lntracellular and whole‐cell patch‐clamp recordings were used to evaluate the actions of different metabotropic glutamate receptor (mGluR) agonists on the synaptic inputs evoked on principal cells of ...the rat mesencephalon. Bath application of the group Ill mGluR agonists l‐2‐amino‐4‐phosphonobutyric acid (l‐AP4) and l‐serine‐O‐phosphonobutanoate (l‐SOP) did not change the holding current of the cells held at resting potential (‐60 mV) but produced a dose‐dependent inhibition of the amplitude of the excitatory and inhibitory events. l‐AP4 and l‐SOP were more effective at inhibiting the excitatory postsynaptic currents (EPSCs) than the GABAA and GABAB inhibitory postsynaptic currents (IPSCs). The suppressing effects of l‐AP4 and l‐SOP were antagonized by (S)‐2‐amino‐2‐methyl‐4‐phosphonobutanoic acid (MAP‐4) but not by ±‐α‐methyl‐4‐carboxyphenylglycine (MCPG). Moreover, the group II agonist (2S, 1′S, 2′S)‐(carboxycyclopropyl)glycine (l‐CCG1) and the group I agonist (RS)‐3,5‐dihydrophenylglycine (3,5‐DHPG) depressed in a dose‐related manner the EPSC, the GABAA IPSC and the GABAB IPSC. The suppressing effect of the two mGluRs agonists was partially antagonized by MCPG but not by MAP‐4. In addition, both l‐CCG1 and 3,5‐DHPG caused an inward shift of the holding current. To characterize the site of action of the metabotropic receptor agonists, experiments were performed to examine the amplitude and ratio of EPSC and GABAA IPSC pairs. The increase of the s2/sl ratio caused by the agonists suggests that the location of the inhibitory mGluRs was presynaptic. These results indicate that the activation of presynaptic mGluRs controls the release of excitatory and inhibitory transmitters on presumed dopaminergic cells within the ventral mesencephalon.
In the present study, expression of the immediate early gene protein products Fos and Jun-B within the dorsolateral striatum, the core and shell of the nucleus accumbens (NAC), the medial prefrontal ...cortex (mPFC), and the ventrolateral orbital cortex was examined. Rats were injected SC with either saline or nicotine (0.5 mg/kg) once daily for 12 days. On day 13, animals received a challenge injection of either saline or nicotine (0.5 or 1.0 mg/kg, SC) and 2 h later their brains were examined for Fos-like (FLI) and Jun-B-like (JLI) immunoreactivity. Chronic nicotine significantly increased basal expression of FLI selectively in the mPFC. Nicotine challenge significantly increased FLI in the mPFC of saline-treated animals and even further increased FLI in the mPFC of nicotine-treated animals. In the shell of the NAC, nicotine challenge also increased FLI in nicotine-treated animals, whereas it increased JLI only in saline-treated animals. After chronic nicotine treatment, injection of D1 receptor antagonist SCH 23390 (0.1 mg/kg, IP) 10 min before a nicotine challenge (0.5 mg/kg, SC), significantly attenuated the nicotine-induced FLI in the mPFC and the shell of the NAC. These results suggest that the regionally selective effect of nicotine challenge on FLI is due to enhanced dopaminergic transmission, mediated via stimulation of D1 receptors.
In a recent study, utilizing single cell recording techniques, we have shown that administration of 5-HT1A receptor antagonists, e.g. (S)-UH-301, to rats concomitantly treated, acute or chronically, ...with the selective serotonin reuptake inhibitor (SSRI) citalopram significantly increases the activity of 5-hydroxytryptamine (5-HT) containing neurons in the dorsal raphe nucleus (DRN). Here we report correlative experiments using microdialysis in freely moving animals to measure extracellular levels of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) in the frontal cortex, a major projection area for DRN-5-HT neurons. Acute administration of (S)-UH-301 (2.5 mg/kg s.c.) or citalopram (2.0 mg/kg s.c.) increased 5-HT concentrations with a maximum of about 70% and 185%, respectively, above baseline. However, when (S)-UH-301 was administered 30 min before citalopram the maximal increase in 5-HT levels was approximately 400%. In rats chronically treated with citalopram (20 mg/kg/day i.p. for 14 days) basal 5-HT concentrations in the frontal cortex were significantly increased and 5-HIAA concentrations were decreased when measured 10-12 h, but not 18-20 h, after the last injection of citalopram, as compared to basal 5-HT and 5-HIAA concentrations in chronic saline-treated rats. When (S)-UH-301 (2.5 mg/kg s.c.) was administered 12 h, but not 20 h, after the last dose of citalopram it produced a significantly larger increase in extracellular concentrations of 5-HT than in control rats. However, in rats pretreated with a single, very high dose of citalopram, 20 mg/kg i.p., administration of (S)-UH-301 at 12 h after citalopram did not increase 5-HT levels. The augmentation by (S)-UH-301 of the increase in brain 5-HT output produced by acute administration of citalopram is probably due to antagonism of the citalopram induced feedback inhibition of 5-HT cells in the DRN, as previously suggested. However, the capacity of (S)-UH-301 to further increase the already elevated extracellular concentrations of 5-HT in brain in animals maintained on a chronic citalopram regimen, in which significant tolerance to the initial feedback inhibition of DRN-5-HT cells and developed, represents a novel finding. Generally, the reduced feedback inhibition of 5-HT neurons obtained with chronic citalopram treatment, and the associated elevation of brain 5-HT concentrations, may be related to functional desensitization of somatodendritic 5-HT1A autoreceptors in the DRN. This phenomenon may also largely explain the larger increase in 5-HT output produced by (S)-UH-301 in chronic citalopram treated animals as compared to its effect in control animals. Yet, a contributory factor may be a slight, remaining feedback inhibition of the 5-HT cells caused by residual citalopram at 12, but not 20 h after its last administration. Previous clinical studies suggest that addition of a 5-HT1A receptor antagonist to an SSRI in the treatment of depression may accelerate the onset of clinical effects. Moreover, in therapy-resistant cases maintained on SSRI treatment, addition of a 5-HT1A receptor antagonist may improve clinical efficacy. Since the therapeutic effect of SSRIs in depression has been found to be critically linked to the availability of 5-HT in brain, our experiments results support, in principle, both of the above clinically based notions.
