as GABAergic neurons within a few days of transplantation into the adult mouse neocortex. These results demonstrate that the transplantation of committed neuronal progenitor cells is an effective method for brain repair.

Age Factors↗
PubMed2004

An information-processing analysis of the functional architecture of the primate neocortex.

Working at the systems level of analysis, we will use the term functional architecture to concern what processing components exist, how they are interconnected, and what information-processing functions each is involved in. In this paper, experimental evidence for the primate neocortex is analysed for conclusions concerning the existence of neural areas, for corticocortical connectivity among neural areas, and for the involvement of each cortical neural area in the functioning of the brain. We characterize the information-processing function for each neural area in terms of the types of information it is associated with, and conceive of its activity as processing, storage and transmission of data of the corresponding types for that area. We also adapt concepts of goal, plan, sequence, event and context for the description of information processing in the neocortex. This analysis shows that the primate neocortex consists in the main of a perception hierarchy, an action hierarchy and connections between them. In other words, from an information-processing point of view, the primate neocortex has a hierarchical perception-action architecture.

Animals↗
PubMed2005

Fatty acid amidohydrolase in human neocortex-activity in epileptic and non-epileptic brain tissue and inhibition by putative endocannabinoids.

Increased levels of the endocannabinoid anandamide (AEA) have been observed in connection with neuronal disorders like epilepsy. In order to investigate whether an impaired enzymatic AEA hydrolysis contributes to this phenomenon, the present study determined the activity of fatty acid amidohydrolase (FAAH) in epileptic and non-epileptic human neocortical brain tissue. Additionally, we investigated whether other putative endocannabinoids (2-arachidonylglycerol (2-AG), noladin ether, virodhamine) may also interact with FAAH. AEA hydrolysis was measured by the formation of the product [(3)H]-ethanolamine after separation from the substrate using activated charcoal. FAAH activity was found to be similar in epileptic and non-epileptic human neocortex (0.29 and 0.37 nmol ethanolamine/mg protein/min, respectively). FAAH activity was about 55% higher in rat neocortex. While in human, neocortex noladin ether did not influence AEA hydrolysis, FAAH activity was concentration-dependently inhibited by AEA, 2-AG and virodhamine (IC(50) values 3.3, 3.5 and 13.8 microM, respectively). Our results suggest that, in the course of epilepsy, increased AEA levels are likely due to enhanced formation and not due to decreased hydrolysis. To further increase endocannabinoid activity, the application of FAAH inhibitors might be therapeutically useful in the treatment of neuronal hyperexcitability. Whereas noladin ether did not interact with AEA hydrolysis, this compound, 2-AG and virodhamine may share common enzymatic inactivation mechanisms in human neocortex.

Adolescent↗
PubMed2005

Novel calretinin and reelin expressing neuronal population includes Cajal-Retzius-type cells in the neocortex of adult pigs.

Cajal-Retzius cells and their secreted product reelin are essential for the lamination of the cerebral cortex. In all species studied to date Cajal-Retzius cells form a transient neuronal population that almost completely disappears from the neocortex postnatally. Recently, in the hippocampal formation of adult domestic pig, we have found a large calretinin- and reelin-immunoreactive cell population that morphologically corresponded to Cajal-Retzius cells. In the present study, we examined calretinin- and reelin-immunoreactive neurons in layer I of the prefrontal, temporal, parietal and occipital neocortical areas of newborn, young adult and adult domestic pigs. Large numbers of bipolar or fusiform calretinin-positive cells were found in the upper half of layer I in all examined age groups. The morphology of these neurons resembled that of the Cajal-Retzius cells. Layer I was occupied by a dense calretinin-positive axonal plexus that was similar to the previously described axons of Cajal-Retzius cells in other species. In a similar location, where calretinin-positive cells occurred in layer I, large numbers of reelin-immunoreactive cells were found in all examined age groups. In addition, reelin colocalized with calretinin in layer I neurons. The number of calretinin and reelin-positive neurons decreased from 1 day to one year, but calretinin-positive Cajal-Retzius-type cells still comprised a remarkable large population in 12-month-old animals. Correlated light and electron microscopic examination of calretinin-labeled Cajal-Retzius-type cells indicated that these cells are integrated in the synaptic circuitry of the neocortex. Our results suggest that Cajal-Retzius cells do not disappear inevitably from the mature neocortex in all mammalian species. The function of this cell type is not known, but late persisting Cajal-Retzius-type cells in the domestic pig provide an opportunity to study their neuronal connections and the possible role of reelin in plasticity and regeneration of neocortex.

