Biomedical subjects

P McGonigle

Publications and source records attributed to P McGonigle.

At least 19 recordsLinked to original sources

PubMed2000

Quantitative autoradiographic mapping of rat brain dopamine D3 binding with [(125)I]7-OH-PIPAT: evidence for the presence of D3 receptors on dopaminergic and nondopaminergic cell bodies and terminals.

The regional distribution and cellular localization of dopamine D3 receptors in the rat brain was examined using quantitative autoradiography. [(125)I]7-OH-PIPAT bound in a saturable and reversible manner and exhibited subnanomolar affinity for a single population of GTP-insensitive sites. The pharmacological profile was characteristic of cloned D3 receptors and nonspecific binding was uniformly low. The highest levels of D3 receptors were measured in the islands of Calleja, nucleus accumbens, ventral pallidum, substantia nigra, and lobules 9 and 10 of the cerebellum. The high specific activity of this ligand also allowed detection of D3 receptors in other regions, including the serotonergic dorsal and median raphe nuclei, indicating that the distribution of this receptor is more widespread than previously appreciated. The cellular localization of D3 receptors in regions containing dopaminergic cells and terminals was examined by discrete injection of neurotoxins. Lesion of dopaminergic neurons with 6-hydroxydopamine produced 50% decreases in [(125)I]7-OH-PIPAT binding in the nucleus accumbens and substantia nigra. Quinolinic acid lesion of neurons originating in the nucleus accumbens also produced approximately 50% decreases in D3 receptors in the nucleus accumbens, substantia nigra, and ventral pallidum. 5, 7-Dihydroxytryptamine lesion of serotonergic cells and processes produced no changes in [(125)I]7-OH-PIPAT binding. These results demonstrate the presence of D3 receptors in several brain regions not previously identified and suggest that D3 receptors are expressed at somatodendritic and terminal levels of both dopaminergic and nondo-paminergic cells within the mesolimbic dopamine system.

5,7-Dihydroxytryptamine↗

PubMed2000

Differential regulation of dopamine D2 and D3 receptors by chronic drug treatments.

Regulation of the expression of dopamine D2 and D3 receptors in the rat brain was examined using quantitative autoradiography after chronic (14 day) drug treatments designed to increase or decrease dopamine receptor stimulation. Reserpine treatment depleted endogenous dopamine by more than 90% and significantly increased the binding of [(125)I]NCQ 298 to D2 receptors in the nucleus accumbens, ventral pallidum, and substantia nigra. In contrast, this treatment significantly decreased the binding of [(125)I]7-OH-PIPAT to D3 receptors in each of these regions. Chronic stimulation of D2-like receptors with quinpirole (1 mg/kg/day) or 7-OH-DPAT (1 mg/kg/day) produced decreases in [(125)I]NCQ 298 binding in the nucleus accumbens, ventral pallidum, and substantia nigra as expected. As with depletion, chronic stimulation elicited an opposite response from D3 receptors with significant increases observed in the ventral pallidum and substantia nigra. D3 receptor expression in the nucleus accumbens was unchanged. Baclofen (30 mg/kg/day) or continuous administration of the psychomotor stimulant cocaine (20 mg/kg/day) produced no significant changes in D2 or D3 receptor binding in any region examined. Acute administration of the irreversible antagonist EEDQ (10 mg/kg) nearly eliminated D2 receptor binding in all regions, but inactivated D3 receptors only in the VP and SN, suggesting subtype-specific and region-specific differences in receptor occupancy. The existence of regional and subtype-specific heterogeneities in the regulation of these receptors supports the contention that despite their similar pharmacological profiles, D2 and D3 receptors may mediate different functional responses.

Animals↗

PubMed1999

Physiological and anatomical correlates of the human dentate gyrus: consequences or causes of epilepsy.

