Biomedical subjects

F M Leslie

Publications and source records attributed to F M Leslie.

At least 37 records · Page 2Linked to original sources

PubMed1999

The influence of a low-fat diet on incidence and severity of migraine headaches.

Migraine headaches are a common, debilitating syndrome causing untold suffering and loss of productivity. A review of the literature indicates that high levels of blood lipids and high levels of free fatty acids are among the important factors involved in triggering migraine headaches. Under these conditions, platelet aggregability, which is associated with decreased serotonin and heightened prostaglandin levels, is increased. This leads to vasodilation, the immediate precursor of migraine headache. A high-fat diet is one factor that may directly affect this process. This study, undertaken to evaluate the impact of dietary fat intake on incidence and severity of migraine headache, was conducted over a 12-week period on 54 previously diagnosed migraine headache patients. During the first 28 days, the study subjects recorded all food consumption in a diet diary and maintained a headache diary. At the conclusion of this 28-day baseline period, subjects were individually counseled to limit fat intake to no more than 20 g/day. A 28-day run-in period was allowed for adaptation to the low-fat diet. Results are reported on the final 28-day postintervention period. Subjects significantly decreased the ingestion of dietary fat in grams between baseline (mean 65.9 g/day, p < 0.0001) and the postintervention period (mean 27.8 g/day). The decreased dietary fat intervention was associated with statistically significant decreases in headache frequency, intensity, duration, and medication intake (all p < 0.0001). There was a significant positive correlation between baseline dietary fat intake and headache frequency (r = .44, p = 0.02). This study indicates that a low-fat diet can reduce headache frequency, intensity, and duration and medication intake.

Counseling↗

PubMed1998

In search of the ideal treatment for migraine headache.

Migraine headache is a common syndrome, afflicting millions, that has so far defied a definitive cure. Experimental research studies of the syndrome tend to describe the triggering factors separately. We propose a common denominator--namely, high levels of blood lipids and free fatty acids--as underlying factor in the development of migraine headaches. Biological states that may cause increases in free fatty acids and blood lipids include: high dietary fat intake, obesity, insulin resistance, vigorous exercise, hunger, consumption of alcohol, coffee, and other caffeinated beverages, oral contraceptives, smoking, and stress. Elevated blood lipids and free fatty acids are associated with increased platelet aggregability, decreased serotonin, and heightened prostaglandin levels. These changes lead to the vasodilatation that precedes migraine headache. We suggest that migraine headache should not be seen as an isolated symptom, but as a first signal of potential biochemical imbalances in the body, which can lead to development of chronic disease.

Alcohol Drinking↗

PubMed1998

Nicotine-stimulated release of [3H]norepinephrine from fetal rat locus coeruleus cells in culture.

Acute nicotine administration stimulated [3H]norepinephrine ([3H]NE) release from cultured fetal locus coeruleus (LC) cells. The effect was concentration dependent, with an EC50 of 0.9 microM, and was abolished by removal of calcium from, or addition of tetrodotoxin (500 nM) to, the assay buffer. Other nicotinic receptor agonists stimulated [3H]NE release, with the rank order of potency being (+)-epibatidine > (-)-nicotine > 1,1-dimethyl-4-phenylpiperazinium (DMPP). Whereas (-)-nicotine and (+/-)-epibatidine exhibited equal maximal responses, DMPP was a partial agonist and (-)-cytisine had no agonist activity. Nicotine-stimulated release of [3H]NE was blocked by nicotinic receptor antagonists, with an order of potency of mecamylamine > lobeline > cytisine > methyllycaconitine > dihydro-beta-erythroidine. The pharmacological profile of this nicotinic receptor is largely consistent with that described previously for an alpha4beta2 subunit combination, although discrepancies in the efficacies of agonists were observed. No additivity in NMDA- and nicotine-stimulated [3H]NE release was observed, suggesting a common signal transduction mechanism. However, the pharmacological characteristics of MK-801 blockade of nicotine-induced responses were not consistent with those of an NMDA receptor. We therefore conclude that nicotine directly releases [3H]NE from LC cells and does not act indirectly via activation of glutamate release.

