In rat, the neonatal destruction of nigrostriatal dopamine (DA) neurons by intracerebral administration of 6-hydroxydopamine entails dramatic changes in serotonin (5-hydroxytryptamine, 5-HT) as well as DA function. Most striking is the 5-HT hyperinnervation of the adult neostriatum, associated with increases in density of various 5-HT receptor subtypes and enhanced neuronal responsiveness to the iontophoretic application of 5-HT and its 5- HT(1B/2C) and 5-HT(2A/2C) receptor agonists, m-chlorophenylpiperazine and iododimethoxyphenylaminopropane. The topographical distribution of these changes is consistent with up-regulation and/or increased production and transport of 5-HT(1B) and 5-HT(2A) receptors by the neostriatal projection neurons, as confirmed for the 5-HT(2A) receptor in a recent in situ hybridization study. It is interesting that this study has also shown that increases in both 5-HT(2A) binding and mRNA level were abolished by chronic pretreatment with the DA agonists, apomorphine and SKF 38393, suggesting a regulatory influence of DA in the expression of this 5-HT receptor. D1 receptor binding is known to be slightly reduced in the rostral neostriatum of these rats, a down-regulation apparently imputable to a reduced rate of synthesis of the receptor. In contrast, D2 receptor binding is increased throughout the DA-denervated and 5-HT-hyperinnervated neostriatum, perhaps due to some post-transcriptional modifications. Stereotyped and motor behaviors induced by systemic treatment with D1 and D2 agonists are markedly enhanced in these rats (behavioral supersensitivity), although priming is commonly required to unmask a latent D1 supersensitivity. In the case of oral activity, however, overt behavioral supersensitivity is induced by D1 as well as D2 agonists. Moreover, there is overt supersensitivity of oral activity in response to the 5-HT receptor agonist m- chlorophenylpiperazine, which is presumably imputable to 5-HT(2C) receptors and may be demonstrated even in the absence of supersensitivity to D1 receptor agonist. 5-HT adaptations, therefore, seem to play a role not only in the abnormal spontaneous behavior, but also in the behavioral supersensitivity to 5-HT as well as DA receptor agonists in these rats.

This series of experiments used the multiple learning and memory systems hypothesis of the mammalian nervous system to investigate the possibility that the amygdala, dorsal striatum, and hippocampal systems might, in certain situations, interact to produce behavior in the normal animal. Using variations of the conditioned-cue preference (CCP) task, evidence is presented showing that context-specific information acquired by the hippocampus interferes with acquisition of amygdala-based stimulus-reward learning. It was also demonstrated that there are amygdala-, dorsal striatum-, and hippocampus-based forms of place learning and that cue ambiguity and movement are important factors determining which of these learning and memory systems gain behavioral control in place learning situations. These findings provide evidence for interactions among learning and memory systems and implicate the amygdala and dorsal striatum in some types of non-hippocampal based place learning using distal cues.

The experiments in this thesis investigated the neuropharmacology of memory in the caudate nucleus, using the conditioned emotional response (CER) with visual and olfactory conditioned stimuli (CS). / In experiment 1, post-training, intrastriatal microinjections of both amphetamine and LY 171555, but not SKF 38393: (1) into the posteroventral area improved memory of a visual, but not an olfactory, CER; (2) into the ventrolateral area improved memory of an olfactory, but not a visual, CER. In experiment 2, sulpiride, but not SCH 23390, blocked the memory improving effect of amphetamine. These findings are consistant with the hypothesis that dopamine D2 receptor stimulation mediates the memory enhancement effect of amphetamine in the neostriatum. / In three experiments on a visual CER, pre-training intrastriatal micro-injections of scopolamine impaired acquisition; post-training micro-injections improved consolidation; and pre-testing micro-injections impaired retrieval. These findings are consistant with the hypothesis that striatal muscarinic receptor stimulation mediates some aspects of acquisition and retrieval of sensory-motor memory, and that blockade of these receptors following training has an effect on memory consolidation similar to that of D2-receptor stimulation. / In experiment 6, destruction of the dopaminergic nigrostriatal neurons abolished the memory improving effect of intrastriatal post-training micro-injections of scopolamine and AFDX-384, a specific muscarinic M2 antagonist. These results suggest that the post-training memory improvement produced by muscarinic blockade may be mediated by an M2 receptor, known to be located on dopaminergic nigro-striatal terminals.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.