In this study we have examined the acute effects of systemic administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, in combination with either of the two selective 5-HT1A ...receptor antagonists, (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin (S)-UH-301 or (+)-N-tertbutyl 3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenyl-propionamide dihydrochloride (+)-WAY100135, on the activity of single 5-HT neurons in the dorsal raphe nucleus (DRN) of anesthetized rats using extracellular recording techniques. Acute administration of citalopram (0.3 mg/kg i.v.) significantly decreased the firing rate of DRN-5-HT cells most likely as a result of indirect stimulation of inhibitory somatodendritic 5-HT1A autoreceptors located on 5-HT cells in the DRN. This effect of citalopram was completely reversed by (S)-UH-301 (0.5 mg/kg i.v.) and partly by (+)-WAY100135 (0.5 mg/kg i.v.). Furthermore, the inhibitory effect of citalopram on the activity of 5-HT neurons was significantly attenuated by pretreatment with (S)-UH-301 (0.25 mg/kg i.v.) or (+)-WAY100135 (0.25 mg/kg i.v.). We have also studied the effects of (S)-UH-301 (0.03-0.50 mg/kg i.v.) on the firing rate of single DRN-5-HT cells in rats chronically treated with citalopram (20 mg/kg/day i.p. x 14 days). Administration of (S)-UH-301 significantly and dose-dependently increased the activity of 5-HT cells in citalopram-treated rats, but did not affect these neurons in saline-treated (1 ml/kg/day i.p. x 14 days), control rats. Our results thus suggest that 5-HT1A receptor antagonists can augment both the acute and chronic effects of citalopram on central serotonergic neurotransmission.
The findings that dopamine D3 and D4 receptors are highly expressed in limbic and cortical areas (D4 more than D3), and the fact that the atypical drug clozapine has preferential affinity for the D4 ...receptors have suggested an involvement of these receptors in schizophrenia. Subsequently, many pharmaceutical companies have pursued the approach of developing selective dopamine D3 or D4 antagonists as potential antipsychotics. This review will discuss the current status of selective dopamine D3 and D4 receptor antagonists for the treatment of schizophrenia.
The parasites Trypanosoma brucei cause African trypanosomiasis (sleeping sickness), a severe neuropsychiatric disease with marked disturbances of sleep-wake alternation. The sites of brain lesions ...are not well characterized. The present experimental investigation is focused on the hypothalamic suprachiasmatic nuclei, which play a role of a biological clock entraining endogenous rhythms in the mammalian brain. The electrophysiological properties of these neurons were analyzed in slice preparations from trypanosome-infected rats. The neuronal spontaneous activity, which shows a circadian oscillation, was markedly altered in the infected animals, displaying a reduced firing rate and phase advance of its circadian peak. The direct retinal fibers, which play a pivotal role in entrainment of the circadian pacemaker, displayed a normal density and distribution in the suprachiasmatic nuclei of infected animals after intraocular tracer injections in vivo. At the postsynaptic level, immunohistochemistry and Western blotting revealed in the suprachiasmatic nuclei of infected rats a selective decrease of the expression of glutamate AMPA GluR2/3 and NMDAR1 receptor subunits that gate retinal afferents. These data disclose an impairment of the neuronal functions in the biological clock in African trypanosomiasis, and may serve to unravel functional and molecular mechanisms behind endogenous rhythm disturbances.
Interferon or late effect of radiotherapy? Sandvik, Ulrika; Grillner, Pernilla; Holm, Stefan ...
Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery,
02/2016, Letnik:
32, Številka:
2
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