The presence of paroxysmal discharges in the epileptic human dentate gyrus provides a physiologic basis for hyperexcitability that may initiate seizure discharges during the development of epilepsy. Although these responses can occur with single orthodromic stimulation, data obtained under conditions that weaken synaptic inhibition (e.g., 1 Hz stimulation or bicuculline disinhibition) suggest that paroxysmal discharges may be a more common feature of tissue from temporal lobe epileptic patients than has been reported previously. Hilar cell loss and weakened synaptic inhibition may provide conditions favorable for the activation of N-methyl-D-aspartate acid (NMDA) receptors that would allow triggering of paroxysmal discharges that normally never are evoked in dentate granule cells in nonepileptic humans. As the dentate gyrus in normal animal tissue is not susceptible to intrinsic bursting behavior and is characterized by a relatively short duration excitatory postsynaptic potential even under pharmacologic disinhibition, paroxysmal discharges in the epileptic human dentate gyrus may provide an important clue to understanding the prerequisite conditions for seizure discharge.

Animals↗

PubMed1997

Ontogeny of dopamine D3 receptors in the nucleus accumbens of the rat.

The expression of dopamine D2 and D3 receptors in the developing rat nucleus accumbens and striatum was examined using quantitative receptor autoradiography. Male Sprague-Dawley rats were sacrificed on postnatal day 3, 7, 10, 14, 21, or 60. Sections were labeled with [125I]NCQ 298, which binds to both D2 and D3 receptor subtypes. Binding to D2/D3 receptors in the caudate-putamen appeared as early as P3 (approximately 20% of adult) and approached adult levels (75% of adult) by P21. D2/D3 receptors in the nucleus accumbens and olfactory tubercle developed with a similar time course. [125I]R(+)trans-7-hydroxy-2-(N-n-propyl-N-3'-iodo-2'-propenyl)aminotetra lin ([125I]7-OH-PIPAT) was used to selectively label D3 receptors in adjacent sections. [125I]7-OH-PIPAT binding was absent at P3 and just detectable at P7 and P10 (approximately 5% of adult). Appreciable D3 labeling appeared in the islands of Calleja at P14 and in the nucleus accumbens at P21. [125I]7-OH-PIPAT also detected a very low density of D3 receptors in the caudate-putamen which developed with a profile very similar to that of D3 receptors in the nucleus accumbens. Expression of the D2 receptor subtype therefore appears to precede expression of the D3 receptor subtype. Additionally, D2 receptors in different regions are expressed with a similar developmental profile, but there appears to be more heterogeneity in the ontogeny of forebrain D3 receptor expression.

Aging↗

PubMed1997

Differential effects of three acute stressors on the serotonin 5-HT1A receptor system in rat brain.

The effects of different acute stressors on circulating corticosterone levels, 5-HT1A receptors and 5-HT1A mRNA levels were measured in male Sprague-Dawley rats. Two hours restraint stress, short swim stress (15 min) and long swim stress (30 min) increased circulating corticosterone levels 10-, 13- and 18-fold, respectively, when measured immediately after termination of the stress. Each stressor produced a unique profile of changes in 5-HT1A receptors measured in coronal sections 24 h after the termination of stress with the antagonist [125I]-4-(2'-methoxyphenyl)-1-[2'-(n-2"-pyridinyl)-p-iodobenzamido ] ethylpiperazine and the agonist [3H]-8-hydroxy-2-(di-n-propylamino)tetralin. Restraint stress produced decreases in antagonist binding in the CA3 region and dentate gyrus: agonist binding was decreased only in the dentate gyrus. Despite the larger elevation in circulating corticosterone level measured after short swim stress, no changes in agonist or antagonist binding were detected after this stressor. In contrast, the long swim stress increased antagonist binding in the CA2 region and in layers IV-VI of the cortex: agonist binding was also increased in all regions of the hippocampus and in layers I-VI of the cortex. Thus, restraint and long swim stress produce opposite effects on 5-HT1A receptor expression in different subregions of the hippocampus. Analysis of presynaptic 5-HT1A receptors in the raphe nuclei revealed an increase in antagonist binding in the dorsal raphe following long swim stress. No change in the level of 5-HT1A mRNA measured in adjacent sections was detected following any of the stressors. The role of corticosteroid receptors in these stress-induced alterations of 5-HT1A receptors and the potential significance of these alterations in the context of affective disorders are discussed.

