Local Feedback Mechanism Research Articles

Growth factor regulation of insulin-like growth factor binding protein-6 expression in osteoblasts.

Previously we have shown that transforming growth factor beta (TGF beta) 1, basic fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) BB inhibit the synthesis of insulin-like growth factor (IGF) II, but their effects on IGF binding protein (IGFBP)-6 in osteoblast cultures are not known. IGFBP-6 binds IGF II with high affinity and prevents IGF II-mediated effects, so that a possible mode of regulating the IGF II available to bone cells would be by changing the levels of IGFBP-6. To enhance our understanding of the actions of growth factors on the IGF II axis in bone, we tested the effects of TGF beta 1, basic FGF, PDGF BB, IGF I, and IGF II on the expression of IGFBP-6 in cultures of osteoblast-enriched cells from 22 day fetal rat calvariae (Ob cells). Treatment of Ob cells with TGF beta 1 caused a time- and dose-dependent decrease in IGFBP-6 mRNA levels, as determined by Northern blot analysis. The effect was maximal after 48 h and observed with TGF beta 1 concentrations of 0.04 nM and higher. TGF beta 1 also decreased IGFBP-6 polypeptide levels in the medium, as determined by Western immunoblot analysis. Cycloheximide at 3.6 microM decreased IGFBP-6 transcripts and prevented the effect of TGF beta 1. The decay of IGFBP-6 mRNA in transcriptionally arrested Ob cells was not modified by TGF beta 1. In addition, TGF beta 1 decreased the rates of IGFBP-6 transcription as determined by a nuclear run-on assay. In contrast, basic FGF, PDGF BB, IGF I, and IGF II did not change IGFBP-6 mRNA levels in Ob cells. In conclusion, TGF beta 1 inhibits IGFBP-6 expression in Ob cells by transcriptional mechanisms. Since IGFBP-6 binds IGF II and prevents its effects on bone cells, decreased synthesis of IGFBP-6 induced by TGF beta 1 could be a local feedback mechanism to increase the amount of IGF II available in the bone microenvironment.

Tissue remodeling with micro-structurally based material laws.

Cardiomyocytes and the extracellular collagen matrix which holds them together respond to changes in their mechanical environment by adapting their orientation, size and composition. We examine local mechanical feedback mechanisms affecting the fiber orientation, sheet orientation and passive fiber direction stiffness, using an axisymmetric finite element model of the left ventricle (LV), with material constitutive laws based on the fibrous-sheet microstructure of myocardium.

Controlling spatiotemporal dynamics with time-delay feedback.

We suggest a spatially local feedback mechanism for stabilizing periodic orbits in spatially extended systems. Our method, which is based on a comparison between present and past states of the system, does not require the external generation of an ideal reference state and can suppress both absolute and convective instabilities. As an example, we analyze the complex Ginzburg-Landau equation in one dimension, showing how the time-delay feedback enlarges the stability domain for traveling waves.

Functional role of intrahypothalamic release of oxytocin and vasopressin: consequences and controversies

This brief review of vasopressin (VP) and oxytocin (OT) release into the extracellular space of the supraoptic (SON) and paraventricular (PVN) nuclei focuses on recent data illustrating the significance of their intranuclear release and the potential functional consequences. With the use of in vitro techniques, it has been demonstrated that administration of exogenous OT causes local peptide release and that, in vivo, this facilitates the milk ejection reflex. These findings lead to the idea that endogenous peptides are released into the hypothalamic nuclei. Microperfusion techniques have been used to monitor the dynamics of intranuclear OT and VP release in response to distinct stimuli. It is clear that intranuclear release of OT plays a role during reproductive states (parturition and lactation) and that intranuclear release of VP and OT is involved in osmoregulation. This review discusses 1) the origin of the intranuclearly released peptides, 2) stimuli which cause release into the hypothalamic nuclei, and 3) the function of intranuclear VP and OT, e.g., regulation of local morphology, feedback mechanisms and synchronization, and the possible role in regulating autonomic function and behavior.