Alkaloids↗

PubMed1998

Calcium regulation of agonist binding to alpha7-type nicotinic acetylcholine receptors in adult and fetal rat hippocampus.

Quantitative autoradiography was used to compare the binding properties of alpha7-type nicotinic acetylcholine receptors in fetal and adult rat hippocampus. Whereas there were high levels of 125I-alpha-bungarotoxin (125I-alpha-BTX) binding throughout fetal hippocampal field CA1, there was a significant decrease in binding site density in the adult. The affinity of 125I-alpha-BTX binding, as well as alpha-cobratoxin and nicotine potency to displace 125I-alpha-BTX, did not change with age. Addition of Ca2+ to the assay buffer did not alter 125I-alpha-BTX binding, or alpha-cobratoxin inhibition of 125I-alpha-BTX binding, although it significantly increased nicotine affinity at both ages. The effect of Ca2+ on agonist affinity was dose-dependent, with an EC50 value of 0.25-0.5 mM. Ca2+ also significantly increased the cooperativity of nicotine displacement curves in stratum oriens of the adult, but not in the fetus. These findings indicate that the properties of hippocampal 125I-alpha-BTX binding sites are largely similar across age. Ca2+ selectively enhances the affinity of agonist binding, with no change in antagonist binding. This ionic effect may result from potentiation of agonist binding to a desensitized state of the alpha7 nicotinic acetylcholine receptor and may represent an important neuroprotective mechanism.

Age Factors↗

PubMed1998

Neonatal treatment with 192 IgG-saporin produces long-term forebrain cholinergic deficits and reduces dendritic branching and spine density of neocortical pyramidal neurons.

The role of basal forebrain-derived cholinergic afferents in the development of neocortex was studied in postnatal rats. Newborn rat pups received intraventricular injections of 192 IgG-saporin. Following survival periods ranging from 2 days to 6 months, the brains were processed to document the cholinergic lesion and to examine morphological consequences. Immunocytochemistry for choline acetyltransferase (ChAT) and in situ hybridization for ChAT mRNA demonstrate a loss of approximately 75% of the cholinergic neurons in the medial septum and nucleus of the diagonal band of Broca in the basal forebrain. In situ hybridization for glutamic acid decarboxylase mRNA reveals no loss of basal forebrain GABAergic neurons. Acetylcholinesterase histochemistry demonstrates a marked reduction of the cholinergic axons in neocortex. Cholinergic axons are reduced throughout the cortical layers; this reduction is more marked in medial than in lateral cortical areas. The thickness of neocortex is reduced by approximately 10%. Retrograde labeling of layer V cortico-collicular pyramidal cells reveals a reduction in cell body size and also a reduction in numbers of branches of apical dendrites. Spine densities on apical dendrites are reduced by approximately 20-25% in 192 IgG-saporin-treated cases; no change was detected in number of spines on basal dendrites. These results indicate a developmental or maintenance role for cholinergic afferents to cerebral cortical neurons.

Acetylcholinesterase↗

PubMed1998

Opioid receptor and peptide mRNA expression in proliferative zones of fetal rat central nervous system.

There is increasing evidence to suggest that opioid peptides may have widespread effects as regulators of growth. To evaluate the hypothesis that endogenous opioids control cellular proliferation during neural development, we have used in situ hybridization to examine opioid peptide and receptor mRNA expression in neuroepithelial zones of fetal rat brain and spinal cord. Our data show that proenkephalin mRNA is widely expressed in forebrain germinal zones and choroid plexus during the second half of gestation. In contrast, prodynorphin mRNA expression is restricted to the periventricular region of the ventral spinal cord. Little mu or delta receptor mRNA expression was detected in any regions of neuronal proliferation prior to birth. However, kappa receptor mRNA is widely expressed in hindbrain germinal zones during the 3rd week of gestation. Our present findings support the hypothesis that endogenous opioids may regulate proliferation of both neuronal and non-neuronal cells during central nervous system development. Given the segregated expression of proenkephalin mRNA in forebrain neuroepithelium and kappa receptor mRNA within hindbrain, different opioid mechanisms may regulate cell division in rostral and caudal brain regions.