Animals↗

PubMed1997

Mossy fiber reorganization and its possible physiological consequences in the dentate gyrus of epileptic humans.

It is unlikely that MF reorganization is the cause of epilepsy, but it may affect the progression of the disease, i.e., the frequency or severity of seizures. We propose that early events, yet undiscovered, lead to an increased likelihood of excitability. This hyperexcitability, which initially may not be manifested in overt seizures, may erode vulnerable hilar neurons that serve an important inhibitory function, as illustrated in Fig. 6-15. As inhibition is lost, hyperexcitability reaches the level of clinically manifested seizures that are severe enough to lead to substantial loss of hilar neurons. When the loss of these cells is sufficiently high, MF reorganization occurs, first to neighboring hilar neurons and later to dendrites of granule cells (Fig. 6-15). Thus, the functional consequence of MF reorganization may provide a compensatory form of inhibition, as well as a circuit for feedback excitation. Although definitive evidence indicating that MF reorganization contributes to the acceleration or progression of epilepsy is missing, the findings to date are consistent with this hypothesis. In the event that reorganization contributes to the epileptic condition, treatments that reduce indicators of neuropathology may lead to a reduction of seizure frequency and severity. Evidence suggests that reorganization in the dentate gyrus may follow the pathways of neuronal processes of hilar neurons that have died. Thus, further study of the events that guide MF reorganization may hold important clues for developing methods for targeting regenerating axons following central nervous system injury.

Dentate Gyrus↗

PubMed1996

Changes in behavioral sensitivity to SKF-38393 and quinpirole following withdrawal from continuous cocaine administration in rats.

The effects of withdrawal from continuous administration of cocaine on spontaneous locomotor activity and behavioral sensitivity to SKF-38393 and quinpirole were examined in rats. Subdermal minipumps that delivered either saline or 20 mg/kg/day cocaine hydrochloride were implanted for 14 days. Spontaneous locomotor activity, SKF-38393-induced (10 mg/kg, SC) grooming and tongue protrusions, and quinpirole-induced locomotor activity and stereotypy (0.32 and 1.0 mg/kg, SC) were examined either 4-5 h or 7 days after removal of the minipumps. Animals withdrawn from cocaine for 4 h exhibited a decrease in spontaneous locomotor activity relative to saline-pretreated controls, whereas animals withdrawn for 7 days did not differ from controls. Animals withdrawn from cocaine for 4 h did not differ from controls in their sensitivity to SKF-38393, whereas animals withdrawn from cocaine for 7 days exhibited an increase in SKF-38393-induced tongue protrusions relative to controls. In contrast, animals withdrawn from cocaine for 4 h exhibited a decrease in quinpirole-induced locomotion, whereas animals withdrawn for 7 days did not differ from controls. There were no differences in sensitivity to quinpirole-induced stereotypy relative to controls at either withdrawal period. These findings suggest that an increased sensitivity of D1-like receptors emerges within 7 days during the course of withdrawal from continuous cocaine administration, whereas a change in sensitivity of D2-like receptors may occur early during withdrawal but normalizes within 7 days.

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

PubMed1996

Time-course of recovery of 5-HT1A receptors and changes in 5-HT1A receptor mRNA after irreversible inactivation with EEDQ.

In this study, the relationship between the expression of 5-HT1A receptors and level of receptor mRNA in discrete regions of rat brain was examined by inactivation of 5-HT1A receptors with the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; i.p., 10 mg/kg) and measurement of the time-course of receptor recovery and changes in receptor mRNA levels. Inactivation of 5-HT1A receptors ranged from 84% in the dorsal raphe to 97% in the cortex 12 h after administration of EEDQ. Receptor levels returned to 62-100% of control levels by day 7 and the rate of recovery was uniform across all regions examined. The rate of recovery of 5-HT1A receptors labeled by the agonist [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) and by the putative antagonist [125I]4-(2'-methoxy)phenyl-1-[2'-(N-2"-pyridinyl)-p-iodobenzamido] ethylpiperazine ([125I]p-MPPI) did not differ across regions, suggesting that the ratio of high versus low affinity states of the 5-HT1A receptor remains relatively constant during receptor recovery. However, there did appear to be a short lag in the recovery of sites labeled with the agonist. Significant increases in 5-HT1A receptor mRNA levels were observed as early as 12 h after treatment in all regions but the magnitude of these increases varied. The time-courses of recovery of 5-HT1A receptors and changes in mRNA levels were not parallel in individual regions. Moreover, inactivation of low (8-26%) to moderate (29-57%) levels of 5-HT1A receptors produced no change in mRNA levels, whereas inactivation of greater than 90% elicited a robust increase in mRNA levels. Thus, changes in 5-HT1A receptor expression are not mediated exclusively by changes in mRNA levels and extensive receptor inactivation is required to trigger transcriptional regulation.

