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Biomedical subjects

G Henderson

Publications and source records attributed to G Henderson.

At least 55 records · Page 3Linked to original sources

Older Medicare enrolees' choices for insured services.

OBJECTIVES: The Medicare Trust Fund is expected to be bankrupt in the next decade, thus threatening the viability of the Medicare Program. We have ascertained what Medicare enrollees' priorities for insured services would be, and why, if it were fiscally necessary to limit Medicare benefits to maintain the viability of the Program. DESIGN: A cross-sectional survey using anonymous, inperson interviews and an innovative instrument to elicit choices. SETTING: General Internal Medicine outpatient clinic at a university teaching hospital. PARTICIPANTS: One hundred five adults, 65 years of age and older, who had primary care physician visits between July and September 1995. MEASUREMENTS: Desire to personally select insurance benefits, insurance benefit choices, and the reasons for selection or rejection of benefits. RESULTS: Subjects of various educational and economic backgrounds were able to carry out the selection process with relative case, and four-fifths of respondents preferred to make their own choices about insured services. The most frequently selected services were hospitalization, outpatient care, prescription drugs, eye care, and home care, in descending order. Subjects selected 52 different combinations of services. Only 2% of respondents picked the current Medicare service package. The reasons given for selection varied by service; cost and current or anticipated need for a service were the most frequently cited forces driving the choices made. CONCLUSION: These data suggest that Medicare enrollees prefer some element of choice about their health insurance coverage. Their choices vary widely and differ from the current Medicare package.

Aged↗

Processing of DNA prior to illegitimate recombination in mouse cells.

In mammalian cells, the predominant pathway of chromosomal integration of exogenous DNA is random or illegitimate recombination; integration by homologous recombination is infrequent. Homologous recombination is initiated at double-strand DNA breaks which have been acted on by single-strand exonuclease. To further characterize the relationship between illegitimate and homologous recombination, we have investigated whether illegitimate recombination is also preceded by exonuclease digestion. Heteroduplex DNAs which included strand-specific restriction markers at each of four positions were generated. These DNAs were introduced into mouse embryonic stem cells, and stably transformed clones were isolated and analyzed to determine whether there was any strand bias in the retention of restriction markers with respect to their positions. Some of the mismatches appear to have been resolved by mismatch repair. Very significant strand bias was observed in the retention of restriction markers, and there was polarity of marker retention between adjacent positions. We conclude that DNA is frequently subjected to 5'-->3' exonuclease digestion prior to integration by illegitimate recombination and that the length of DNA removed by exonuclease digestion can be extensive. We also provide evidence which suggests that frequent but less extensive 3'-->5' exonuclease processing also occurs.

Animals↗

The orphan opioid receptor and its endogenous ligand--nociceptin/orphanin FQ.

Following the elucidation of the amino acid sequences of the mu-, delta- and kappa-opioid receptors, a new 'orphan opioid receptor' was cloned with a high degree of homology to the 'classical' opioid receptors. The endogenous opioid peptides show little or no activity at this new receptor; however, a novel endogenous peptide for the orphan opioid receptor has been isolated and sequenced. Here, Graeme Henderson and Sandy McKnight review recent findings on this new receptor and its endogenous ligand, and address the contentious issue of whether activation of this receptor results in hyperalgesia or analgesia.

Analgesia↗

The effect of hypoxaemia on drug disposition in chronic respiratory failure.

OBJECTIVE: The influence of hypoxaemia on the disposition of two common drugs has been examined in ten adults with stable chronic respiratory failure. METHODS: There were two experimental periods in this cross-over study: during these periods supplemental oxygen was either withheld or administered to impose clinical hypoxaemia or maintain normoxaemia, respectively. Each participant received either oral (40 mg) or intravenous (20 mg) frusemide combined with oral paracetamol (500 mg) on consecutive days of the two experimental periods. RESULTS: The total (bound plus unbound) plasma clearance of frusemide during hypoxaemia (arterial oxygen tension, PaO2 < or = 50 Torr) was not significantly different from the value during normoxaemia (PaO2 > or = 60 Torr) [76.9 and 62.4 ml.min-1]. The volume of distribution was not affected by acute hypoxaemia (121 ml.kg-1 without and 109 ml.kg-1 with oxygen; P > 0.05). Renal and non-renal clearances of frusemide were similar during the period of hypoxaemia (31 and 38 ml.min-1, respectively) compared to respective values during supplemental oxygen delivery (29 and 32 ml.min-1). The absolute bioavailability of frusemide during hypoxaemia (0.62) was not different to that obtained during normoxaemia (0.56). The combined sodium and potassium excretion rate (expressed as a function of the frusemide excretion rate) was not altered by changing the oxygen tension. The pharmacokinetics of paracetamol were unaffected by hypoxaemia.