To characterize corticostriatal projections from rodent sensorimotor cortex, the anterograde tracers biotinylated dextran amine (BDA) and fluororuby (FR) were injected into the whisker representations of the primary motor (MI) and somatosensory (SI) cortices. Reconstructions of labeled terminals and their beaded varicosities in the neostriatum and thalamus were analyzed quantitatively to determine the degree of labeled overlap in both of these subcortical structures. Corticostriatal projections from the vibrissal representation in MI were more extensive than corresponding projections from SI. Both cortical areas sent dense projections to the dorsolateral neostriatum, but the MI vibrissal representation also projected to regions located more rostrally and medially. Despite these differences, both MI and SI projected to overlapping parts of the dorsolateral neostriatum. Tracer injections in both cortical areas also produced dense anterograde and retrograde labeling in the medial sector of the posterior complex of the thalamus (POm). Because POm is somatotopically organized and has reciprocal connections with both SI and MI cortices, the amount of labeled overlap in POm was used to indicate whether the tracers were injected into corresponding whisker representations of MI and SI. We found that the proportion of labeled overlap in the neostriatum was highly correlated with the amount of labeled overlap in POm. These results indicate that the rodent neostriatum receives convergent projections from corresponding regions in MI and SI cortex. Furthermore, the thalamocortical projections of the POm indicate that it may modulate corticostriatal outputs from corresponding representations in MI and SI.

No description available.

No description available.

To explore associations of neostriatal (NST) endogenous levels of dopamine (DA) and serotonin (5-HT) with sensitivity of their receptors, graded doses of 6-hydroxydopamine HBr (0 to 400 μg, ICV; 6-OHDA; desipramine pretreatment, 20 mg/kg IP) were given to rats between birth (P 0) and P 42. Numbers of vacuous chewing movements (VCMs) induced by SKF 38393 or m-chlorophenylpiperazine (m-CPP), respective DA D1 and 5-HT2 agonists, were subsequently determined. Enhanced SKF 38393-induced VCMs occurred when NST DA was reduced 97%-98% by high dose 6-OHDA (100-134 μg) at P 0 or P 3, but not in rats with 95%-97% loss in DA produced by 6-OHDA at P7 (134 μg) or P3 (67 μg). Enhanced m-CPP-induced VCMs occurred even when NST 5-HT content was not elevated after 6-OHDA (134 μg at P 10). Accordingly, D1 and 5-HT receptor sensitivity is not correlated with respective NST DA and 5-HT contents. The stage of ontogeny at the time of DA denervation may be the governing influence on receptor sensitivity.

