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Biomedical subjects

L J Wallace

Publications and source records attributed to L J Wallace.

At least 19 recordsLinked to original sources

AMPA glutamate receptor activation in the posterior zona incerta inhibits amphetamine- and apomorphine-induced stereotypy.

Previous work demonstrated that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor antagonism in the zona incerta (ZI) dorsal to the subthalamic nucleus inhibits stereotypy in rats. The current investigation was undertaken to determine if AMPA receptors in a more caudal portion of the ZI have a role in the expression of stereotyped behavior. Rats were injected bilaterally with AMPA into the posterior ZI dorsal to the substantia nigra, and immediately given a systemic injection of d-amphetamine (10 mg/kg, s.c.) or apomorphine (1 mg/kg s.c.). AMPA produced a dose-dependent inhibition of stereotypy induced by both drugs which was prevented by the coadministration of the AMPA/kainic acid antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX) (0.5 microgram/0.5 microliter). A dose of AMPA as low as 62.5 ng completely abolished the oral component of stereotypy induced by both apomorphine and amphetamine. This dose of AMPA alone had no significant effect on spontaneous locomotor activity but enhanced the locomotor response stimulated by amphetamine (10 mg/kg, s.c.) due to an inhibition of stereotypy. The finding that activation of AMPA receptors in the posterior ZI inhibits stereotypy shows a contrast to results in the neighboring medial ZI dorsal to the subthalamic nucleus, where blockade of AMPA/kainic acid glutamate receptors with DNQX inhibits stereotypy.

Animals

Stimulation of locomotor activity by intra-accumbens AMPA is not inhibited by neonatal 6-hydroxydopamine-induced lesions.

The involvement of dopamine in the hypermotility responses to amphetamine s.c. or AMPA injected into the nucleus accumbens was evaluated in adult rats depleted of dopamine as neonates with 6-hydroxydopamine. The hypermotility response to amphetamine was markedly inhibited in the lesioned animals, while that to AMPA was enhanced. In addition, the hypermotility produced by AMPA in these rats was not inhibited by sulpiride+SCH-23390; however, it was inhibited completely by alpha-methyl-p-tyrosine. These results suggest that the hypermotility produced by AMPA requires endogenous dopamine, but is mediated by a different mechanism than that produced by amphetamine.

Amphetamine

AMPA/kainic acid glutamate receptor antagonism in the zona incerta dorsal to the subthalamic nucleus inhibits amphetamine-induced stereotypy bur not locomotor activity.

The effect of 6,7-dinitroquinoxaline-2,3-dione (DNQX), an alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainic acid glutamate receptor antagonist, injected into the zona incerta (ZI) was investigated to determine whether the behavioral responses to systemic amphetamine involve AMPA/kainic acid receptors in this brain region. Rats were injected bilaterally in the ZI with either vehicle or DNQX (1 microgram/0.5 microliter) and immediately given a systemic injection of D-amphetamine (0.5, 1.0 or 10.0 mg/kg, s.c.). Locomotor activity was recorded for 1 h. DNQX did not significantly affect hypermotility stimulated with 0.5 and 1.0 mg/kg amphetamine, but markedly increased the level of locomotor activity elicited by the higher dose, 10 mg/kg. To test the hypothesis that the enhanced locomotor response to high dose amphetamine was due to an inhibition of stereotyped behavior, the effect of DNQX in the ZI on amphetamine and apomorphine-induced stereotypy was investigated. DNQX significantly inhibited stereotypy induced by amphetamine (10 mg/kg) and apomorphine (1 mg/kg), with the onset of inhibition of amphetamine-induced stereotypy corresponding to the onset of enhanced locomotor activity. Ibotenic acid lesions of the ZI produced similar results, having an insignificant effect on locomotor activity stimulated by low dose amphetamine (1 mg/kg) and an attenuation of apomorphine-induced stereotypy which was of a magnitude comparable to that produced by DNQX. Thus, the AMPA/kainic acid subtypes of glutamate receptors in the ZI may be involved in the regulation of motor function mediated via striatal output but not mesolimbically generated locomotor activity.