Acetaminophen↗

Ca2+ entry following store depletion in SH-SY5Y neuroblastoma cells.

Ca2+ entry following Ca2+ store depletion was examined in the human neuroblastoma cell line, SH-SY5Y, by measuring the concentration of intracellular free Ca2+ ([Ca2+]i) with fura-2. Application of the muscarinic agonist oxotremorine-M (oxo-M) caused an increase in [Ca2+]i. This consisted of a peak, mediated by release of Ca2+ from internal stores followed by a sustained plateau, mediated by Ca2+ entry across the plasma membrane. The Ca2+ entry resulted from depletion of intracellular Ca2+ stores This pathway was further characterized in the presence of thapsigargin, an inhibitor of the Ca2+ ATPase involved in replenishing IP3-sensitive stores. Stores were first depleted with oxo-M and thapsigargin in the absence of extracellular Ca2+. After washout of oxo-M, subsequent exposure to Ca2+ evoked reproducible increases in [Ca2+]i. Application of oxo-M plus Ca2+ had little effect on the increases in [Ca2+]i, indicating that in SH-SY5Y cells, agonist-dependent pathways contribute little to Ca2+ entry following store depletion. Mn2+, Sr2+ and Ba2+ were permeable through this pathway. Mn2+ and Ba2+ also showed slight permeability in the absence of store depletion. Ca2+ entry following store depletion was blocked by La3+ (IC50 = 75 nM) and by SKF 96365. La3+ blocked Mn2+ entry through the pathway activated by store depletion but did not affect basal Mn2+ permeability. These results indicate that SH-SY5Y neuroblastoma cells have an agonist-independent Ca2+ entry pathway activated by store depletion.

Barium↗

delta- and mu-opioid receptor mobilization of intracellular calcium in SH-SY5Y human neuroblastoma cells.

1. In this study we have investigated delta and mu opioid receptor-mediated elevation of intracellular Ca2+ concentration ([Ca2+]i) in the human neuroblastoma cell line, SH-SY5Y. 2. The Ca(2+)-sensitive dye, fura-2, was used to measure [Ca2+]i in confluent monolayers of SH-SY5Y cells. Neither the delta-opioid agonist, DPDPE ([D-Pen2,5]-enkephalin) nor the mu-opioid agonist, DAMGO (Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol enkephalin) elevated [Ca2+]i when applied alone. However, when either DPDPE or DAMGO was applied in the presence of the cholinoceptor agonist, carbachol (100 nM-1 mM) they evoked an elevation of [Ca2+]i above that caused by carbachol alone. 3. In the presence of 1 microM or 100 microM carbachol, DPDPE elevated [Ca2+]i with an EC50 of 10 nM. The elevation of [Ca2+]i was independent of the concentration of carbachol. The EC50 for DAMGO elevating [Ca2+]i in the presence of 1 microM and 100 microM carbachol was 270 nM and 145 nM respectively. 4. The delta-receptor antagonist, naltrindole (30 nM), blocked the elevations of [Ca2+]i by DPDPE (100 nM) without affecting those caused by DAMGO while the mu-receptor antagonist, CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Pen-Thr-NH2) (100 nM-1 microM) blocked the elevations of [Ca2+]i caused by DAMGO (1 microM) without affecting those caused by DPDPE. 5. Block of carbachol activation of muscarinic receptors with atropine (10 microM) abolished the elevation of [Ca2+]i by the opioids. The nicotinic receptor antagonist, mecamylamine (10 microM), did not affect the elevations of [Ca2+]i caused by opioids in the presence of carbachol. 6. Muscarinic receptor activation, not a rise in [Ca2+]i, was required to reveal the opioid response. The Ca2+ channel activator, maitotoxin (3 ng ml-1), also elevated [Ca2+]i but subsequent application of opioid in the presence of maitotoxin caused no further changes in [Ca2+]i. 7. The elevations of [Ca2+]i by DPDPE and DAMGO were abolished by pretreatment of the cells with pertussis toxin (200 ng ml-1, 16 h). This treatment did not significantly affect the response of the cells to carbachol. 8. The opioids appeared to elevate [Ca2+]i by mobilizing Ca2+ from intracellular stores. Both DPDPE and DAMGO continued to elevate [Ca2+]i when applied in nominally Ca(2+)-free external buffer or when applied in a buffer containing a cocktail of Ca2+ entry inhibitors. Thapsigargin (100 nM), an agent which discharges intracellular Ca2+ stores, also blocked the opioid elevations of [Ca2+]i. 9. delta and mu Opioids did not appear to mobilize intracellular Ca2+ by modulating the activity of protein kinases. The application of H-89 (10 microM), an inhibitor of protein kinase A, H-7 (100 microM), an inhibitor of protein kinase C, protein kinase A and cyclic GMP-dependent protein kinase, or Bis I, an inhibitor of protein kinase C, did not alter the opioid mobilization of [Ca2+]i. 10. Thus, in SH-SY5Y cells, opioids can mobilize Ca2+ from intracellular stores but they require ongoing muscarinic receptor activation. Opioids do not elevate [Ca2+]i when applied alone.

