摘要:

AbstractThis study evaluated the utility of(S)‐N‐[(1‐ethyl‐2‐pyrrolidinyl)methyl]‐5‐(3‐[18F]fluoropropyl)‐2,3‐dimethoxybenzamide ([18F]fluoropropylepidepride), [18F]5‐FPrEpid, as a ligar d for PET studies of cerebral dopamine D2 receptors. The in vitro affinity for the rat striatal dopamine D2 receptor, KD138 pM, was determined by Scatchard analysis of in vitro binding to rat striatal homogenate. The apparent lipophilicity, log kw1.6, was measured with reverse phase HPLC at pH 7.5. The receptor specificity was determined by competitive displacement of [18F]5‐FPrEpid by a variety of neurotransmitter ligands. Only dopamine D2 ligands displaced [18F]5‐FPrEpid with high affinity. Positron tomographic imaging studies in primates of [18F]5‐FPrEpid demonstrated a stable striatal uptake. of 0.02% injected dose/ml for up to 5 h after injection. The striatal: cerebellar ratio increased from 2 at 15 min, to 7 at 200 min, and to 10 at 300 min. Striatal uptake was displaceable by haloperidol (1 mg/kg) or raclopride (2.5 mg/kg) to cerebellar levels with a t1/2of washout of 9 or 15 min. Striatal uptake was mildly susceptible to displacement by d‐amphetamine (1–2 mg/kg) released endogenous dopamine; d‐amphetamine administration produced a 10%/h increase in the rate of striatal washout. Although uptake in the striatum is reversible, an equilibrium between receptor bound [18F]5‐FPrEpid in striatum and [18F]5‐FPrEpid in plasma is not reached within 5 h

ISSN:0887-4476    

DOI:10.1002/syn.890150302

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe applicability of using the standard 3‐compartment model to describe the neuropharmacokinetics of a high affinity substituted benzamide was investigated. We performed the following experiments using the [18F]‐5‐(3‐fluoropropyl) analog of epidepride ([18F]5‐FPrEpid), a potent dopamine D2 receptor antagonist: constant left ventricular infusion, first‐pass clearance, varying ligand specific activity, and displacing bound ligand with varying amounts of unlabelled ligand. Taken together, the information from these experiments rigorously tests the standard 3‐compartment model. The obtained data and predictions from the model of the kinetic behavior of the ligand are inconsistent. The measured and model predicted dissociation rate (measured Koff= 0.065 min−1, model prediction Koff= 0.007 min−1) and the equilibrium dissociation constant (measured KD= 0.14 nM, model prediction KD= 2.2 nM) differ by an order of magnitude. Furthermore, the model cannot be used to accurately estimate the receptor density. We postulate that the synapse geometry and physical relationship between receptors are necessary components of a model that describes the pharmacokinetics of [18F]5‐FPrEpid. ©

ISSN:0887-4476    

DOI:10.1002/syn.890150303

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractExtracellular recordings of single neurons within the nucleus accumbens (NAS) of halothane‐anesthetized rats have revealed that systemic nicotine injections (0.5 and 1.0 mg/kg, s.c.) inhibit the action potentials of normally inactive NAS neurons, evoked by fimbria stimulation (fimbria‐driven responses, n = 18). These nicotine inhibitions of fimbria‐driven NAS action potentials appear to be centrally mediated because they were reversed by subsequent systemic injections of the centrally acting nicotinic acetylcholine (nAch) antagonist, mecamylamine (1.0 mg/kg, s.c., n = 6), but not by the peripherally acting nAch antagonist, hexamethonium (2.0 mg/kg, s.c., n = 6). Fimbria‐driven NAS neurons were also tested with morphine (2.5 mg/kg, s.c.) in some experiments. Consistent with many past observations (Hakan et al., 1989), morphine did not affect these driven neurons. In other experiments, nicotine‐induced inhibition of NAS fimbria‐driven units was followed by haloperidol (0.5 mg/kg, s.c.), in attempts to reveal the possible role of dopamine in these effects. Haloperidol was successful at reversing nicotine inhibitions in only some cases (n = 2/6). Thus, the role of dopamine in these NAS responses to nicotine remains unclear. In contrast to the fimbria‐driven NAS responses, spontaneously active NAS neurons were not affected by nicotine injections yet were subsequently inhibited with systemic morphine. These results suggest a specific neuro‐pharmacological organization in the region of the nucleus accumbens that may relate to the qualitative and subjective differences in the experiential effects of different psychoactive drugs. Iontophoretic studies designed to localize further the site of these nicotine effects on NAS neurons are in progress. © 1993