Animals

Effect of serotonergic agonists in the nucleus accumbens on d-amphetamine-stimulated locomotion.

Serotonergic projections from the raphe nuclei are thought to modulate locomotor activity in the rat, and serotonin injection into the nucleus accumbens attenuates the hypermotility elicited by amphetamine. The purpose of the present study was to characterize the effects of various classes of serotonergic agonists administered into the nucleus accumbens on d-amphetamine-stimulated locomotor activity in order to determine which serotonin receptor subtypes are involved. Administration of the nonselective 5-HT agonist quipazine, the 5-HT-1 agonist mCPP, the 5-HT-1a agonist 8-OH-DPAT, the 5-HT-1b agonist CGS-12066B, and the 5HT-1c/2 agonist DOI did not inhibit d-amphetamine-stimulated locomotor activity. Pronounced lateral head weaving was noted after 8-OH-DPAT administration. The combination of the 5-HT-1a agonist 8-OH-DPAT and the 5-HT-1b agonist CGS-12066B, however, did inhibit d-amphetamine-stimulated locomotor activity. In contrast, the 5-HT-3 agonist 1-phenylbiguanide enhanced the locomotor effect of d-amphetamine. This effect was partially reversed by the 5-HT-3 antagonist MDL-7222. These studies suggest that serotonin has complex and multiple effects on the regulation of locomotor activity within the nucleus accumbens.

Animals

Pectineus tendon surgery for the management of canine hip dysplasia.

Pectineus tendonectomy is a useful procedure for relieving pain and rehabilitating the dysplastic dog in select cases. Relief of pain is believed to come from a combination of releasing tension on the hip joint capsule and providing a better loading contact surface on the articular cartilage owing to the increased abduction of the hind legs after surgery. Some pain relief also may come from the release of tension on the pectineus muscle. The modified procedure described in this article results in less seroma formation and less reattachment of the severed ends of the pectineus tendon of origin than the procedure originally described by the author.

Animals

alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor antagonists in the nucleus accumbens and ventral pallidum decrease the hypermotility response to psychostimulant drugs.

The purpose of this study was to determine the role of alpha-amino-3-hydroxy- 5-methylisoxazole-4-propionate (AMPA)/kainate excitatory amino acid receptors in the nucleus accumbens and the ventral pallidum in the hypermotility responses to amphetamine, caffeine and scopolamine. To accomplish this, we determined the effects of intracranial injections of 6,7-dinitroquinoxaline-2,3-dione (DNQX) and gamma-D-glutamylaminomethyl-sulfonate (GAMS), which inhibit the responses to AMPA, quisqualate and kainate in electrophysiological and behavioral studies. The bilateral administration of either DNQX (1 micrograms/0.5 microliters) or GAMS (5 micrograms/0.5 microliters) into the nucleus accumbens inhibited the locomotor stimulation produced by amphetamine (0.5 mg/kg s.c.) but not by caffeine (20 mg/kg s.c.) or scopolamine (0.5 mg/kg s.c.). However, the bilateral administration of either of the two antagonists into the ventral pallidum inhibited the response to all three stimulants. The administration of 6-amino-7-fluroquinoxaline-2,3-dione, a chemical analog of DNQX that does not bind to AMPA receptors, into either the nucleus accumbens or the ventral pallidum did not inhibit the locomotor stimulation produced by amphetamine. Neither DNQX nor GAMS injected into either the nucleus accumbens or the ventral pallidum produced significant changes in the locomotor activity of animals not injected with the stimulants. These results suggest that activation of AMPA/kainate receptors in the nucleus accumbens is important in the stimulation of locomotion produced by amphetamine, whereas activation of these receptors in the ventral pallidum is involved in the hypermotility response to all three central nervous system stimulants.

Animals

Activation of AMPA/kainic acid glutamate receptors in the zona incerta stimulates locomotor activity.

Direct injections of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), an AMPA/quisqualic acid receptor agonist, into the medial or posterior zona incerta (ZI) produced a marked stimulation of locomotor activity accompanied by a postural change. Similar responses were obtained by injection of kainic acid (KA) into the same areas. The behavioral effects of AMPA and KA were antagonized by coinjection of 6,7-dinitroquinoxaline-2,3-dione (DNQX), and non-N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. In contrast, injections of NMDA or ibotenic acid failed to significantly stimulate locomotor activity. These results suggest that the AMPA/kainate glutamate receptor subtypes in the zona incerta may have a functional role in regulating locomotor activity.