Control of ovarian function in cattle

The control of ovarian function in cattle involves the complex interaction of local and systemic feedback mechanisms. This control system ensures that in greater than 96% of cows only one follicle will ovulate each oestrous cycle. A better understanding of the mechanisms involved should lead to improved synchronisation of oestrus in herds, thereby increasing the success rate of artificial insemination, improve the effectiveness of superovulation regimes and provide opportunities for the induction of twinning. It has been estimated that modest improvements in these areas would benefit the UK cattle industry by at least £200 million per year.Follicular growth in cattle occurs in a wave-like pattern with usually three waves, sometimes two waves but rarely four waves, of follicles growing and regressing each oestrous cycle. This follicle wave pattern is also present during periods of anoestrus. Each follicle wave, which is usually preceeded by a rise in peripheral FSH concentrations, is characterized by the emergence, from the pool of growing follicles, of a large ‘dominant’ follicle.

Control of ovarian function in cattle

The control of ovarian function in cattle involves the complex interaction of local and systemic feedback mechanisms. This control system ensures that in greater than 96% of cows only one follicle will ovulate each oestrous cycle. A better understanding of the mechanisms involved should lead to improved synchronisation of oestrus in herds, thereby increasing the success rate of artificial insemination, improve the effectiveness of superovulation regimes and provide opportunities for the induction of twinning. It has been estimated that modest improvements in these areas would benefit the UK cattle industry by at least £200 million per year.Follicular growth in cattle occurs in a wave-like pattern with usually three waves, sometimes two waves but rarely four waves, of follicles growing and regressing each oestrous cycle. This follicle wave pattern is also present during periods of anoestrus. Each follicle wave, which is usually preceeded by a rise in peripheral FSH concentrations, is characterized by the emergence, from the pool of growing follicles, of a large ‘dominant’ follicle.

The interaction of katabatic winds and the formation of blue-ice areas in East Antarctica

AbstractBlue-ice areas (BIAs) are an extreme example of a local mass-balance gradient and are furthermore reasonably stable in time and space owing to local feed-back mechanisms. A meteorological experiment, performed in and around a blue-ice area in Dronning Maud Land. East Antarctica, showed that during drifting-snow conditions surface wind speed over the blue ice behind the mountain barrier is equal to that away from the mountains, when corrected for surface roughness and stability. This implies that use of diagnostic katabatic wind models to estimate divergence of drifting snow can be extended to the situation where nunataks are involved in preventing the drifting snow from passing, which is the case for most BIAs. A diagnostic model is tested for a two-dimensional profile in Terre Adélie. after which it is applied to entire East Antarctica. The present order-of-magnitude estimate shows that areas sensitive to blue-ice formation appear where precipitation is low and mean annual wind speed is high, i.e. in Dronning Maud Land and the drainage basin of Lambert Glacier. The results appeared to be especially sensitive to a change in inversion strength: a decrease in inversion strength weakens the katabatic flow, and thus the amount of snowdrift transport, reducing the area where BIAs can develop.

The interaction of katabatic winds and the formation of blue-ice areas in East Antarctica

AbstractBlue-ice areas (BIAs) are an extreme example of a local mass-balance gradient and are furthermore reasonably stable in time and space owing to local feed-back mechanisms. A meteorological experiment, performed in and around a blue-ice area in Dronning Maud Land. East Antarctica, showed that during drifting-snow conditions surface wind speed over the blue ice behind the mountain barrier is equal to that away from the mountains, when corrected for surface roughness and stability. This implies that use of diagnostic katabatic wind models to estimate divergence of drifting snow can be extended to the situation where nunataks are involved in preventing the drifting snow from passing, which is the case for most BIAs. A diagnostic model is tested for a two-dimensional profile in Terre Adélie. after which it is applied to entire East Antarctica. The present order-of-magnitude estimate shows that areas sensitive to blue-ice formation appear where precipitation is low and mean annual wind speed is high, i.e. in Dronning Maud Land and the drainage basin of Lambert Glacier. The results appeared to be especially sensitive to a change in inversion strength: a decrease in inversion strength weakens the katabatic flow, and thus the amount of snowdrift transport, reducing the area where BIAs can develop.