Aging↗
PubMed2001

Biogenic amines in the human neocortex in patients with neocortical and mesial temporal lobe epilepsy: identification with in situ microvoltammetry.

Biogenic amines in well defined subtypes of human temporal lobe epilepsy (TLE) have not been well characterized. Specimens from five patients with neocortical TLE (NTLE) and nine with mesial TLE (MTLE) were immediately placed in Ringer's lactate; stearate indicator microelectrodes were placed in temporal gray matter, Ag/AgCl reference microelectrodes and auxiliary microelectrodes were placed 3-7 mm contralaterally to the indicator microelectrode. Dopamine (DA), ascorbic acid (AA), norepinephrine (NE) and serotonin (5-HT) were identified by their characteristic oxidative potentials in vitro. Four of five patients with NTLE had NE depletion in temporal neocortex while eight of nine patients with MTLE had high concentrations of NE (chi-square P<0.01). Significant concentrations of DA were present in the temporal lobes of three of five NTLE patients but in only one of the nine MTLE patients (chi-square P<0.05). 5-HT was present in the neocortex of both NTLE and MTLE patients in similar concentrations. AA was found in the neocortex of one NTLE patient. These data support an association between NE depletion and NTLE. The relative NE deficiency along with the consistent presence of DA in NTLE patients suggest an impairment in the catecholamine pathway. The presence of AA, a co-factor in NE synthesis, in the neocortex of one NTLE patient may also be related since AA is a cofactor in NE synthesis.

Biogenic Amines↗
PubMed1999

Differential expression of c-fos mRNA in the rat neocortex by in situ hybridization.

The c-fos mRNA expression pattern in rat neocortex, was determined in the rat kept in a 12:12 light/dark cycle, in constant dark, or in constant light by in situ hybridization. At the beginning of the light period, c-fos mRNA was induced both in the neocortex and suprachiasmatic nucleus (SCN). Transiently increased c-fos mRNA expression was detected from 0830 to 0900 and soon declined to basal levels. Immediately prior to the beginning of the dark period, c-fos mRNA expression also increased and remained elevated in the neocortex following the dark period. In the constant dark group, c-fos mRNA expression showed no transient elevation at the beginning of the light period. On the other hand, c-fos mRNA expression in the constant light group increased during their subjective dark period as well as normal light/dark cycle. These results demonstrate a circadian pattern of c-fos mRNA expression in the neocortex which is similar to that observed previously in the inner and outer nuclear layers of the retina.

Animals↗
PubMed1999

Ultra-miniature headstage with 6-channel drive and vacuum-assisted micro-wire implantation for chronic recording from the neocortex.

We describe a head-stage, with precision microtranslators for the chronic placement of micro-wire electrodes in the neocortex, that minimizes compressive damage to the brain. The head-stage has a diameter of 5.8 mm and allows six electrodes, separated by 450 microm on a hexagonal grid, to be individually and continuously positioned throughout a depth of approximately 3 mm. Suction is used to transiently support the dura against a curved array of tubes that guide and stabilize the electrodes as a means to prevent compression of the neocortex as the electrodes breach the dura. With this headstage we recorded extracellular signals in a rat immediately after surgery. Single-unit waveforms at a given electrode position were stable for at least several hours in the freely behaving animal and were obtained throughout the depth of the neocortex for at least 2 months. Electrophysiological records and histological examination showed that the upper layers of the neocortex were intact and minimally damaged after the implantation.

Animals↗
PubMed1998

Cajal-Retzius cells and the development of the neocortex.

The dual origin, structural organization, and evolving ascending stratification of the mammalian neocortex are explored from a developmental perspective. Layer I and subplate (layer VII) zone of the neocortex evolve first from a primordial plexiform neuropil that is established throughout the non-olfactory telencephalon and that is common to amphibians, reptiles and mammals. The remaining laminations (strata) of the neocortex evolve later, between layer I and the subplate zone, from the cortical plate (CP), which represents a multilayered mammalian evolutionary feature. The attraction of CP neurons towards layer I, their progressive ascending (inside-out) placement, common early differentiation stage (regardless of size, location, cortical depth, or eventual functional role, or all of these), and the unique morphologic features of its pyramidal neuron are developmental processes controlled by layer I and its Cajal-Retzius cells. Based on the role of these early neurons and of layer I, a new theory of neocortical cytoarchitectonics and nomenclature is proposed to explain the basic structural and functional organization of the mammalian neocortex, the morphology of its pyramidal cells, and the addition of new pyramidal cell strata that characterize its phylogenetic evolution.