Animals↗

PubMed1997

Codistribution of nicotinic acetylcholine receptor subunit alpha3 and beta4 mRNAs during rat brain development.

We have used in situ hybridization to characterize the ontogeny of alpha3 and beta4 nicotinic acetylcholine receptor (nAChR) subunit mRNA expression in rat brain. Transcripts for both subunits were detected in embryonic brain, although overlapping expression of alpha3 mRNA was only evident in areas of strong beta4 mRNA expression, including the medial habenula, locus coeruleus, the cerebellar primordium, and several motor and sensory brainstem nuclei. During the perinatal period, the independent expression of alpha3 mRNA declined, and greater correspondence in the temporal and spatial expression of alpha3 and beta4 subunit mRNAs emerged. In general, beta4 mRNA expression preceded that of alpha3 mRNA by 1 to 2 days. Overlapping expression patterns were transiently detected in the caudate putamen, basal forebrain, frontal and visual cortices, and in the CA3 field of hippocampus. Codistribution that lasted throughout development and into adulthood was noted in a number of brain areas, including the retrosplenial cortex, subiculum, medial habenula, interpeduncular nucleus, locus coeruleus, and brainstem motor nuclei. In many of these regions, alpha5 subunit mRNA was also expressed. Colocalization of alpha3 and beta4 mRNAs with choline acetyltransferase mRNA was detected in cholinergic neurons of the brainstem motor nuclei, nucleus ambiguus, dorsal motor nucleus of the vagus, motor trigeminal nucleus, and facial nucleus, but not in most forebrain cholinergic cells. The extensive correspondence in temporal and spatial distribution of alpha3 and beta4 mRNAs throughout postnatal brain development suggests that these subunits may be coordinately regulated and may form functional neuronal nAChRs with significant developmental roles.

Animals↗

PubMed1997

Alpha2B adrenoceptor mRNA expression during rat brain development.

The expression of alpha2B adrenoceptor mRNA in developing and adult rat brain was examined, using in situ hybridization with S-labeled riboprobes. In the adult we have detected more widespread expression than previously reported, with moderate to strong hybridization signals in the fundus striati, olfactory tubercles, septum, thalamus and Purkinje cells of the cerebellum. In addition, there was low expression in the endopiriform nucleus, claustrum, cortex, caudate-putamen and spinal trigeminal nucleus of the brain stem. During embryonic development, there was intense, transient mRNA expression in the developing vascular plexus and vasculature which disappeared by birth. In most brain areas which exhibit mRNA expression in the adult, expression started during late embryonic development; with the exception of the thalamus, where expression was differentially regulated in sensory and non-sensory thalamic nuclei starting at the end of the first postnatal week. In addition, there was transiently upregulated expression in the caudate-putamen and cerebellar Purkinje cells during late embryonic and early postnatal development, respectively. This transient expression correlates with the time of neuronal migration and differentiation in these structures and complements the developmental expression of alpha2A and alpha2C adrenoceptors. These results suggest that alpha2B adrenoceptors may play a role in angiogenesis and in mediating neurotrophic functions of norepinephrine in some brain areas.

Aging↗

PubMed1997

Expression of alpha 2 adrenoceptors during rat brain development--I. Alpha 2A messenger RNA expression.