Brain Neoplasms↗

The effect of nociceptin on Ca2+ channel current and intracellular Ca2+ in the SH-SY5Y human neuroblastoma cell line.

The human neuroblastoma cell line SH-SY5Y expresses the 'orphan' opioid receptor (ORL1). We have demonstrated that nociceptin, the putative endogenous ligand for ORL1, produces a concentration-dependent inhibition of the N-type calcium channel current in these cells (IC50 42 nM). In addition, in the presence of carbachol, nociceptin increased the intracellular concentration of Ca2+ (EC50 60 nM). Both effects of nociceptin were blocked by pertussis toxin pretreatment but not by the opioid antagonists CTAP (1 microM), naltrindole (1 microM) and naloxone (10 microM).

Amino Acid Sequence↗

Depression of glutamatergic transmission by nociceptin in the neonatal rat hemisected spinal cord preparation in vitro.

The present study explored the action of nociceptin, the putative endogenous ligand for the orphan opioid receptor (ORL1), on the rat hemisected spinal cord preparation. Electrical stimulation of a dorsal root evokes a glutamatergic population ventral root potential (DR-VRP) in the corresponding ventral root. Low intensity stimulation evokes two A fibre-mediated components; a compound action potential of motoneurones superimposed on a population e.p.s.p. (excitatory postsynaptic potential); at higher stimulus intensities sufficient to activate C fibres a more prolonged population e.p.s.p. is evoked. All three components were depressed by nociceptin in a concentration-dependent manner with IC50 values (s.e.mean) of 119 +/- 2 nM (n = 4), 241 +/- 3 nM (n = 4) and 32 +/- 2 nM (n = 4), respectively. The depressant actions of nociceptin (30 nM and 300 nM) were not reversed by the opioid antagonist naloxone (1 microM). Nociceptin (100 nM and 300 nM) had no effect on the afferent volleys in the dorsal root. Nociceptin therefore appears to be acting as an inhibitory peptide at the spinal level through a naloxone-insensitive opioid receptor.

Amino Acid Sequence↗

Baclofen inhibition of the hyperpolarization-activated cation current, Ih, in rat substantia nigra zona compacta neurons may be secondary to potassium current activation.

1. The properties of the hyperpolarization-activated cation current (Ih), and its modulation by gamma-aminobuturic acid-B (GABAB) receptor activation and protein kinase A, were investigated using whole cell voltage clamp of substantia nigra zona compacta principal neurons in rat midbrain slices in vitro. 2. At 30 degrees C, Ih activated between -75 and -155 mV, with a V1/2 of -115 mV. At 35 degrees C, the activation curve shifted positive by 10 mV. Ih had an estimated reversal potential of -27 mV. Ion substitution experiments showed that the current was carried by Na+ and K+. 3. Application of the GABAB receptor agonist baclofen (30 microM) induced an outward potassium current (GIRK), increased neuronal membrane conductance and inhibited Ih. The inhibition of Ih was voltage independent. Baclofen induced an 11-mV positive shift in the reversal potential of Ih. 4. Extracellular barium (300 microM) markedly reduced the baclofen-evoked outward current and associated increase in membrane conductance due to GIRK activation. There was also very little inhibition of Ih by baclofen in the presence of barium. When cesium was the major intracellular cation, both the increase in membrane conductance due to GIRK activation and the inhibition of Ih evoked by baclofen were reduced by a similar extent. 5. Neither forskolin (10 microM) nor the protein kinase A inhibitor, H89 (10 microM), had any effect on Ih or its inhibition by baclofen. 6. These data suggest that the inhibition of Ih by baclofen is secondary to the activation of GIRK, i.e., due directly to alteration of membrane conductance, rather than a distinct effect, and is not mediated by inhibition of adenylyl cyclase.