Animals↗

PubMed1996

Regional variability in changes in 5-HT2A receptor mRNA levels in rat brain following irreversible inactivation with EEDQ.

In this study, the relationship between the expression of 5-HT2A receptors and level of 5-HT2A receptor mRNA in discrete regions of rat brain was examined by inactivating 5-HT2A receptors with the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 10 mg/kg, i.p.) and measuring the time course of receptor recovery and changes in mRNA levels. In untreated controls, the distribution and levels of 5-HT2A receptors labeled with [3H]ketanserin and receptor mRNA labeled with a 230-base 33P-labeled riboprobe were found to be highly correlated in most sub-regions of the cortex, the caudate-putamen and the claustrum but not in the piriform cortex or the hippocampus. Administration of EEDQ produced 90-99% inactivation of 5-HT2A receptors and the rate of receptor recovery was uniform in most regions studied. 5-HT2A receptors in most regions reached control levels by day 14, the lone exception being the caudate-putamen where receptors reached only 56% of control by day 14. Following inactivation of receptors with EEDQ there was a transient increase in levels of 5-HT2A receptor mRNA in several regions. Although rates of receptor recovery were uniform, four distinct patterns of mRNA response were observed: (1) early elevation followed by late elevation, (2) early elevation only, (3) late elevation only, and (4) no detectable change. The absence of a direct relationship between changes in 5-HT2A receptor mRNA and 5-HT2A receptor recovery in this model system suggests that transcriptional regulation is not the mechanism controlling the recovery of these receptors after irreversible inactivation. This study also lends support to the idea that alternative mechanisms may play a role in 5-HT2A receptor regulation after other pharmacological and physiological manipulations. The regional variability in 5-HT2A mRNA regulation reported here highlights the importance of using techniques with a high level of anatomical resolution to study changes in 5-HT2A receptor mRNA levels.

Animals↗

PubMed1996

Pharmacological and immunological characterization of N-methyl-D-aspartate receptors in human NT2-N neurons.

NT2 cells are a clonal line of human teratocarcinoma cells that exhibit N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity after terminal differentiation into NT2-N neurons. In this study, we used modulation of glutamate excitotoxicity to characterize the pharmacological properties and specific antibodies to determine the individual subunits of NMDA receptors expressed by NT2-N neurons. The glycine site antagonist 7-chlorokynurenic acid completely blocked glutamate toxicity in a dose-dependent manner. Histamine and the polyamine agonists spermine and spermidine enhanced glutamate toxicity in a dose-dependent manner consistent with expression of an NR1-NR2B combination of subunits. The efficacy of polyamine agonists suggests the expression of one or more splice variants of the NR1 subunit that lack the putative surface loop encoded by exon 5. Surprisingly, the putative inverse agonists diaminodecane and diaminododecane also enhanced toxicity in a dose-dependent manner. The antagonists arcaine and ifenprodil completely blocked glutamate toxicity in NT2-N cells. The atypical antagonist ifenprodil inhibited toxicity with a uniformly high affinity characteristic of interaction with the NR1-NR2B combination of subunits. Expression of both NR1 and NR2 subunits were detected by Western blot analysis. Neither protein was detectable in undifferentiated cells. In contrast, 70-fold lower levels of the NR2A subunit were detected in both differentiated and undifferentiated cells. The pharmacological and immunological results indicate that a functional NR1-NR2B combination of subunits is expressed by NT2-N neurons. Despite the immunological detection of NR2A subunit, no functional combination of NR1 and NR2A subunits could be demonstrated.