Animals

Stimulation of mono- and diacylglycerol lipase activities in ibotenate-induced lesions of nucleus basalis magnocellularis.

Ibotenic acid was injected into the nucleus basalis magnocellularis region of rat brain in order to study whether an elevation of lipase activities was associated with the degeneration of cholinergic neurons in this potential animal model of Alzheimer's disease. Two plasma membrane fractions were prepared from different regions of ibotenate injected (right hemisphere) and non-injected (left hemisphere) rat brain. One plasma membrane fraction was from synaptosomes (SPM) and the other from glial and neuronal cell bodies (PM). Activities of mono- and diacylglycerol lipases in these plasma membrane fractions were markedly increased (3- to 5-fold) in hippocampus, midbrain and frontal cortical regions of rat brain at 10 days after the injection of ibotenate. The activity of choline acetyltransferase was decreased in frontal cortex but unchanged in hippocampus and midbrain. Our results suggest that the increase in lipase activity is much more widespread and non-specific than is the decrease in cholinergic function.

Alzheimer Disease

The role of endogenous dopamine in the hypermotility response to intra-accumbens AMPA.

The present study was designed to investigate the role of dopamine in the locomotor stimulant response produced by the bilateral administration of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) into the nucleus accumbens. The hypermotility produced by lower doses of AMPA (up to 0.25 microgram) was inhibited by either SCH23390 or sulpiride, a D1 and D2 receptor antagonist, respectively. The locomotor response to a higher dose of AMPA (0.5 microgram) was greater than the maximum response to intra-accumbal injection of amphetamine and was significantly inhibited only when both the D1 and D2 antagonists were administered together. Alpha-Methyl-p-tyrosine inhibited the locomotor response to AMPA (0.5 microgram), and this inhibition was reversed by the co-injection of AMPA with either SKF38393, a D1 agonist, or quinpirole, a D2 agonist, at doses which were ineffective in the absence of AMPA. AMPA when infused into the nucleus accumbens produced an increase in extracellular dopamine, suggesting that AMPA can enhance dopamine efflux. The injection of AMPA into the nucleus accumbens significantly increased the DOPAC/dopamine ratio, which is different from the decrease in ratio reported for amphetamine. These data suggest that the stimulation of locomotor activity by intra-accumbal AMPA may be the result of an enhancement in dopamine efflux as well as a change in the response to dopaminergic receptor activation.

Amphetamine

Effects of morphine in the nucleus accumbens on stimulant-induced locomotion.

This study assessed the effects of morphine in the nucleus accumbens on motility elicited by dopaminergic and other classes of drugs, using locomotor activity as the measured response. Dopaminergic stimulants, d-amphetamine (10 micrograms) or dopamine (20 micrograms, 2 hours after nialamide, 200 mg/kg, IP) induced large increases in locomotor activity when injected into the nucleus accumbens. This response was blocked by coadministration of morphine (5 micrograms). The hypermotility response elicited by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA; 0.5 micrograms), an excitatory amino acid agonist, was also abolished by coadministration of morphine. Increasing the dose of AMPA to 1.5 micrograms partially overcame the morphine block, while increasing the dose of amphetamine to 50 micrograms did not. In other experiments, morphine (5 micrograms) injected into the nucleus accumbens blocked the hypermotility elicited by systemic caffeine (10 mg/kg, SC) or scopolamine (0.5 mg/kg, SC) or intra-accumbal MK-801 (5 micrograms). However, picrotoxin (0.15 or 0.5 microgram) injected into the nucleus accumbens elicited a hypermotility that was not attenuated by coinjection of morphine (5 or 10 micrograms). These data demonstrate that opiate and dopaminergic pathways have competing actions on the regulation of locomotion in the nucleus accumbens. Furthermore, the results with combinations of picrotoxin and morphine suggest the presence of two distinct locomotor pathways or a GABA receptor site "downstream" from the morphine site in a single pathway.