The distribution of alpha 2A adrenoceptor messenger RNA expression in developing rat brain was characterized using in situ hybridization with 35S-labeled riboprobes. Intense hybridization signal was detected as early as embryonic day 14 in several areas adjacent to the forebrain and hindbrain germinal zones and in central noradrenergic neurons. A marked increase in messenger RNA expression was observed throughout the brain during late prenatal development, consistent with the migration and maturation of neurons in developing brain structures. In embryonic brain, there was a temporal and spatial correspondence in the appearance of alpha 2A messenger RNA expression and binding sites labeled with [3H]idazoxan or p-[125I]iodoclonidine, indicating translation into receptor protein at an early stage of development. Whereas the presynaptic expression remained constant throughout development, there was an early postnatal decline of alpha 2A receptor expression in many brain regions, including the olfactory bulb, cortex, caudate-putamen, hippocampus, thalamus, hypothalamus and medulla. Thereafter, messenger RNA expression increased, establishing an adult-like pattern during the second postnatal week, but remained low in areas such as the caudate-putamen, thalamus and hippocampus, which do not exhibit extensive expression in the adult. The transient perinatal expression of this alpha 2 adrenoceptor type, which coincides with a period of hyperreactivity to sensory stimuli in the locus coeruleus, may indicate a specific functional role for the alpha 2A receptor in the developing rat brain. The early and intense expression in olfactory structures suggests an involvement in early olfactory learning. The pattern of widespread, transient expression of alpha 2A receptors in the fetal brain is in marked contrast to the postnatal development of the alpha 2C receptor type.

Aging↗

PubMed1997

Expression of alpha 2 adrenoceptors during rat brain development--II. Alpha 2C messenger RNA expression and [3H]rauwolscine binding.

The distributions of alpha 2C adrenoceptor messenger RNA and high-affinity [3H]rauwolscine binding sites were characterized in developing rat brain. Using in situ hybridization with 35S-labeled riboprobes directed against the third intracellular loop, alpha 2C messenger RNA expression appeared in an adult-like pattern during the first and second postnatal weeks, in the anterior olfactory nucleus, caudate-putamen, olfactory tubercles, islands of Calleja and hippocampus, following the time-course of maturation of these structures. Only in the cerebellum was alpha 2C messenger RNA transiently expressed during the critical period of granule cell development. High-affinity [3H]rauwolscine binding sites were detected using receptor autoradiography and revealed a similar spatial and temporal time-course of appearance during rat brain development. The highest numbers of binding sites were detected in the olfactory tubercles and islands of Calleja, and moderate numbers in the anterior olfactory nucleus, caudate-putamen and hippocampus. Like alpha 2C messenger RNA expression, high-affinity [3H]rauwolscine binding sites were transiently expressed in the cerebellum. In some areas (e.g., the substantia nigra), [3H]rauwolscine binding sites were detected even though alpha C2 messenger RNA expression was absent. The strong spatial and temporal correspondence between messenger RNA expression and radioligand binding supports the conclusion that [3H]rauwolscine selectively labels alpha 2C adrenoceptors in the rat brain. The developmental pattern which was observed is in marked contrast to the early, transient expression of the alpha 2A adrenoceptor. Thus, the alpha 2A and alpha 2C receptor types may serve distinct functional roles in the developing brain.

Animals↗

PubMed1997

Glial regulation of alpha 7-type nicotinic acetylcholine receptor expression in cultured rat cortical neurons.

Primary embryonic cortical cultures were used as an in vitro model to evaluate the influence of glia on developmental expression of alpha 7-type nicotinic acetylcholine receptors in rat brain. In cells cultured in serum-containing medium without mitotic inhibitors, specific 125I-alpha-bungarotoxin binding to alpha 7-type nicotinic receptors was maximal 4-8 days after plating. Treatment with 5'-fluorodeoxyuridine (80 microM) from 1 to 3 days in vitro significantly reduced glial proliferation and concomitantly increased 125I-alpha-bungarotoxin binding, whereas plating onto a glial bed layer decreased binding. There was no significant binding to pure glial cultures. Treatment-induced changes in neuronal binding resulted from alterations in receptor density, with no change in affinity. 5'-Fluorodeoxyuridine treatment also increased cellular expression of alpha 7 receptor mRNA but had no effect on N-[3H]methylscopolamine binding to muscarinic receptors. Glial conditioned medium decreased 125I-alpha-bungarotoxin binding in both control and 5'-fluorodeoxyuridine-treated cultures, suggesting the release of a soluble factor that inhibits alpha 7-type nicotinic receptor expression. An additional mechanism of glial regulation may involve removal of glutamate from the surrounding medium, as added glutamate (200 microM) increased 125I-alpha-bungarotoxin binding in astrocyte-poor cultures but not in those that were astrocyte enriched. These results suggest that glia may serve a physiological role in regulating alpha 7-type nicotinic receptors in developing brain.