Adenylyl Cyclases↗

Repression of protein kinase C and stimulation of cyclic AMP response elements by fumonisin, a fungal encoded toxin which is a carcinogen.

Fusarium moniliforme (FM) is a major fungal pathogen of corn and is involved with stalk rot disease. FM is widely spread throughout the world, including the United States. Most strains of FM produce several mycotoxins, the most prominent of which is called fumonisin. Recent epidemiological studies indicated that ingestion of fumonisin correlates with a higher incidence of esophageal cancer in Southern and Northern Africa and China. Furthermore, fumonisin causes a neurodegenerative disease in horses, induces hepatic cancer in rats, and induces pulmonary edema in swine. Considering that high levels of fumonisin have been detected in healthy and diseased corn grown in the United States, fumonisin may pose a health threat to humans and livestock animals. Structurally, fumonisin resembles sphingolipids which are present in the membranes of animal and plant cells. At the present time, very little is known concerning the mechanism by which fumonisin elicits its carcinogenic effect. Our studies indicate that fumonisin represses expression of protein kinase C and AP-1-dependent transcription. In contrast, fumonisin stimulated a simple promoter containing a single cyclic AMP response element. Since fumonisin did not alter protein kinase A activity, it appears that cyclic AMP response element activation was independent of protein kinase A. It is hypothesized that the ability of fumonisin to alter signal transduction pathways plays a role in carcinogenesis.

Animals↗

Distribution of medical insurance in China.

This paper investigates factors related to the distribution of medical insurance coverage in China, using information from an eight-province household survey of almost 16,000 individuals, conducted in 1989. Results of bivariate analyses show that medical insurance coverage, defined very broadly, varies considerably by individual and regional characteristics. Age, gender, education, occupation, employment sector, urbanization, level of industrial and commercial development, and province are all related to being insured or not. In addition, we find that the type of insurance program available to people varies by these same factors, and that the benefits provided by the seemingly uniform public and worker programs also vary, especially by province and degree of urban development. When the individual and regional variables are considered together in logistic regression analyses, the factors most strongly statistically related to the likelihood of being insured are where one works and where one lives. The distribution of insurance benefits in China appears to result in a pattern in which the rural and the poor, who are often at great risk of illness, are less likely to have medical insurance.

Adolescent↗

Central sensitization as a result of surgical pain: investigation of the pre-emptive value of pethidine for ovariohysterectomy in the rat.

The development of central hypersensitivity as a result of a routine surgical procedure, midline ovariohysterectomy, was investigated in rats using the paw pressure test (PPT) and tail-flick latency (TFL) tests of spinal reflex activity. In addition, the modulating effect of pre-emptive versus post-operative administration of pethidine (a short-acting pure mu-opioid agonist) on the development of central hypersensitivity was studied. Initial experiments indicated that pethidine (15 mg/kg, i.m.) gave sub-maximal increases in thresholds for 60 min, and also that the administration of an anaesthetic did not unduly prolong the action of pethidine. Subsequently, 24 female Wistar rats were allocated to 1 of 4 treatment protocols: (1) anaesthesia without analgesics; (2) anaesthesia and surgery (midline ovariohysterectomy) without analgesics; (3) anaesthesia and surgery with pre-operative administration of pethidine; (4) anaesthesia and surgery with post-operative administration of pethidine. Thirty-five minutes after the end of anaesthesia thermal and mechanical nociceptive thresholds were measured at stepwise increasing intervals for 480 min. Changes were expressed as percentage changes from baseline (PPT) or deviation from expected values (TFL). Area under the threshold versus time response curves (AUCs) were also calculated for the following time sectors: 30-90, 90-150, 150-270, 270-390 and 390-510 min post-anaesthetic. Results of the TFL testing did not indicate the development of any significant hyperalgesia in any groups, but the results of the PPT did. In the time sectors 150-270 and 270-390 min post-anaesthetic, the AUCs in rats subjected to anaesthesia and surgery with either post-operative administration of pethidine or surgery with no analgesic drug administration, were significantly lower than the AUCs in rats given analgesics pre-operatively or those subjected to general anaesthesia alone (P < 0.01), Mann-Whitney). In summary, it appears that pethidine, in this protocol, prevented the development of surgically induced hyperalgesia when it was given pre-emptively.