ISSN:0887-4476    

DOI:10.1002/syn.890150304

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractIn adult rats, methamphetamine produces biochemical alterations in brain serotonin (5‐HT) neurons. Since 5‐HT is critical to the development of fetal 5‐HT neurons and target tissues, we hypothesized that in utero exposure to methamphetamine could result in long‐term alterations in postnatal 5‐HT systems. Pregnant Sprague‐Dawley rats, administred either saline or (±)methamphetamine (5 mg/kg, s.c., b.i.d.) from gestational day 13 to 20, were divided into three treatment groups: Saline‐injected/Ad Lib Fed (VEH); Saline‐injected/Pair Fed (PF); and methamphetamine injected (METH). Prenatal methamphetamine exposure did not alter litter size, gender number, or progeny birth weights. Functional alterations in serotonergic systems were determined in postnatal day (PD) 70 male progeny and in PD 30 female progeny by measuring changes in 5‐HT mediated increases in plasma hormones following a single injection of the 5‐HT releaser p‐chloroamphetamine (PCA; 8 mg/kg). Prenatal metham‐phetamine produced long‐term marked (−30 to −62%) attenuation of plasma renin responses to PCA in male and female progeny. In contrast, no alterations were observed in the ACTH, corticosterone, or prolactin responses to PCA in male and female progeny. Prenatal methamphetamine did not alter basal levels of any hormones measured regardless of gender. No significant differences were observed in the density of cortical or hypothalamic 5‐HT uptake sites, or in the density of cortical 5‐HT1or 5‐HT2receptors in male progeny. The lack of significant differences in cortical 5‐HT uptake sites observed between PF and METH treated dams 2 days post‐parturition indicates that methamphet‐amine was not neurotoxic to the pregnant dams. These data, which demonstrate long‐term postnatal deficits in 5‐HT mediated renin secretion, suggest selective functional alterations of brain 5‐HT systems in male and female progeny exposed in

ISSN:0887-4476    

DOI:10.1002/syn.890150305

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractAutoradiographic techniques were used to study the distribution of histamine H2‐receptors as labeled with [125I]iodoaminopotentidine in the brains of patients affected by human neurodegenerative pathologies, as compared with control cases. The highest levels of histamine H2binding sites in control cases were found in the caudate, putamen, and accumbens nuclei. In Huntington's chorea, the levels of histamine H2receptor binding sites were found to be markedly decreased in virtually all regions examined, particularly in the putamen and globus pallidus lateralis. The loss of binding sites was related to the grade of the disease. Losses were more marked in grade III disease cases. The possible influence of neuroleptic treatment, commonly used in Huntington's patients, was studied by including samples from clinically treated schizophrenic patients. A moderate increase in the densities of [125I]iodoaminopotentidine was found in the globus pallidus of these patients. In Parkinson's disease, the levels of histamine H2‐receptor binding sites were found not to be significantly different from those of control cases. These results were comparable with those obtained from unilaterally neurotoxin‐lesioned guinea pigs. Similar losses of binding sites were observed in the quinolinic acid lesioned striatal intrinsic neurons in the guinea pig, whereas lesioning dopaminergic cell bodies in the substantia nigra with 6‐hydroxydopamine did not produce any significant change. These results strongly suggest that histamine H2‐receptors are expressed by striatal neurons, which degenerate in Huntington's chorea, but not by nigral dopaminergic neurons and may play a role in the regulation of the intact striato‐nigral pathway. © 1993 Wil