Amphetamine

Characterization of muscarinic receptors of bovine adrenal chromaffin cells: binding, secretion and anti-microtubule drug effects.

1. Binding of [3H]QNB to adrenal membranes is saturable, specific and to a single class of receptors. 2. Tubulozole, and not other microtubule drugs, inhibits [3H]QNB binding. 3. Pretreating cultured chromaffin cells with oxotremorine, a muscarinic receptor agonist, has no effect on either basal, nicotine (10 microM) or K(+)-stimulated catecholamine release and failed to enhance secretion of submaximal concentrations of nicotine (3-5 microM). 4. These results confirm that binding of [3H]QNB is associated with muscarinic receptors on bovine adrenal medullary tissue. 5. These studies also demonstrate that although bovine adrenal chromaffin cells possess muscarinic receptors, these receptors do not appear to be coupled to secretory processes.

Adrenal Glands

Neurokinin A increases short-circuit current across rat colonic mucosa: a role for vasoactive intestinal polypeptide.

1. Neurokinin A (NKA) is a mammalian tachykinin distributed principally in the nervous system, including the myenteric innervation of the gut. 2. NKA may be involved in neurogenic inflammation and as a modulatory factor in the diarrhoea associated with mucosal inflammation of inflammatory bowel disease (ulcerative colitis). 3. We evaluated the effect of NKA on the short-circuit current ISC, assumed to reflect electrogenic chloride secretion, across muscle-stripped rat colonic mucosa mounted in Ussing chambers. 4. Serosal addition of NKA produced a concentration-dependent (0.1-100 nM) increase in ISC with an EC50 (half-maximal effective concentration) value of 7.5 nM. The maximum (mean +/- S.E.M.) increase in ISC (microA/cm2) for NKA was 111 +/- 10. 5. Tetrodotoxin (0.5 microM) and bumetanide (10 microM), but not atropine (1.0 microM), hexamethonium (100 microM) or pyrilamine (10 microM), significantly inhibited NKA-induced increases in ISC. 6. The response to NKA was attenuated by 45 min pre-treatment with antisera raised against vasoactive intestinal polypeptide (VIP). Moreover, prior desensitization to VIP attenuated the effect of NKA. 7. These studies suggest that NKA increases ISC in rat colon, in part, through a non-cholinergic neural mechanism involving VIP.

Animals

Hypervariable minisatellite DNA is a hotspot for homologous recombination in human cells.

Hypervariable minisatellite DNA sequences are short tandemly repeated sequences that are present throughout the human genome and are implicated to enhance recombination. We have constructed a consensus hypervariable minisatellite sequence and analyzed its effect on homologous recombination in human cells in culture. The consensus sequence d(AGAGGTGGGCAGGTGG)6.5 is shown to stimulate homologous recombination up to 13.5-fold. The stimulation occurs at a distance and in both directions but does show a quantitative directionality. Stimulation occurs in a codominant manner, and the sequence is inherited equally in the products. Enhancement is maintained, but at a reduced level, when double-strand breaks are introduced into the substrates. Multiple unselected recombination events are promoted, and preferential stimulation of reciprocal exchange events is demonstrated.

Animals

The Z-DNA motif d(TG)30 promotes reception of information during gene conversion events while stimulating homologous recombination in human cells in culture.

Tracts of the alternating dinucleotide polydeoxythymidylic-guanylic [d(TG)].polydeoxyadenylic-cytidylic acid [d(AC)], present throughout the human genome, are capable of readily forming left-handed Z-DNA in vitro. We have analyzed the effects of the Z-DNA motif d(TG)30 upon homologous recombination between two nonreplicating plasmid substrates cotransfected into human cells in culture. In this study, the sequence d(TG)30 is shown to stimulate homologous recombination up to 20-fold. Enhancement is specific to the Z-DNA motif; a control DNA fragment of similar size does not alter the recombination frequency. The stimulation of recombination is observed at a distance (237 to 1,269 base pairs away from the Z-DNA motif) and involves both gene conversion and reciprocal exchange events. Maximum stimulation is observed when the sequence is present in both substrates, but it is capable of stimulating when present in only one substrate. Analysis of recombination products indicates that the Z-DNA motif increases the frequency and alters the distribution of multiple, unselected recombination events. Specifically designed crosses indicate that the substrate containing the Z-DNA motif preferentially acts as the recipient of genetic information during gene conversion events. Models describing how left-handed Z-DNA sequences might promote the initiation of homologous recombination are presented.