Animals↗

PubMed1996

Regulation of alpha7 nicotinic acetylcholine receptors in the developing rat somatosensory cortex by thalamocortical afferents.

Distributions of alpha7 nicotinic acetylcholine receptor (nAChR) mRNA and [125]alpha-bungarotoxin (alpha-BTX) binding sites in the developing rat somatosensory cortex were characterized in relation to acetylcholinesterase (AChE) histochemical staining of thalamocortical terminals to investigate the role of this receptor in cortical development. Using quantitative in situ hybridization and receptor autoradiography, elevated levels of mRNA and binding-site expression were first detected at post-natal day 1 (P1) in deep and superficial layers, just beneath the AChE-stained thalamocortical terminals. Onset of expression occurred approximately 1 d after ingrowth of AChE-stained thalamocortical afferents. By P5, mRNA and binding-site expression exhibited a disjunctive, barrel-like pattern in layer IV and, more clearly, in layer VI. The mRNA and binding-site expressions peaked at approximately 1 week postnatal and then declined to adult levels. Unilateral electrolytic or cytochemical lesions placed in the thalamic ventrobasal complex at P0 (just as thalamocortical afferents are innervating the cortex) and at P6 (when the somatotopic map is well established) resulted in a marked reduction of alpha7 nAChR mRNA and [125]alpha-BTX binding-site levels in layers IV and VI, indicating their regulation by thalamocortical afferents. With P6 lesions, this reduction was observed as early as 6 hr postlesion. These results suggest that alpha7 nAChRs are localized primarily on cortical cells in rat somatosensory cortex and provide further evidence for thalamocortical influence on cortical ontogeny. These data also suggest a role for cholinergic systems during a critical period of cortical synaptogenesis.

Aging↗

PubMed1995

Localization of alpha 7 nicotinic receptor subunit mRNA and alpha-bungarotoxin binding sites in developing mouse somatosensory thalamocortical system.

Previous studies in rat, showing a transient pattern of expression of the alpha 7 nicotinic acetylcholine receptor in the ventrobasal thalamus and barrel cortex during the first 2 postnatal weeks, suggest that these receptors may play a role in development of the thalamocortical system. In the present study, in situ hybridization and radiolabeled ligand binding were employed to examine the spatiotemporal distribution of alpha 7 mRNA and alpha-bungarotoxin binding sites in the thalamocortical pathway of mouse during early postnatal development. As in the rat, high levels of alpha 7 mRNA and alpha-bungarotoxin binding sites are present in the barrel cortex of mouse during the first postnatal week. Both alpha 7 mRNA and its receptor protein are observed in all cortical laminae, with the highest levels seen in the compact cortical plate, layer IV, and layer VI. When viewed in a tangential plane, alpha 7 mRNA and alpha-bungarotoxin binding sites delineate a whisker-related barrel pattern in layer IV by P3-5. Quantitative analysis reveals a dramatic decrease in the levels of expression of alpha 7 mRNA and alpha-bungarotoxin binding sites in the cortex by the end of the second postnatal week. Unlike in the rat, only low levels of alpha 7 mRNA or alpha-bungarotoxin binding sites are present in the ventrobasal complex of the mouse thalamus. The broad similarities between the thalamocortical development of rat and mouse taken together with the present results suggest that alpha 7 receptors located on cortical neurons, rather than on thalamic neurons, play a role in mediating aspects of thalamocortical development.

Animals↗

PubMed1995

Developmental expression of alpha 7 neuronal nicotinic receptor messenger RNA in rat sensory cortex and thalamus.