Animals↗

Putative pre- and postsynaptic ATP-sensitive potassium channels in the rat substantia nigra in vitro.

Pre- and postsynaptic adenosine 5'-triphosphate-sensitive potassium (ATP-K+) currents were studied using whole-cell recordings from substantia nigra zona compacta "principal" neurons in midbrain slices. The GABAA and GABAB receptor-mediated synaptic potentials were unaffected by the ATP-K+ channel inhibitor glibenclamide (30 microM) or by the opener diazoxide (500 microM), indicating that ATP-K+ channels on GABA-ergic terminals are not active, nor can they be activated pharmacologically, under control conditions. However, application of a glucose-free solution to reduce intracellular ATP levels caused a reduction of the GABAB IPSP in all neurons. This was substantially reversed by the sulfonylurea inhibitor tolbutamide (300 microM) in 50% of the neurons tested. The reduction of the GABAB IPSP was a presynaptic effect since postsynaptic hyperpolarizations induced by the GABAB receptor agonist baclofen (10 microM) were unaffected by glucose-free solutions. Diazoxide (500 microM) induced a slowly developing hyperpolarization or outward current in 64% of principal neurons, which was tolbutamide- (100-300 microM) or glibenclamide- (30 microM) sensitive. In contrast, the GABAB receptor agonist baclofen (30 microM) induced a rapid hyperpolarization or outward current in all neurons tested that was unaffected by tolbutamide (300 microM). Although both the diazoxide-induced current and the baclofen-induced current were inhibited by Ba2+ (300 microM), the currents elicited by diazoxide and baclofen summated. The reversal potential for the diazoxide-induced current was also less negative than that for baclofen, which was close to EK. In the presence of intracellular cesium, diazoxide induced a tolbutamide-sensitive inward current in a proportion of neurons, indicating that it has other actions in addition to activating a potassium current. Our results suggest that functional ATP-K+ channels exist both pre- and postsynaptically in the SN, where they modulate the activity of principal neurons. They are different to the potassium channels activated by the GABAB receptor agonist baclofen.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

Pharmacokinetics and pharmacodynamics of dichloroacetate in children with lactic acidosis due to severe malaria.

Lactic acidosis frequently complicates severe malaria in African children, and is a strong independent predictor of mortality. We tested the hypothesis that sodium dichloroacetate (DCA), an activator of pyruvate dehydrogenase, rapidly reduces hyperlactataemia in this patient population. Eighteen children with severe malaria and capillary plasma lactate > or = 5 mM were randomized to receive either intramuscular quinine plus a single 50 mg/kg intravenous infusion of DCA in saline, or quinine plus intravenous saline alone. Two patients in each treatment group died following randomization. Thirty minutes after treatment, the mean plasma lactate was 28% below pretreatment baseline values in the DCA group, but was unchanged in the placebo group. Throughout the first 4 h after treatment, mean plasma lactate in the DCA-treated patients was significantly less than that in controls (p = 0.003). Thereafter, mean plasma lactate declined in both groups and was < 2 mM 10 h after treatment. DCA was well tolerated and did not alter quinine pharmacokinetics. A single intravenous dose of DCA rapidly improved lactic acidosis in African children with severe malaria, suggesting that DCA may be a useful adjunct in the initial treatment of these patients, and may increase their chance of survival by improving a major complication of their illness.

Acidosis, Lactic↗

Gonadotropin requirements of the developing follicle.

OBJECTIVE: To evaluate follicular FSH and LH requirements during suppression of endogenous gonadotropins with the GnRH antagonist Nal-Glu and whether LH-like activity could be supplied by administering subcutaneous hCG. DESIGN: Randomized clinical trial. PARTICIPANTS: Thirty-two normally cycling females in the late follicular phase (dominant follicle mean diameter > or = 14 mm). INTERVENTION: Twelve normal women were randomized to receive 150 IU IM FSH with or without 75 IU SC hCG; 11 subjects were randomized to receive 225 IU FSH with or without 50 IU SC hCG; 9 women received 150 or 225 IU IM hMG. Subjects returned the next day for repeat blood sample and ultrasound. RESULTS: Continued follicular maturation, as evidenced by rising E2 levels, correlated with serum immunoactive and bioactive FSH levels and was unrelated to bioactive LH-hCG. Two hundred twenty-five international units of exogenous FSH consistently supported follicular maturation. There was a similar increase in mean follicular diameter in women with an E2 rise versus those with a plateau or fall. In subjects receiving SC mini-dose hCG, serum bioactive LH-hCG levels were increased significantly and were similar to levels before Nal-Glu. CONCLUSIONS: During administration of a GnRH-a, the maturing follicle appears to require only FSH support. In markedly hypogonadotropic women, mini-dose hCG may be a more practical alternative to recombinant LH to promote normal follicle maturation.