Extracellular 5‐Hydroxytryptamine in Median Raphe Nucleus of the Conscious Rat Is Decreased by Nanomolar Concentrations of 8‐Hydroxy‐2‐(Di‐n‐Propylamino)tetralin and Is Sensitive to Tetrodotoxin

Extracellular 5-hydroxytryptamine (5-HT) in the median raphe and dorsal hippocampus was measured using in vivo microdialysis. Administration of 60 mM K+ through the probe into the median raphe region significantly increased 5-HT output from the median raphe and the right dorsal hippocampus. Local infusion of 10 microM tetrodotoxin into the median raphe region substantially decreased 5-HT in the median raphe and left and right dorsal hippocampus. Systemic administration (0.3 mg/kg s.c.) of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) decreased the 5-HT levels in the dialysates from both the median raphe region and dorsal hippocampus. Administration of 30 nM 8-OH-DPAT through the dialysis probe into the median raphe region decreased 5-HT output from the median raphe and dorsal hippocampus significantly, whereas at concentrations from 60 nM to 10 microM, no significant effects were found in either region. With 100 microM 8-OH-DPAT, a significant increase was seen in the median raphe region, but not in dorsal hippocampus. Similar findings were obtained following microinjections of different doses of the compound into the median raphe region. The results of this study indicate that the somatodendritic release of 5-HT is impulse flow-dependent. Moreover, the decrease of 5-HT in the median raphe region by low nanomolar concentrations of 8-OH-DPAT supports the notion that somatodendritic 5-HT release is subject to a local negative feedback mechanism through 5-HT1A autoreceptors.

Role of growth hormone and intrafollicular peptides in follicle development in cattle

Ovarian function in cattle is controlled by complex local and systemic feedback mechanisms which ensure that in >96% of estrous cycles only one follicle will ovulate. Although there is a primary requirement for gonadotropins in stimulating follicular growth, particularly during the final stages of follicle maturation, it is now becoming apparent that locally-produced factors, such as insulin-like growth factor-I (IGF-I) and inhibin, have a modulating role. In addition to gonadotropins, other systemic agents such as metabolic hormones (GH, IGF-I and insulin), can also influence follicular growth. The ability to control the growth of the dominant follicle, together with improved understanding of the competing mechanisms controlling follicular recruitment and growth, should enable more precise control of ovarian function and superovulation in cattle.

A laser Doppler instrument for in vivo measurements of blood flow in single renal arterioles.

A laser Doppler instrument has been developed to measure the blood flow in single vessels for the study of the dynamics of local control mechanisms. A commercial blood perfusion monitor, designed to measure blood perfusion in a vascular field containing many randomly oriented blood vessels, was modified to perform measurements of blood flow in a single arteriole. In vitro tests of the instrument revealed that the relationship between blood flow and Doppler shift was not a simple linear function. Causes of nonlinearity are revealed and proper use of the device avoids the problem. The device was applied to efferent arterioles that are visible on the surface of the rat kidney. An angiotensin converting enzyme inhibitor and graded doses of angiotensin II were used to perturb kidney blood flow. The induced changes in whole kidney blood flow, measured with an electromagnetic flow probe, and in single efferent arteriolar blood flow, measured with the new instrument, were correlated. An oscillation at approximately 0.035 Hz, previously described in the tubular pressure and attributed to a local feedback mechanism acting on arteriolar resistance, was found in the arteriolar blood flow. The new instrument is easy to use and provides temporal resolution not available with more conventional methods used for flow measurement in the microcirculation.

Specific effects by the psychotomimetic drugsd-amphetamine and phencyclidine on the performance of an aversely motivated successive visual discrimination in the rat

Rats were trained to perform a conditioned avoidance response to white noise in a conventional two-compartment "shuttle-box". The partition between the compartments had two openings, however, and the correct passage (leftor right) was signalled by changes in background illumination. In this situation the psychotomimetic compoundsd-amphetamine (4 mg kg(-1) IP) and phencyclidine (PCP) (2 mg kg(-1) SC) were found to selectively disrupt the visual discrimination. Thed-amphetamine-induced abnormal behavior in this situation has previously been linked to excessive dopamine (DA) receptor stimulation, not controlled by nerve impulse flow and its regulation by important local feed-back mechanisms. Thus, the psychotomimetic effects produced by this compound should not only by due to increased DA receptor activationper se, but also to a disruption of normal patterns of firing and release in dopaminergic neurons. There is evidence to suggest that PCP via an excitatory amino acid (EAA) receptor produces a similar net effect on brain meso-limbic dopaminergic neurotransmission via an increased rate of firing, accompanied by regularization of firing (loss of burst activity). In support for a mediation of PCP-induced effects via EAA receptors, the local application of kynurenic acid into the ventral forebrain (4.7µg, bilaterally) was found also to produce a selective disruption of discriminative performance. It should be noted, however, thatd-amphetamine-induced loss of discriminative behavior, but not that induced by PCP, was antagonized by haloperidol (0.1-0.2 mg kg(-1) IP) administration. It is thus possible that at least some effects of PCP in this situation are mediated on the efferent side of the dopaminergic neuron. It is suggested that the abnormal behavior, as evidenced by a loss of discriminative (but not avoidance) behavior, is due to disruption of normal, feed-back regulated, nerve impulse flow.