The distribution of alpha 7 messenger RNA expression was characterized in developing rat cortex and thalamus. Northern blot analysis of neonatal and adult cortex revealed a single messenger RNA transcript of 5.7 kb. Using in situ hybridization with both full length and short 35S-labeled alpha 7 riboprobes, a distinct transient expression of messenger RNA within sensory cortex and thalamus, during early postnatal development, was observed. alpha 7 transcripts were expressed in low levels as early as embryonic day 13 in the ventricular zone of the neocortex, and as early as embryonic day 15 in the thalamic neuroepithelium. A marked increase in messenger RNA levels was observed during the late prenatal period in both sensory and non-sensory regions of the cortex and thalamus. Moderate to high levels of messenger RNA were maintained into the first postnatal week, followed by a decline into adulthood. alpha 7 messenger RNA expression was significantly higher in the anterodorsal, lateral dorsal, ventral posterior medial and ventral posterior lateral thalamic nuclei of postnatal day 7 pups than in adult brains. Expression of messenger RNA within dorsal lateral geniculate, ventral lateral geniculate and medial geniculate did not show a significant reduction with age. Within the developing cortex, messenger RNA expression delineated the primary somatosensory, auditory and visual cortices in a unique laminar pattern that was consistently and significantly higher than in the adult in superficial layer VI. Higher levels of expression were also observed in retrosplenial cortex at postnatal day 7 than in the adult. Tangential sections through postnatal day 7 cortex revealed low levels of alpha 7 messenger RNA expression delineating the primary sensory areas in layer IV, corresponding to acetylcholinesterase-labeled thalamocortical afferents. However, these sensory areas exhibited higher levels of alpha 7 messenger RNA expression and were more clearly defined in layer VI, but not by acetylcholinesterase staining. The distribution of alpha 7 messenger RNA within the developing thalamocortical system parallels the distribution of alpha-bungarotoxin binding sites and suggests that the receptor is localized on both thalamic cells and their cortical target neurons. This transient and distinct pattern of distribution of the alpha 7 neuronal nicotinic receptor, which coincides with the major phase of thalamocortical development, suggests that it may play a functional role in the development of cortical circuitry.

Acetylcholinesterase↗

PubMed1995

Development of delta-opioid receptor subtypes and the regulatory role of weaning: radioligand binding, autoradiography and in situ hybridization studies.

Evidence from behavioral studies suggests that the process of weaning activates the development of a delta-opioid receptor subtype. We now report the influence of weaning on the development of delta receptors in the central nervous system assessed by membrane homogenate binding and autoradiography with selective delta radioligands and by in situ hybridization using a cRNA probe for the delta receptor. Binding was carried out by using [3H][D-Ala2]deltorphin I (DELT I), [3H]IIe5,6-deltorphin II (IIe5,6-DELT II) and [3H]naltrindole (NTI). [3H]IIe5,6-DELT II and [3H]NTI labeled an equivalent number of sites in brain and spinal cord from both weaned and nonweaned 25-day-old rats. The number of sites labeled by [3H]DELT I was similar in nonweaned rats but significantly higher in the brain and cord from weaned animals. Furthermore, the ontogenetic profile of these three ligands was distinct. Quantitative autoradiography showed identical levels of [3H]IIe5,6-DELT II binding in all brain regions in weaned and nonweaned rats. In contrast, levels of [3H]DELT I binding were significantly higher in weaned rats and this difference was localized to the deep layers of the frontal-parietal cortex and to the pontine nucleus. In situ hybridization experiments showed no differences in delta-opioid receptor mRNA density between weaned and nonweaned groups in the regions in which binding differences were observed. Weaning stimulates the development of a subpopulation of delta receptors recognized by [3H]DELT I but not by [3H]IIe5,6-DELT II or NTI. This effect is localized to specific brain regions and does not appear to reflect increased synthesis of mRNA coding for the delta receptor.

Animals↗

PubMed1994

Opioid effects on [3H]norepinephrine release from dissociated embryonic locus coeruleus cell cultures.