Animals↗

PubMed1995

Longitudinal variation in cell density and mossy fiber reorganization in the dentate gyrus from temporal lobe epileptic patients.

Variation in cell loss and mossy fiber reorganization was examined along the longitudinal axis of the dentate gyrus from temporal lobe epileptic (TLE) patients. Previous evidence has indicated that the anterior hippocampus is prone to seizure activity. We compared granule and hilar cell number in addition to Timm stain density of the molecular layer and hilus in more anterior and more posterior specimens of hippocampus obtained from patients surgically treated for intractable epilepsy by the removal of the anterior half of the hippocampus. Granule cells/mm in the more anterior specimen were less than or equal to those in the more posterior specimen locations in 77% of the patients, while there was no significant difference in hilar neuron density between the two blocks. These results demonstrate a significantly greater pathology in the granule cell layer in more anterior specimens and no difference in pathology for hilar neurons. Molecular layer Timm stain density was significantly greater in the more anterior specimen of 71% of the patients. The molecular layer Timm stain density ratio was inversely related to hilar cell density in more anterior specimens, whereas in more posterior specimens there was no significant relationship with hilar cell density. Our observations show that although differences exist among TLE patients for these neuroanatomic measures, pathology was greater in more anterior specimens. The latter result is consistent with the conclusion that seizure activity may originate in the anterior region of the hippocampus in a majority of patients.

Adult↗

PubMed1995

Anatomical localization of SKF-38393-induced behaviors in rats using the irreversible monoamine receptor antagonist EEDQ.

This study was designed to localize the population of dopamine D1-like receptors involved in grooming and oral movements elicited by systemic administration of the D1-selective agonist SKF-38393. Receptors in specific dopamine terminal regions were inactivated by intracranial injection of the nonselective irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). The effect of these injections on behaviors induced by systemic administration of SKF-38393 (10 mg/kg) was measured 48 hours later. The specific populations of D1-like receptors inactivated by the EEDQ injections were identified as a loss of 3H-SCH-23390 binding in a given region using quantitative autoradiography. EEDQ (1.5 micrograms/microliters/side) injected into the nucleus accumbens (NAc) did not alter SKF-38393-induced behaviors. Similarly, injection of EEDQ into the medial caudate-putamen (CPu) failed to alter these behaviors. In contrast, EEDQ (0.15-1.5 micrograms/microliters/side) injected into the lateral CPu decreased both SKF-38393-induced grooming and oral movements, with complete blockade of grooming observed at the highest dose. To determine whether this effect of EEDQ was due to inactivation of D1-like receptors, separate groups of animals were pretreated with SCH-23390 (3 mg/kg, S.C.) 15 min prior to injection with EEDQ. Pretreatment with SCH-23390 prevented the disruption of SKF-38393-induced behaviors, as well as the loss of 3H-SCH-23390-labeled binding sites observed after injection of EEDQ into the lateral CPu. EEDQ injections that produced disruption of SKF-38393-induced behaviors were associated with a greater loss of binding in the lateral CPu relative to other regions examined including the NAc, medial CPu, and globus pallidus. Furthermore, EEDQ injections that produced the greatest loss of 3H-SCH-23390 binding in the latter three regions did not disrupt SKF-38393-induced behavior. These results demonstrate that stimulation of D1-like receptors in the lateral CPu is necessary for behaviors induced by systemic administration of SKF-38393. The results also demonstrate the utility of this "receptor lesion" technique to localize receptor-mediated behaviors.

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

PubMed1994

Time-dependent changes in sensitivity to apomorphine and monoamine receptors following withdrawal from continuous cocaine administration in rats.