An mit Urethan narkotisierten männlichen "Wistar"-Ratten erfolgte die extrazelluläre Einzelableitung der Aktionspotenziale von insgesamt 159 striatalen Neuronen. Mit Hilfe einer Mehrkanalelektrode wurden in die Nähe der Zellen mikroiontophoretisch verschiedene Substanzen appliziert. Die separate Gabe von Serotonin (5-HT), dem 5-HT1A-Rezeptoragonisten 8-OH-DPAT und dem sulfatierten Oktapeptid Cholezystokinin (CCK-8S) führte überwiegend zur Erhöhung der neuronalen Entladungsraten (Wilcoxon-Test signifikant mit p < 0,05), wohingegen der 5-HT2A/2C-Rezeptoragonist DOI nur an wenigen Neuronen einen Effekt induzierte, der hauptsächlich aus einer Reduktion der Entladungsraten bestand. Nach Koapplikation von Serotonin und CCK-8S überwogen ebenfalls aktivierende Effekte (Wt p < 0,05), jedoch wurde die neuronale Responsivität im Vergleich zur Einzelapplikation der beiden Substanzen signifikant reduziert (Chi2 p< 0,01). Da die Serotonin- bzw. 8-OH-DPAT-induzierten Effekte durch die spezifischen 5-HT1A-Rezeptorantagonisten WAY 100635 und S-UH 301 geblockt wurden und eine positive Korrelation der Serotonin- bzw. 8-OH-DPAT-Effekte (p < 0,05) nachgewiesen werden konnte, kann, trotz der entgegengesetzten Ergebnisse früherer Studien, das Vorhandensein von 5-HT1A-Rezeptoren im Neostriatum angenommen werden. Die Grundaktivität der durch Serotonin aktivierten Population war signifikant geringer (p > 0,05) als die der durch Serotonin gehemmten Neurone. Trotzdem zeigte sich keine Abhängigkeit der Responsivität der hier betrachteten Populationen auf die applizierten Serotoninagonisten von der Höhe der neuronalen Ruheentladungsrate. Die meisten der Serotonin-, 8-OH-DPAT-, DOI- bzw. CCK-8S-responsiven Neurone verteilten sich diffus über das gesamte Neostriatum. Nur die durch Serotonin aktivierte Population zeigte eine Präferenz der ventromedialen Bereiche des Neostriatum. Zusammenfassend kann gesagt werden, dass aufgrund der Ergebnisse der vorliegenden Studie die Existenz von 5-HT1A-Rezeptoren innerhalb des Neostriatum der Ratte in hohem Maße angenommen werden kann. Des Weiteren lässt sich vermuten, dass das Zusammenwirken von Serotonin und CCK-8S einen modulatorischen Einfluss auf die normale neuronale Funktion hat. Ob und in welchem Maße dieses letztgenannte Ergebnis eine therapeutische Relevanz zur Behandlung bestimmter Erkrankungen hat, bei denen Störungen im Neostriatum mit ursächlich sind, bleibt zu erforschen. / In rats anaesthetized with urethane single unit activity of 159 neostriatal neurones was extracellularly recorded and several drugs were microiontophoretically ejected. Separate administration of serotonin (5-HT), 8-OH-DPAT (a 5-HT1A/7-receptor-agonist) and the sulfated octapeptide cholecystokinin (CCK-8S) predominantly induced increases in the neuronal discharge rates (Wilcoxon test significant with p < 0,05), whereas the 5-HT2A/2C-receptor agonist DOI affected only a few neurones and mainly reduced firing. After coadministration of CCK-8S and serotonin activating effects also predominated (Wt p < 0,05), but the neuronal responsiveness was significantly reduced (Chi2 p

No / Drugs which upregulate astrocyte glutamate transport may be useful neuroprotective compounds by preventing excitotoxicity. We set up a new system to identify potential neuroprotective drugs which act through GLT-1. Primary mouse striatal astrocytes grown in the presence of the growth-factor supplement G5 express high levels of the functional glutamate transporter, GLT-1 (also known as EAAT2) as assessed by Western blotting and (3)H-glutamate uptake assay, and levels decline following growth factor withdrawal. The GLT-1 transcriptional enhancer dexamethasone (0.1 or 1 muM) was able to prevent loss of GLT-1 levels and activity following growth factor withdrawal. In contrast, ceftriaxone, a compound previously reported to enhance GLT-1 expression, failed to regulate GLT-1 in this system. The neuroprotective compound riluzole (100 muM) upregulated GLT-1 levels and activity, through a mechanism that was not dependent on blockade of voltage-sensitive ion channels, since zonasimide (1 mM) did not regulate GLT-1. Finally, CDP-choline (10 muM-1 mM), a compound which promotes association of GLT-1/EAAT2 with lipid rafts was unable to prevent GLT-1 loss under these conditions. This observation extends the known pharmacological actions of riluzole, and suggests that this compound may exert its neuroprotective effects through an astrocyte-dependent mechanism.