Morphology and innervation of the buccal glands of the southern hemisphere lamprey, Geotria australis

The buccal glands of adults of the Southern Hemisphere lamprey Geotria australis consist of a pair of small, bean-shaped, hollow sacs, embedded within the basilaris muscle in the region below the eyes and to either side of the piston cartilage. Each gland, which is lined by a simple columnar epithelium and surrounded by an incomplete layer of skeletal muscle, discharges its contents into the oral cavity via a long, narrow duct. In downstream migrating young adults, the epithelial cells are low columnar, intermediate in electron density, and contain dark-staining inclusions and numerous lipid-like droplets. After saltwater acclimation, the epithelial cells become taller and the numbers of dark-staining inclusions increase whereas those of lipid-like droplets decline. By the end of the marine phase, the epithelium is more folded and now also contains dark and light cells. The ultrastructure of the epithelium shows the characteristics of both apocrine and merocrine secretion. Although intra-epithelial nerve endings were not observed, axons and occasional neurons are present in the lamina propria. Since the skeletal muscle capsule is also well innervated and contains neurons, a local feed-back mechanism may regulate the release of buccal gland fluid by monitoring the luminal pressure. Contractions of the skeletal muscle capsule and movements of the basilaris muscle during feeding would presumably assist the movement of secretion along the duct. The secretion possesses anticoagulating and haemolytic properties.

Metabolic adaptations in goat mammary tissue during long-term incomplete milking.

Lactating goats were milked incompletely in one gland and normally in the other gland twice daily for 24 weeks. Yields of the incompletely milked glands were adjusted so that a calculated 100 ml milk remained in the gland at the end of milking. On average this residual volume was greater by 7.6% of the total milk volume than that left after normal milking and was 25.9% greater than the capacity of the alveoli. After 24 weeks, the weekly milk yield of the incompletely milked gland was 23.8% lower than that of the other gland (P less than 0.001) when expressed in relation to cell number. The metabolic capacity of secretory cells in the two glands was measured in serial tissue biopsies. Two weeks of incomplete milking had no effect on enzyme activities or metabolic fluxes in the incompletely milked gland, but after 24 weeks the activities of several key enzymes were significantly lower in this gland. This was associated with a reduced rate of synthesis of total protein and casein in explants freshly prepared from the tissue. The rate of lactose synthesis also tended to be lower in explants from the incompletely milked gland. Secretory cell number in the two glands was similar at the end of incomplete milking. The data indicate that incomplete milking over a long period caused partial secretory cellular involution via a local chemical feedback mechanism in the gland.

Regulation of gastric somatostatin secretion in the mouse by luminal acidity: A local feedback mechanism

The present study was designed to determine whether somatostatin secretion induced by histamine or pentagastrin in the isolated luminally perfused mouse stomach was a direct effect of the secretagogues on gastric somatostatin cells or an indirect effect mediated by the increase in luminal acidity. Perfusion of the lumen with exogenous acid (80–480 nmol/min) caused an increase in somatostatin secretion in proportion to the increase in luminal acidity. The increase in somatostatin secretion was resistant to tetrodotoxin and attained maximal levels (61.6% ± 8.7% above basal level) similar to those elicited by maximal doses of secretagogues. Conversely, neutralization of basal acid secretion with bicarbonate (20–160 nmol/min) caused a decrease in somatostatin secretion in proportion to the decrease in luminal acidity. Similarly, neutralization of the secretagogue-induced increments in acid secretion with bicarbonate or inhibition of the increments with cimetidine abolished the corresponding increments in somatostatin secretion. It is proposed that acid-induced release of somatostatin in proximity to parietal cells serves as a negative feedback mechanism restraining acid secretion.

The release of catecholamines from the adrenal medulla and its modulation by alpha 2-adrenoceptors in the anaesthetized dog.