The effects of withdrawal from continuous administration of cocaine on behavioral sensitivity to apomorphine and monoamine receptor density were examined in rats. Subdermal minipumps that delivered either saline or 20 mg/kg/day cocaine hydrochloride were implanted for 2 weeks. Apomorphine-induced stereotypy (0.5 mg/kg, SC) was examined in separate groups of rats either 4 hr or 7, 28, or 60 days after removal of the minipumps. Transient enhanced sensitivity to apomorphine-induced stereotypy occurred during the course of withdrawal. Animals withdrawn from cocaine for 4 hours did not differ from controls in their sensitivity to apomorphine, whereas animals withdrawn from cocaine for 7 days exhibited an increase in apomorphine-induced oral stereotypy relative to controls. However, the enhanced stereotypy response was no longer evident in animals withdrawn for 28-60 days. The animals were sacrificed after behavioral testing, and their brains were assayed for changes in monoamine receptor density in the frontal cortex, caudate-putamen, and nucleus accumbens. The density of 3H-SCH-23390-labeled D1 receptors was altered in all three regions examined in a time-dependent manner that paralleled the changes in behavioral sensitivity to apomorphine. There was a transient decrease in D1 receptor density that was evident by 7 days following withdrawal from continuous cocaine administration and was no longer evident 28 or 60 days posttreatment. There were no changes in 3H-spiroperidol-labeled D2 receptors, 125-pindolol-labeled beta-adrenergic receptors, or 3H-ketanserin-labeled 5-HT2 receptors in any of the regions examined at both 4 hr and 7 days after termination of the cocaine infusion. These findings are discussed in terms of their relevance to developing pharmacologic treatments for withdrawal from cocaine.

Animals↗

PubMed1994

Polyamine effects on the NMDA receptor in human brain.

Polyamines are thought to modulate the activation of NMDA receptors through a unique allosteric regulatory site. The effects of polyamines on the binding of [3H]MK-801 were measured in cortical and hippocampal tissue surgically removed from patients with temporal lobe epilepsy (TLE). The polyamine agonist spermidine increased the binding of [3H]MK-801 in the cortex in a dose-dependent manner and this effect could be blocked by the weak partial agonist diethylenetriamine (DET). Spermidine decreased the Kd of [3H]MK-801 for the NMDA receptor but did not alter the density of receptors. Spermidine had essentially the same effect on Kd and Bmax measured in the dentate gyrus of TLE subjects and the cortex and dentate gyrus of postmortem controls. Moreover, there was no difference in the density of binding sites between postmortem and TLE subjects in either region. The binding of [3H]MK-801 in human cortex was decreased by 30% by incubation with DET or by prewashing the tissue sections. In contrast, DET did not alter the binding of [3H]MK-801 in rat cortex and prewashing sections produced an increase rather than a decrease in binding. These results suggest that there are different endogenous modulators for the polyamine site in rat and human tissue. The inverse agonist 1,10-diaminodecane decreased the binding of [3H]MK-801 in a dose-dependent manner. These results suggest that the fundamental modulatory properties of polyamines in rat and human tissues are essentially the same and that endogenous polyamines may regulate human NMDA receptors.

Adult↗

PubMed1994

Regional profile of developmental changes in the sensitivity of the N-methyl-D-aspartate receptor to polyamines.

The NMDA receptor exhibits increased sensitivity to stimulation during early development compared with the adult. In this study, we examined modulation of the NMDA receptor by polyamines during development to see if it correlates with differences in the functional responsiveness of the NMDA receptor. [3H]MK-801 binding was measured in discrete brain regions in the presence and absence of polyamines in 3-, 7-, 15-, 25-, and 60-day-old Sprague-Dawley rats. [3H]MK-801 binding increased between postnatal days 3 and 15, with adult levels of binding being reached between days 15 and 25. Spermidine (75 microM) caused maximal stimulation of [3H]MK-801 binding during early development, ranging from 250% in the thalamus to 450% in the caudate putamen at postnatal day 3. This effect gradually declined to levels seen in the adult by postnatal days 15-25. During all developmental stages, the stimulation seen was greater in the caudate putamen compared with the hippocampus. Diethylenetriamine (1 mM) exhibited similar developmental and regional heterogeneity in its effects on [3H]MK-801 binding, producing substantial stimulation of binding in the neonate, but not in the adult. The EC50 and Emax values for the stimulatory effect of spermidine were significantly higher at day 7 compared with the adult. Unlike spermidine and diethylenetriamine, there was no regional variation in the effects of the putative "polyamine site" inverse agonist 1,10-diaminodecane at any age and only a slightly attenuated inhibition at postnatal day 3 compared with the adult.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1993

Polyamines modulate the neurotoxic effects of NMDA in vivo.