Adult↗

The herpes simplex virus type 2 gene which encodes the large subunit of ribonucleotide reductase has unusual regulatory properties.

Expression of herpes simplex virus type 2 (HSV-2) encoded ribonucleotide reductase (RR) is required for growth of the virus in non-dividing cells. The functional enzyme is composed of a large (RRA) and small (RRB) subunit and the enzyme is expressed as a delayed early activity. The promoter of RRA contains a cis-acting motif (TAATGARAT) which resembles those found in immediate early (IE) genes suggesting RRA is an IE gene. When primate cells were infected with HSV-2, low levels of RRA transcripts were expressed in the presence of cycloheximide indicating RRA is not a true IE gene. Conditions which allow for efficient RRA RNA expression in the presence of cycloheximide were identified in human cells. A phorbol ester, 12-O-tetradecanoyl phorbol-13- acetate (TPA), and hydroxyurea increased the level of RRA RNA expression in the presence of cycloheximide. Hydroxyurea and TPA also stimulated RRA promoter activity in transient assays suggesting these agents induced factors which transactivated the RRA promoter. Expression of an intact c-myc gene transactivated the RRA promoter more than 30-fold in transient assays. Although expression of an intact retinoblastoma gene (Rb) had a slight stimulatory effect on the RRA promoter, mutant Rb proteins also stimulated the RRA promoter. These studies demonstrated that inducible factors in permissive cells increase the steady state levels of RRA RNA in the presence of cycloheximide.

Animals↗

Equity and the utilization of health services: report of an eight-province survey in China.

This paper investigates equity with respect to one component of welfare in China--the provision and use of health services. Based upon a large-scale survey of almost 16,000 individuals in eight provinces in China, we examine a sub-sample of working-age adults who have identified themselves as injured or ill during the four weeks prior to being interviewed. We found that, beyond the level of severity of the reported condition, very few individual-level factors are related to the use of services when ill or injured. Only gender (female) and employment in state-run enterprises are associated with higher patterns of use. These results suggest that China has achieved a very wide distribution of clinics and other services at the local level, and that they are widely used by those who identify need for them. It is rare to be over half an hour away by bike from some form of care and the majority of care appears to be reasonably inexpensive. This broad availability of services contrasts with recent reports from China stressing declining accessibility, and paints a picture of relatively equal access to health care.

Adult↗

Localization of high affinity [3H]glibenclamide binding sites within the substantia nigra zona reticulata of the rat brain.

The rat substantia nigra zona reticulata contains a high density of binding sites for glibenclamide, an adenosine triphosphate-sensitive potassium channel inhibitor, but the precise location of glibenclamide binding sites within this area has not previously been examined. By combining neurochemical lesion and autoradiographical studies we have shown that high affinity [3H]glibenclamide binding sites are located on striatonigral terminals. Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle or of quinolinic acid into the striatum were performed in anaesthetized adult rats to lesion the nigrostriatal and striatonigral pathways respectively. Autoradiography was performed on coronal sections of midbrain with [3H]glibenclamide, [3H]YM-09151-2 (dopamine D2 receptor antagonist) and [3H]SCH 23390 (dopamine D1 receptor antagonist) at three rostrocaudal levels of the substantia nigra. Under the conditions of the incubation [3H]glibenclamide binds primarily to the high affinity site. Following the 6-hydroxydopamine nigrostriatal lesion, D2 receptor binding was reduced (by up to 67%) on the lesioned side at all three levels of the substantia nigra whereas D1 receptor and glibenclamide binding were not significantly affected. In contrast, following striatonigral pathway lesion with quinolinic acid D2 receptor binding was unchanged on the lesioned side, but both D1 receptor and glibenclamide binding were reduced at all three levels (by up to 85% and 63% in the area of maximum lesion, respectively). In adjacent sections, the pattern of D1 binding loss was closely paralleled by the loss of glibenclamide binding. These results demonstrate that the high affinity glibenclamide binding sites of the substantia nigra zona reticulata are, at least in part, located on the terminals of striatonigral projection neurons.

Adenosine Triphosphate↗