The adrenal nerve of anaesthetized and vagotomized dogs was electrically stimulated (10 V pulses of 2 ms duration for 10 min) at frequencies of 1, 3, 10, and 25 Hz. There was a correlation between the frequency of stimulation and the plasma concentrations of epinephrine, norepinephrine, and dopamine in the adrenal vein, mainly after the 1st min of stimulation and the maximal concentration was reached sooner with higher frequencies of stimulation. Moreover, the relative percentage of catecholamines released in response to the electrical stimulation was not changed by the frequency of stimulation. To test the hypothesis that a local negative feedback mechanism mediated by alpha 2-adrenoceptors exists in the adrenal medulla, the effects of the systemic administration of clonidine (alpha 2-antagonist) on the concentrations of catecholamines in the adrenal vein were evaluated during the electrical stimulation of the adrenal nerve (5 V pulses of 2 ms duration for 3 min) at 3 Hz. Moreover, the effects of the systemic injections of more specific alpha 2-agonist and antagonist (oxymetazoline and idazoxan) were tested on the release of catecholamines in the adrenal vein in response to electrical stimulation of the splanchnic nerve at 1 and 3 Hz frequencies. The injection of 0.5 mg/kg of yohimbine caused a significant increase in the concentrations of epinephrine and norepinephrine in the adrenal vein induced by the electrical stimulation of the adrenal nerve and the injection of 15 micrograms/kg of clonidine had no effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of the milk ejection reflex in the rat.

Extracellular recordings were made from neurones in or near the supraoptic nucleus in suckled lactating rats under urethane anaesthesia to investigate the mechanism by which the firing of oxytocin cells is synchronized during reflex milk ejection. Cells synaptically driven but not antidromically activated by neural stalk stimulation, which thus probably receive an afferent input from supraoptic neurones, were classified as 'regular' or 'bursters' on the basis of their spontaneous electrical activity. The majority (twelve out of eighteen) of synaptically excited cells (o.d.+) were bursters and the majority of inhibited (o.d.-) cells (eleven out of nineteen) were regular, but only one o.d.+ burster showed any change of activity (inhibition) before milk ejection. Putative oxytocin cells in suckled lactating rats showed a firing pattern between milk-ejection bursts which could not be distinguished from that of putative oxytocin cells in male animals. The mode interspike interval between milk ejections was 47.1 +/- 3.1 ms (mean +/- S.E. of mean) compared with 47.3 +/- 3.3 ms in male rats, and fewer than 1.4% of interspike intervals were less than 20 ms in duration. By contrast, within milk-ejection bursts 40% of interspike intervals were in the range 8-20 ms. Short trains (10 or 20) of pulses applied to the neural stalk at regular (5 min) intervals, in an attempt to simulate the initial part of the milk ejection burst, failed to trigger bursts. In only 2 of 150 tests was the interval between train and milk-ejection burst less than 10 s, and after the pulse train all but one cell showed reduced activity for 1-3 s. The trains of pulses were however not without effect: they significantly (P less than 0.01) enhanced the chance of a milk-ejection burst occurring within the next 2.5 min. Our observation that pulse trains do not trigger bursts suggests that local positive feed-back mechanisms are not responsible for orchestrating the activation of oxytocin cells during the milk-ejection reflex. Moreover, because spontaneous tiring pattern is the same in lactating and non-lactating rats, we found no evidence that the anatomical changes in the synaptic organization within the supraoptic nuclei in lactation have any influence on the firing of oxytocin cells. It is likely, however, since pulse trains alter the timing of milk ejections, that oxytocin released locally in the region of the supraoptic nucleus can influence reflex milk ejection.(ABSTRACT TRUNCATED AT 400 WORDS)

Hematopoietic regulatory factors produced in long-term murine bone marrow cultures and the effect of in vitro irradiation