Animals

Effects of thromboxane A2 on thoracic aorta of young and old rats: use of selective thromboxane receptor antagonists.

Thromboxane A2 (TXA2) is a bioactive metabolite of arachidonic acid which produces vascular smooth muscle contraction and blood platelet aggregation. The goal of this study is to establish whether there are age-dependent differences of vascular contractility to TXA2. Thoracic aorta of F-344 rats of age 4-6 months (young) and 22-23 months (old) were used as a model to examine responses to U46619 [(15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid; a TXA2 agonist] alone or in the presence of prostanoid (SQ 29,548) or nonprostanoid (trimetoquinol, TMQ) endoperoxide/TXA2 receptor antagonists. Maximal contractile responses (84 and 89% relative to KCl) and EC50 values (23 and 55 nmol/l, respectively) to U46619 were the same in aortic strips of young and old animals. Experimentally determined pA2 and pKB values for SQ 29,548 and TMQ as antagonists of U46619-mediated contraction were unchanged in aorta of young (9.09 and 5.83, respectively) and old (9.41 and 6.10, respectively) rats. We conclude that the reactivity and population of TXA2 receptors in rat vascular smooth muscle are unaffected by the aging process.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5

Characterization of Ile,Ser-bradykinin-induced changes in short-circuit current across rat colon.

The effects of Ile,Ser-bradykinin (TK) on electrolyte secretion across mucosa of rat distal colon were determined and compared to those of bradykinin (BK). A segment of colon stripped of muscularis was mounted in an Ussing chamber for monitoring short-circuit current (Isc). Serosal application of TK and BK produced a concentration-dependent and transient increase in Isc with EC50(nM) values of 2.0 +/- 0.6 and 1.7 +/- 0.7, respectively. At a concentration of 1.0 microM, TK produced a maximal response of 130 +/- 18 compared to 75 +/- 13 microA/cm2 for BK. Increases in Isc induced by BK and TK were significantly (P less than .001) inhibited (90 +/- 4% for BK and 87 +/- 5% for TK) by serosal addition of bumetanide (10 microM). The lipoxygenase/cyclooxygenase inhibitor, eicosa-5,8,11,14-tetraynoic acid (0.1 mM), inhibited (P less than .01) the response to BK by 67 +/- 9% and to TK by 51 +/- 8%. Moreover, the cyclooxygenase inhibitor indomethacin (5.0 microM) significantly (P less than .05) inhibited the Isc response to 1.0 nM BK and 1.0 nM TK. Atropine (1.0 microM) did not block the effects of either kinin. Finally, the BK antagonist D-Arg0[Hyp3,Thi5,8,DPhe7]-bradykinin (2.0 microM) competitively antagonized the effect of BK and TK, shifting the concentration curve competitively to the right by 6-fold and 16-fold respectively. Another BK antagonist, [D-Phe7]-bradykinin (20 microM), also exhibited similar blockade effects. In this model, although some differences exist, BK and TK appear to act by the same mechanism, which may involve arachidonic acid metabolites.

Animals

Sensory nerves and urinary bladder function: effects of diabetes, capsaicin and acrylamide treatment.

1. A comparison was made of the proposed neurotoxic effects of acrylamide, capsaicin, and diabetes on rat urinary bladder pressure responses elicited by infusion of buffer into the organ (distension). 2. Treatment with capsaicin or acrylamide completely abolished the bladder pressure responses. 3. After 4 weeks of diuresis equivalent to that of the diabetic model, the pressure response was markedly diminished compared to control. This response was greatly increased following L-DOPA, which augments the micturition reflex. 4. After 4 weeks of streptozoticin-induced diabetes, the pressure response was slightly diminished compared to control and most closely resembled the response from the diuretic group treated with L-DOPA.

Acrylamides