The ability of polyamines to alter NMDA-induced neurotoxicity in neonatal rats was examined to determine whether polyamines modulate NMDA receptor activity in vivo. Unilateral injections of NMDA and/or polyamines were made into the striatum of 7-day-old rats. After 5 days, the brains were removed and 20 microns thick coronal sections were cut and stained with Cresyl violet. A computer-based image analysis system was used to densitometrically measure the cross-sectional area of intact tissue in the control and injected hemispheres. Administration of NMDA (5-40 nmol) produced a dose-dependent tissue damage that ranged from 7 to 52% of the area of the uninjected hemisphere. The polyamine agonist spermine (10-500 nmol) dose-dependently exacerbated the toxicity of a 15 nmol dose of NMDA, increasing the size of the lesion by up to 50%. Administration of spermine alone produced dose-dependent tissue damage that ranged from 9 to 52%. The damage produced by both NMDA and spermine could be completely inhibited by co-administration of the NMDA antagonist MK-801. The polyamine inverse agonist 1,10-diaminodecane (DA-10, 50-400 nmol) inhibited the damage produced by NMDA in a dose-dependent manner, with a maximal inhibition of 50%. Administration of DA-10 alone produced limited damage at doses above 100 nmol. The weak partial agonist diethylenetriamine had no effect by itself or on NMDA-induced toxicity at the doses tested. These results indicate that polyamines can modulate the activity of NMDA receptors in vivo and suggest that polyamines or related compounds may have important therapeutic potential as neuroprotective agents.

Animals↗

PubMed1993

Anatomical differentiation within the nucleus accumbens of the locomotor stimulatory actions of selective dopamine agonists and d-amphetamine.

The effects of local injections of dopamine receptor agonists into various areas within the nucleus accumbens or the medial caudate-putamen on the generation of locomotor activity were examined. Combinations of 0.32 microgram/side of the dopamine receptor agonists SKF 38393 (D1) and quinpirole (D2) produced increases in locomotor activity that varied according to the rostral-caudal placement of the cannulae within the nucleus accumbens. The greatest levels of locomotion were generated by injections into a region in the caudal-central nucleus accumbens, with lower levels of activity elicited by injections into more rostral or caudal regions. A similar pattern of responses was produced by administration of the indirect dopamine agonist d-amphetamine. These results indicate that there is marked heterogeneity in the response of discrete sub-regions of the nucleus accumbens to dopamine receptor stimulation and that this heterogeneity is functionally expressed in the mediation of the locomotor effects of dopaminergic agonists.

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

PubMed1993

Thyroid and thyroxine effects on adrenoreceptors in relation to circadian activity.

Experiments were conducted to ascertain if changes in central adrenergic receptors could be associated with altered circadian activity patterns induced by thyroparathyroidectomy (TPX) and thyroxine. An initial experiment used TPX and sham-operated rats that had been exposed to dim red light for 7 months. The alpha and beta receptor densities were compared in the suprachiasmatic nuclei (SCN), preoptic (PO), septum, and caudate-putamen. TPX animals showed significant reductions in beta 1 and beta 2 receptor densities in SCN and PO, and alpha 1 densities in SCN, but no other changes. A second experiment, lasting 4 months, examined the effects of thyroxine, which has been shown to reverse the period-shortening effects of TPX surgery. Thyroxine significantly increased beta 1 receptors in both the SCN and ventromedial hypothalamus (VMH), the only regions that displayed significant reductions in TPXs during the second experiment. Increases of sevenfold and threefold were observed in the SCNs of TPXs and shams, respectively, but thyroxine's action in the VMH was limited to TPX animals, an effect that mimics thyroxine's action on circadian activity rhythms.

Animals↗