The nature of hematopoietic regulatory factors elaborated by the adherent (stromal) cells of long-term murine bone marrow cultures and the effect of in vitro stromal irradiation (XRT) on the production of these factors was investigated. Using an in situ stromal assay employing a double layer of semisolid agar, it was possible to demonstrate stromal elaboration of at least two colony-stimulating activities, ie, granulocyte/macrophage colony-stimulating activity (G/M- CSA) and megakaryocyte colony-stimulating activity (Meg-CSA). Exposure of the stroma to XRT resulted in dose-dependent elevations of both activities that correlated inversely with total myeloid cell mass as determined by concurrent reductions in total supernatant cell recoveries from irradiated cultures. Mixture experiments that combined control and irradiated stroma revealed that the hematopoietically active control stroma could block detection of XRT-related G/M-CSA elevations. These data implicate a local negative feedback mechanism in the regulation of hematopoiesis. Antiserum directed against purified L cell colony-stimulating factor (CSF) reduced granulocyte/macrophage colony formation in the target layer but did not effect the increased Meg-CSA. While a radioimmunoassay for L-cell type CSF was unable to detect significant differences in concentrated media from control and irradiated cultures, bioassays of these media revealed XRT-related G/M- CSA elevations. These results indicate that the G/M-CSA elaborated in these cultures is immunologically distinct from the Meg-CSA produced, and although distinct from L cell CSF, the G/M-CSA is crossreactive with the L cell CSF antiserum. Morphologic, histochemical, and factor VII antigen immunofluorescent studies were performed on the stromal cell population responsible for production of these stimulatory activities. In addition to “fat” cells, the stromal cells remaining after XRT were composed of two predominant cell populations. These included a major population of acid phosphatase and nonspecific esterase-positive macrophage-like cells and a minor population of factor VII antigen negative epithelioid cells.

Hematopoietic Regulatory Factors Produced in Long-Term Murine Bone Marrow Cultures and the Effect of In Vitro Irradiation

The nature of hematopoietic regulatory factors elaborated by the adherent (stromal) cells of long-term murine bone marrow cultures and the effect of in vitro stromal irradiation (XRT) on the production of these factors was investigated. Using an in situ stromal assay employing a double layer of semisolid agar, it was possible to demonstrate stromal elaboration of at least two colony-stimulating activities, ie, granulocyte/macrophage colony-stimulating activity (G/M-CSA) and megakaryocyte colony-stimulating activity (Meg-CSA). Exposure of the stroma to XRT resulted in dose-dependent elevations of both activities that correlated inversely with total myeloid cell mass as determined by concurrent reductions in total supernatant cell recoveries from irradiated cultures. Mixture experiments that combined control and irradiated stroma revealed that the hematopoietically active control stroma could block detection of XRT-related G/M-CSA elevations. These data implicate a local negative feedback mechanism in the regulation of hematopoiesis. Antiserum directed against purified L cell colony-stimulating factor (CSF) reduced granulocyte/macrophage colony formation in the target layer but did not effect the increased Meg-CSA. While a radioimmunoassay for L-cell type CSF was unable to detect significant differences in concentrated media from control and irradiated cultures, bioassays of these media revealed XRT-related G/M-CSA elevations. These results indicate that the G/M-CSA elaborated in these cultures is immunologically distinct from the Meg-CSA produced, and although distinct from L cell CSF, the G/M-CSA is crossreactive with the L cell CSF antiserum. Morphologic, histochemical, and factor VII antigen immunofluorescent studies were performed on the stromal cell population responsible for production of these stimulatory activities. In addition to "fat" cells, the stromal cells remaining after XRT were composed of two predominant cell populations. These included a major population of acid phosphatase and nonspecific esterase-positive macrophage-like cells and a minor population of factor VII antigen negative epithelioid cells.

Effects of the potential neuroleptic peptide des-tyrosine 1-γ-endorphin and haloperidol on apomorphine-induced behavioural syndromes in rats and mice

The effects of haloperidol and Des-Tyr 1-γ-endorphin (DTγE) were studied on climbing induced in mice by high doses of apomorphine and on the yawning syndrome induced in rats by low doses of apomorphine. Haloperidol in a dose of 0.0046 mg/kg s.c. potentiated climbing whereas at higher doses climbing was inhibited (ED 50=0.03 mg/kg). DTγE had no effect on climbing under normal conditions in doses up to 2 mg/kg s.c.. After three days of handling and saline pre-injections DTγE potentiated climbing in doses from 0.1 to 1 mg/kg. Haloperidol inhibited yawning induced by low doses of apomorphine (ED 50=0.01 mg/kg). DTγE, on the other hand, potentiated yawning induced by low apomorphine at doses of 0.02 and 0.04 mg/kg s.c.. From the point of view that low doses of apomorphine predominantly activate presynaptic dopamine autoreceptors while higher doses predominantly activate postsynaptic dopamine receptors the following tentative conclusions are drawn. 1) Haloperidol blocks presynaptic dopamine autoreceptors at low doses and postsynaptic dopamine receptors at higher doses. 2) DTγE sensitizes presynaptic dopamine autoreceptors at low doses, thereby strengthening the local feedback mechanism at the dopaminergic nerve ending, and sensitizes postsynaptic dopamine receptors at higher doses.