The acute and chronic effects of opioid exposure on [3H]norepinephrine ([3H]NE) release were examined in cell cultures of embryonic rat locus coeruleus (LC). Initial morphological and biochemical characterization of the cultures indicated that the cells exhibited properties similar to those observed in situ. Specific [3H]NE uptake was saturable with a Km value of 222 +/- 52 nM. [3H]NE accumulated by LC cells was released in response to 20 mM K+ stimulation, in a calcium-dependent manner. Both components of neurotransmitter release, spontaneous and K+ evoked, were significantly inhibited by beta-endorphin, with the latter being maintained in the presence of tetrodotoxin. The pharmacology of the opioid effect was consistent with that of mu-receptor activation. The effect of chronic exposure to the mu-selective agonist fentanyl (1 microM) was examined following 4 days of drug treatment. Although there was no significant effect of fentanyl on K(+)-evoked [3H]NE release, these cells were tolerant to the acute inhibitory effect of beta-endorphin. These results indicate that this is an appropriate system for examining the effects of acute and chronic opioid treatment on noradrenergic cells in vitro. In addition, this system may be useful as a CNS model for examining mechanisms that underlie tolerance and dependence following chronic opioid exposure.

Animals↗

PubMed1993

Long-term changes in striatal opioid systems after 6-hydroxydopamine lesion of rat substantia nigra.

The effects of unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway on striatal opioid peptides and receptors were determined at different time-intervals, from three days up to 24 weeks, post-lesion. Mu, delta and kappa opioid binding site densities in the ipsilateral caudate-putamen were decreased by 25-50% in rats which exhibited a greater than 90% loss of dopamine uptake sites. Differentiation of radioligand binding to kappa1 and kappa2 subtypes demonstrated a selective loss of kappa2 sites post-lesion. The onset of significant 6-hydroxydopamine lesion-induced changes in striatal opioid binding sites was delayed with respect to the loss of dopamine uptake sites. Furthermore, maximal loss of dopamine uptake sites was apparent within seven days post-lesion, but not until two to four weeks for mu, delta and kappa sites. In animals which exhibited an incomplete loss of dopamine uptake sites (less than 80%) there was no significant change in opioid binding site density. Striatal proenkephalin and prodynorphin messenger RNA levels were increased and decreased, respectively, after complete 6-hydroxydopamine lesion. Modulation of peptide messenger RNA levels was apparent within seven days and was maintained up to 24 weeks post-lesion. In contrast, proenkephalin and prodynorphin messenger RNA levels were unchanged in animals which exhibited an incomplete loss of striatal dopamine uptake sites. Taken together, these observations suggest that the majority of mu, delta and kappa2 opioid binding sites are localized on non-dopaminergic elements in the caudate-putamen, but that substantia nigra innervation plays a role in the control of striatal opioid receptor expression. The 6-hydroxydopamine lesion-induced decreases in striatal opioid binding site density may, in part, be a function of agonist-induced receptor downregulation. Alternatively, both opioid receptor and peptide expression in the caudate-putamen may be directly, but independently, regulated by ventral mesencephalic neurons.

Animals↗

PubMed1992

Opioid receptor changes in weaver mouse striatum.

The dopaminergic projection from the substantia nigra to the patch and matrix compartments of the caudate-putamen undergoes a spontaneous, early postnatal degeneration in mice which carry the weaver gene. The projection to nucleus accumbens is relatively spared. Dopaminergic afferents have been shown to be important modulators of striatal opioid receptor expression. In the present study, opioid receptor localization in the caudate-putamen and nucleus accumbens of control and weaver mice was examined by quantitative autoradiography. Mu, delta and kappa opioid receptors were differentially distributed in nucleus accumbens and in patch and matrix compartments of the caudate-putamen. In animals which were homozygous for the weaver gene, the density of mu opioid receptors in both patch and matrix compartments was unchanged with respect to control mice. In contrast, the density of delta and kappa opioid receptors was significantly decreased in weaver caudate-putamen and nucleus accumbens. The significance of these results with respect to opioid receptor expression and Parkinson's disease is discussed.

Animals↗