Animals↗
PubMed1999

Dopamine D1 receptor modulation of glutamate receptor messenger RNA levels in the neocortex and neostriatum of unilaterally 6-hydroxydopamine-lesioned rats.

The effect of treatment with the D1 dopamine receptor agonist SKF 38393 on the expression of metabotropic glutamate receptor 1, 3, 4 and 5 receptor subtypes and of the glutamate N-methyl-D-aspartate ionotropic receptor subunits NRI, NR2A and NR2B was analysed using in situ hybridization. We studied the neocortex and neostriatum of normal rats and of rats unilaterally treated with 6-hydroxydopamine, a neurotoxin that, after intracerebral injection into the ventral tegmental area, causes selective degeneration of the ascending dopamine pathway. In the 6-hydroxydopamine-lesioned rats, metabotropic glutamate receptor subtype 3 messenger RNA levels were ipsilaterally increased in the neocortex and neostriatum, while the levels of metabotropic glutamate receptor subtype 4 messenger RNA were bilaterally increased in both regions. When administered to the 6-hydroxydopamine-lesioned rats, the D1 receptor agonist SKF 38393 (3 x 20 mg/kg, s.c.) produced a bilateral decrease in the expression of the metabotropic glutamate receptor subtype 1 and 5 receptor messenger RNA levels in the neocortex and neostriatum. In the neostriatum, SKF 38393 attenuated the ipsilateral increase in the expression of striatal metabotropic glutamate receptor subtype 3 messenger RNA produced by the 6-hydroxydopamine lesion. Furthermore, SKF 38393 produced a bilateral decrease in the levels of NRI receptor subunit messenger RNA and, in contrast, an increase in the striatal NR2B messenger RNA levels. All of these effects were abolished by the D1 receptor antagonist SCH 23360. These results indicate a differential D1 receptor-mediated modulation of the expression of some glutamate receptor subtypes in the neostriatum and neocortex, in agreement with the idea of a functional coupling between dopamine and excitatory amino acid systems in both regions. Thus, pharmacological targeting of excitatory amino acid systems could provide alternative or complementary treatment strategies for diseases involving dopaminergic systems in the striatum (e.g., Parkinson's disease) and cortex (e.g., schizophrenia).

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2004

Cannabinoid CB1 receptor-mediated modulation of evoked dopamine release and of adenylyl cyclase activity in the human neocortex.

1. The present study investigated the binding characteristics of various ligands to cannabinoid CB(1) receptors in human neocortex and amygdala. In addition, the functionality of CB(1) receptors in the human neocortex was assessed by examining the effects of CB(1) receptor ligands on evoked [(3)H]-dopamine (DA) release in superfused brain slices and on synaptosomal cAMP accumulation. 2. Saturation-binding assays in human neocortical and amygdala synaptosomes using a radiolabelled cannabinoid receptor agonist ([(3)H]-CP55.940) revealed pK(d) values of 8.96 and 8.63, respectively. The numbers of binding sites (B(max)) were 3.99 and 2.67 pmol (mg protein)(-1), respectively. 3. Various cannabinoid receptor ligands inhibited [(3)H]-CP55.940 binding with rank order potencies corresponding to those of previous studies in animal tissues. 4. Electrically evoked [(3)H]-DA release from human neocortical slices was inhibited by CP55.940 (IC(50) 6.76 nm, I(max) 65%) and strongly enhanced by the cannabinoid receptor antagonist AM251. However, [(3)H]-DA release was not influenced in rat neocortex. In human tissue, the estimated endocannabinoid concentration in the biophase of the release-modulating CB(1) receptors was 1.07 nm, expressed in CP55.940 units. 5. K(+)-evoked [(3)H]-DA release in the presence of tetrodotoxin (TTX) was strongly inhibited by CP55.940 in humans, but not in rats. 6. In human tissue, CP55.940 inhibited forskolin-stimulated cAMP accumulation (IC(50) 20.89 nm, I(max) 35%). AM251 blocked this effect and per se increased forskolin-stimulated cAMP accumulation by approximately 20%. 7. In conclusion, cannabinoids modulate [(3)H]-DA release and adenylyl cyclase activity in the human neocortex. CB(1) receptors are located on dopaminergic nerve terminals and seem to be tonically activated by endocannabinoids.

Adenylyl Cyclases↗