ISSN:0887-4476    

DOI:10.1002/syn.890150306

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractImmunocytochemistry and in situ hybridization techniques were used for investigating changes in cholecystokinin immunoreactivity and mRNA in the cerebral cortex and hippocampus after kainic acid‐induced limbic seizures in the rat. Marked increases in cholecystokinin mRNA concentrations were observed in layers II/III and V/VI of the cerebral cortex, in CA1 pyramidal neurons of the hippocampus, and in presumptive basket cells of the dentate gyrus 1 and 2 days after the acute seizures. Whereas cholecystokinin mRNA contents returned to normal in the cerebral cortex and the CA1 sector at later intervals, high concentrations were observed in basket cells even 2 months after the initial seizures. Accordingly, cholecystokinin‐like immunoreactivity was intensified in the cerebral cortex, CA1 sector and in presumed basket cells of the hippocampus 30 days after kainic acid. Besides its high content in basket cells, cholecystokinin‐like immunoreactivity was primarily present in neuronal fibers or diffusely distributed in the respective brain area. In the hippocampus, strongly enhanced staining for cholecystokinin was also observed in the alveus, the stratum lacunosum moleculare, and in the inner molecular layer, suggesting increased concentrations of the peptide in afferent and efferent fibers of the hippocampus.The present experiments suggest a strong activation of cholecystokinin systems in the brain after kainic acid‐induced limbic seizures in the rat. This is indicated by pronounced increases in cholecystokinin mRNA in the cortex and individual cell types of the hippocampus (basket cells, granule cells, and CA1 pyramidal neurons). The subsequent increases in cholecystokin immunoreactivity even surpass those in mRNA. The observed changes may be part of the self‐defense mechanisms that protect the animals during subsequent epileptic episodes. © 1993 Wiley

ISSN:0887-4476    

DOI:10.1002/syn.890150307

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractPrevious electrophysiological experiments have emphasized the importance of the firing pattern for the functioning of midbrain dopamine (DA) neurons. In this regard, excitatory amino acid receptors appear to constitute an important modulatory control mechanism. In the present study, extracellular recording techniques were used to investigate the significance of GABAB‐receptor activation for the firing properties of DA neurons in the substantia nigra (SN) in the rat. Intravenous administration of the GABAB‐receptor agonist baclofen (1–16 mg/kg) was associated with a dose‐dependent regularisation of the firing pattern, concomitant with a reduction in burst firing. At higher doses (16–32 mg/kg), the firing rate of the DA neurons was dose‐dependently decreased. Also, microiontophoretic application of baclofen regularized the firing pattern of nigral DA neurons, including a reduction of burst firing. Both the regularisation of the firing pattern and inhibition of firing rate produced by systemic baclofen administration was antagonized by the GABAB‐receptor antagonist CGP 35348 (200 mg/kg, l.v.). The GABAA‐receptor agonist muscimol produced effects on the firing properties of DA neurons that were opposite to those observed following baclofen, i.e., an increase in firing rate accompanied by a Cecreased regularity. The NMDA receptor antagonist MK 801 (0.4–3.2 mg/kg, i.v.) produced a moderate, dose‐dependent increase in the firing rate of the nigral DA neurons as well as a slightly regularized firing pattern. Pretreatment with MK 801 (3.2 mg/kg, i.v., 3–10 min) did neither promote nor prevent the regularisation of the firing pattern or inhibition of firing rate on the nigral DA neurons produced by baclofen. The present results clearly show that GABAB‐receptors can alter the firing pattern of nigral DA neurons, hereby counterbalancing the previously described ability of glutamate to induce burst Firing activity on these neurons.

ISSN:0887-4476    

DOI:10.1002/syn.890150308

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

ISSN:0887-4476    

DOI:10.1002/syn.890150309

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

ISSN:0887-4476    

DOI:10.1002/syn.890150310

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

ISSN:0887-4476    

DOI:10.1002/syn.890150311

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY