Biomedical subjects

M Morelli

Publications and source records attributed to M Morelli.

At least 55 records · Page 3Linked to original sources

PubMed1997

Behavioural sensitization in 6-hydroxydopamine-lesioned rats is related to compositional changes of the AP-1 transcription factor: evidence for induction of FosB- and JunD-related proteins.

Rats with unilateral dopamine denervation exhibit turning behaviour in response to the selective D1 agonist SKF 38393 only after a previous exposure to dopamine agonists. We demonstrate here that this 'priming' phenomenon is related to both an increased expression of the pre-existing AP-1 complex and the occurrence of novel AP-1 complexes which are formed by FosB- and JunD-related proteins. While the former protein is expressed as a consequence of the dopamine denervation, the latter is related to the first exposure to a dopamine agonist. Pre-treatment with MK-801, an antagonist for glutamatergic receptors, prevents both the priming development and the AP-1 compositional changes. Rotational behaviour induced by SKF 38393 closely correlates with the presence of the priming AP-1 complexes, regardless of the capability of the D1 agonist to induce the immediate-early gene cFos.

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

PubMed1997

Priming of 6-hydroxydopamine-lesioned rats with L-DOPA or quinpirole results in an increase in dopamine D1 receptor-dependent cyclic AMP production in striatal tissue.

Priming with a dopamine agonist greatly enhances the behavioral effectiveness of dopamine D1 receptor agonists in rats with 6-hydroxydopamine lesions of the nigrostriatal pathway. The present study investigated the influence of priming on cyclic AMP production in striatal slices. Stimulation of dopamine D1 receptors with dopamine or the dopamine D1 receptor agonist, 1-phenyl-6-Cl-7,8-diol-2,3,4,5-tetrahydro-(1H)-3-benzazepine (SKF 81297), increased cyclic AMP production in the lesioned striatum of rats primed with L-3,4-dihydroxyphenylalanine (L-DOPA) by 329% and 405%, respectively, whereas in drug-naive rats the increase was 183% and 187%, respectively. Priming with quinpirole produced similar results. It is suggested that priming with either L-DOPA or a dopamine D2 receptor agonist results in increased effectiveness of dopamine D1 signal transduction, apparently not only related to previous stimulation of D1 receptors.

Animals↗

PubMed1997

Adenosine A2A receptor agonists increase Fos-like immunoreactivity in mesolimbic areas.

Expression of the early-gene c-fos is an useful method for studying potential sites of action of drugs active in the CNS. Stimulation of adenosine A2A receptors by CGS 21680 (5 mg/kg) induced an increase in Fos-like immunoreactivity in the rat nucleus accumbens shell, while in the rostral pole and core CGS 21680 induced Fos-like immunoreactivity only after a high dose. CGS 21680 (5 mg/kg) stimulated c-fos expression also in the lateral septal nucleus and dorso-medial striatum, but not in the dorso-lateral striatum. A similar pattern of Fos-like immunoreactivity was obtained after administration of the A2A agonist HENECA (5 mg/kg) which displays higher selectivity for A2A receptors than CGS 21680. Administration of the selective A2A antagonist SCH 58261 counteracted CGS 21680-induced Fos-like immunoreactivity. Lesions of the dopaminergic mesostriatal projection by 6-hydroxydopamine and stimulation of dopamine D2/D3 receptors by quinpirole, prevented CGS 21680-induced Fos-like immunoreactivity in the nucleus accumbens shell. The present results show that stimulation of A2A receptors induces a profile of c-fos expression similar to that of atypical neuroleptics. A2A receptor stimulation has been reported to have dopamine antagonistic actions, it is therefore suggested that A2A agonists might have antipsychotic activity without producing extrapyramidal side effects.

Adenosine↗

PubMed1997

Adenosine A2A receptor antagonism potentiates L-DOPA-induced turning behaviour and c-fos expression in 6-hydroxydopamine-lesioned rats.

In order to investigate the role of adenosine A2A receptor blockade on dopamine-mediated motor responses, contralateral turning behaviour and expression of the early-gene c-fos was evaluated in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway. SCH 58261, (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1 , 5-c]pyrimidine) a potent and selective antagonist of adenosine A2A receptors (5 mg/kg i.p.), induced a 70-fold increase in the contralateral turning behaviour induced by a low dose (2 mg/kg i.p.) of the dopamine precursor L-DOPA (L-3, 4-dihydroxyphenylalanine). Expression of c-fos as measured by Fos-like immunoreactivity after SCH 58261 plus L-DOPA was also potentiated as compared with L-DOPA alone, both in striatum and globus pallidus of the 6-hydroxydopamine-lesioned side of the brain. SCH 58261 induced a less marked potentiation (7-fold) of turning behaviour induced by dopamine D2 receptor stimulation with quinpirole, while Fos-like immunoreactivity in the striatum and globus pallidus was not affected. Previous studies have shown that SCH 58261 strongly potentiated dopamine D1 receptor-mediated responses. The results of the present study therefore indicate that the positive interaction between SCH 58261 and L-DOPA, in 6-hydroxydopamine-lesioned rats, is mainly due to an interaction with dopamine D1 receptors. The data also suggest that adenosine A2A receptor antagonists might be useful for potentiating the effects of L-DOPA in Parkinson's disease.

Animals↗

PubMed1997

Dopamine/glutamate interaction as studied by combining turning behaviour and c-Fos expression.

Dopamine (DA) and glutamate N-methyl-D-aspartate (NMDA) receptors extensively interact in the mediation of motor behaviours originated in basal ganglia. In unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, this interaction is of a different sign depending on whether D1 or D2 receptors are stimulated. Contralateral turning behaviour induced by D1 agonists is potentiated by the NMDA antagonist MK 801, while turning behaviour induced by D2 agonists is decreased. NMDA receptors not only modulate the acute turning behaviour induced by DA agonists but also the long-term effects induced by stimulation of DA receptors. MK 801, in fact, prevents the sensitization (priming) of D1-mediated turning behaviour induced by a single exposure to a DA agonist. Prevention of priming by MK 801, also appears to be different depending on whether D1 or D1/D2 receptors are stimulated. Studies on c-fos expression induced by DA D1 agonists in the 6-OHDA lesioned striatum show that detection of Fos-like immunoreactivity correlates to the long-term but not the acute effects induced by DA receptor stimulation and NMDA receptor blockade.

Animals↗

PubMed1997

Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia.

Increasing evidence suggests that antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the basal ganglia are involved in the motor depressant effects of adenosine receptor agonists and the motor stimulant effects of adenosine receptor antagonists, such as caffeine. The GABAergic striatopallidal neurons are regulated by interacting adenosine A2A and dopamine D2 receptors. On the other hand, the GABAergic striatonigral and striatoentopeduncular neurons seem to be regulated by interacting adenosine A1 and dopamine D1 receptors. Furthermore, behavioural studies have revealed interactions between adenosine A2A and dopamine D1 receptors that occur at the network level. These adenosine-dopamine receptor-receptor interactions might offer new therapeutic leads for basal ganglia disorders.

Animals↗

PubMed1996

C-Fos expression as a molecular marker in corticotropin-releasing factor-induced seizures.

Expression of Fos-like protein has been shown to increase after seizures in several types of experimentally induced epilepsies. The intracerebroventricular (icv) injection of murine corticotropin-releasing factor (CRF) in rats (10 micrograms), shows an electroencephalographic (EEG) spiking activity restricted to the amygdaloid-hippocampal area. This EEG seizure pattern represents a unique model of localized epileptic activity induced by a neuropeptide. C-fos expression after icv CRF has been considered a useful tool in mapping areas involved in stress and in seizure activity. Our results show that 1 microgram and 10 micrograms CRF are able to induce c-fos activation in several brain areas. Moreover, the present study not only details c-fos expression increase in brain areas directly involved in spiking activation, such as the amygdaloid-hippocampal region, but also maps the possible contribution of other regions to seizure manifestations.

Animals↗

PubMed1996

Human heart rate variability and sleep stages.

With the aim of better understanding the dynamic changes in sympatho-vagal tone occurring during the night, human heart rate variability (HRV) during the various sleep stages was evaluated by means of autoregressive spectral analysis. Each recording consisted of an electroencephalogram, an electrooculogram, and electromyogram, and electrocardiogram, and a spirometry trace. All of the data were sampled and stored in digital form. Sleep was analysed visually, but HRV was analysed off-line by means of original software using Burg's algorithm to calculate the LF/HF ratio (LF: 0.04-0.12 Hz; HF: 0.15-0.35 Hz) for each sleep stage. Seven healthy subjects (four males; mean age 35 years) were enrolled in the study. Our findings show a progressive and significant reduction in the LF/HF ratio through sleep stages S1-S4, as a result of an increase in the HF component; this indicates the prevalence of parasympathetic activity during slow-wave sleep. During wakefulness, S1 and REM, the LF/HF values were similar and close to 1.

Adult↗

PubMed1996

Effect of MK 801 on priming of D1-dependent contralateral turning and its relationship to c-fos expression in the rat caudate-putamen.

In rats with a unilateral 6-hydroxydopamine lesion of the ascending dopamine neurons, we investigated the relationship between the expression of Fos-like immunoreactivity in the caudate-putamen and contralateral turning behavior in response to dopamine agonists during the induction and expression of sensitization (priming) to D1-dependent turning behavior. Priming was induced by apomorphine (0.1 mg/kg s.c.) or by SKF 38393 (10 mg/kg s.c.) 14 days after 6-hydroxydopamine lesions and was expressed by challenge with SKF 38393 (3 mg/kg s.c.). In the induction phase of priming, administration of MK 801 (0.1 mg/kg s.c.) potentiated contralateral turning but differentially influenced stimulation of Fos expression in the caudate-putamen by apomorphine and by SKF 38393. Thus, MK 801 reduced in the expression phase of priming the stimulation of Fos expression by apomorphine in the dorsolateral caudate-putamen, but did not affect that by SKF 38393. MK 801, while preventing priming of SKF 38393-induced turning by apomorphine, failed to affect priming by SKF 38393. MK 801, given with apomorphine in the induction phase, reduced the stimulation of Fos expression in the dorsolateral caudate-putamen by SKF 38393. No such inhibitory effect of MK 801 on SKF 38393-stimulated Fos expression was observed in rats primed with SKF 38393. These results are consistent with the possibility that MK 801 disrupts sensitization of D1 transduction by reducing the activation of c-fos by the DA agonist during the induction phase of priming.

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

PubMed1996

Blockade of A2a adenosine receptors positively modulates turning behaviour and c-Fos expression induced by D1 agonists in dopamine-denervated rats.

In rats with unilateral 6-hydroxydopamine lesions of the dopaminergic nigrostriatal pathway, administration of the A2a adenosine antagonist SCH 58261 alone did not induce any motor asymmetry but strongly potentiated the contralateral turning behaviour induced by the dopamine D1 agonist SKF 38393. SCH 58261 also increased the number of Fos-like positive nuclei induced by SKF 38393 in the 6-hydroxydopamine-lesioned striatum. Intense potentiation of D1-dependent turning behaviour and c-Fos expression was also observed after administration of the A2a/A1 antagonist CGS 15943. Administration of the A1 adenosine receptor antagonist DPCPX induced a small potentiation of D1-mediated contralateral turning while c-Fos expression induced by SKF 38393 was not modified. The results suggest that endogenous adenosine acting on A2a receptors can exert an inhibitory influence on the functional expression of D1-mediated responses in dopamine-denervated rats, and propose new possible therapeutic approaches in the treatment of Parkinson's disease.

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

PubMed1995

Modulation of dopamine D1-mediated turning behavior and striatal c-fos expression by the substantia nigra.

In order to study the possible contribution of the substantia nigra (SN) in the positive interaction between dopamine D1 receptor agonists and glutamate antagonists in unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, the effect of the D1 agonist, SKF 38393, was studied in combination with intranigral infusions of glutamate antagonists of the NMDA (MK 801, CPP) or AMPA (NBQX) type of receptor. Local infusion into the SN of the 6-OHDA lesioned side of MK 801, CPP or NBQX at doses inducing no or minimal behavioral effects significantly increased the turning behavior and the expression of c-fos induced, in the lesioned caudate-putamen (CPu), by a parenteral administration of SKF 38393. The same result was obtained after intra-SN infusion of the GABA agonist, muscimol. High doses of MK 801, CPP or muscimol infused into the SN produced intense contralateral turning per se and induced a sparse c-fos expression in the lesioned CPu which was antagonized by parenteral administration of MK 801. The results indicate that a depression of SN pars reticulata efferent neurons potentiates D1-mediated responses and suggest that this area may play a role in the positive interaction between glutamate antagonists and D1 receptor agonists.

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

PubMed1995

Adenosine A2 receptors stimulate c-fos expression in striatal neurons of 6-hydroxydopamine-lesioned rats.

The induction of the early-gene c-fos after administration of the adenosine A2a receptor agonist CGS 21680, was studied in the striatum of normal rats or in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal neurons. CGS 21680 (2.25 mg/kg) induces c-fos expression in the 6-hydroxydopamine-lesioned striatum, while up to 40 mg/kg fails to induce c-fos in the intact striatum or in the striatum of normal rats. Blockade of muscarine receptors by scopolamine (5 mg/kg) partially prevents, and stimulation of dopamine D2 receptors by quinpirole (0.5 mg/kg) completely reverses, CGS 21680-induced c-fos expression in the 6-hydroxydopamine-lesioned striatum. In turn, CGS 21680 partially reverses c-fos expression induced by quinpirole in the lesioned globus pallidus. CGS 21680, in addition, dose-dependently reduces the turning behavior induced by quinpirole (0.5 mg/kg) in 6-hydroxydopamine-lesioned rats. The results suggest that CGS 21680 induces c-fos expression in the striatum through direct and indirect mechanisms related to the ability of A2a receptors to stimulate cyclic AMP formation or acetylcholine release which in turn would activate c-fos through muscarinic receptors.

Adenosine↗

PubMed1995

Benefits and complications of laparoscopic pelvic lymphadenectomy for detection of stage D1 prostate cancer: a multicenter experience.

One hundred fifty-eight consecutive patients with clinically localized prostate cancer were submitted to staging laparoscopic pelvic lymphadenectomy (LPL) at 5 cooperative centers with one or more of the following conditions which were considered as risk factors for nodal disease: clinical stage C (or T3) disease, serum prostate-specific antigen > 20 ng/ml, Gleason sum > 6. The mean number of lymph nodes removed was 11 (range 2-29). Metastases from prostate cancer were found in 41 patients (25.9%). The proportion of lymph node-positive patients increases significantly with the presence of one, two or three of the conditions considered as risk factors (p < 0.00005). The benefit of LPL is limited to the lymph node-positive patients who can be spared a second operation.

Humans↗

PubMed1995

Intranigral injections of glutamate antagonists modulate dopamine D1-mediated turning behavior and striatal c-fos expression.

The contribution of the substantia nigra (SN) in the positive interaction between dopamine D1 receptor agonists and glutamate antagonists was studied in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of dopaminergic nigro-striatal pathway. Local infusion into the SN of the 6-OHDA lesioned side of NMDA glutamate antagonists MK 801 and CPP or the AMPA antagonist NBQX at doses inducing none or minimal behavioral effects, significantly increased the turning behavior and the expression of c-fos induced, in the lesioned caudate-putamen (CPu), by a parenteral administration of SKF 38393. High doses of MK 801 or CPP infused into the SN produced intense contralateral turning per-se but induced only sparse c-fos expression in the lesioned CPu. The results show that a depression of SN pars reticulata efferent neurons, potentiates D1-mediated responses and suggest that this area may play a role in the positive interaction between glutamate antagonists and D1 receptor agonists.

Animals↗

PubMed1995

Dopamine mediated responses in 6-hydroxydopamine lesioned rats involve changes of the signal transduction.

A single dose of the D1 agonist SKF 38393 (3 mg/kg) produces contralateral turning in unilaterally 6-hydroxydopamine lesioned rats only after a previous exposure of the animals to a dopamine agonist. This priming phenomenon is here investigated by studying the phosphorylation of DARPP-32, a dopamine- and cyclic AMP-regulated phosphoprotein functionally linked to D1 receptors in striatum. Dephospho-form of DARPP-32 in striatal tissue was measured by a back-phosphorylation assay. While the levels of DARPP-32 protein, as measured by quantitative immunoblotting, remained unchanged, a significant decrease of dephospho-DARPP-32 was observed in the denervated striatum of primed rats, indicating an increased phosphorylation in vivo of DARPP-32 in response to the D1 agonist. This study shows that an alteration of the dopamine-dependent signal transduction is related to the behavioral response to dopamine agents, suggesting a possible mechanism involved in the effects of these drugs in parkinsonian patients.

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

PubMed1994

Adenosine A2 receptors interact negatively with dopamine D1 and D2 receptors in unilaterally 6-hydroxydopamine-lesioned rats.

In rats bearing a unilateral 6-hydroxydopamine lesion of the dopaminergic nigro-striatal pathway, stimulation of adenosine A2 receptors by CGS 21680 reduced the contralateral turning behavior induced by L-3,4-dihydroxyphenylalanine (L-DOPA). Administration of CGS 21680 completely blocked the contralateral turning induced by the dopamine D1 receptor agonist, SKF 38393, and reduced the turning induced by the dopamine D2 receptor agonist, LY 171555. Quinolinic acid lesion of the striatum or 6-hydroxydopamine lesion of the dopaminergic nigro-striatal neurons demonstrated that [3H]CGS 21680 binding sites are associated to striatal intrinsic neurons. This study provides evidence for a negative postsynaptic interaction of both dopamine D1 and D2 receptors with adenosine A2 receptors.

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

PubMed1994

Differential effect of MK 801 and scopolamine on c-fos expression induced by L-dopa in the striatum of 6-hydroxydopamine lesioned rats.

In rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigro-striatal pathway, striatal D1-receptor-stimulated c-fos expression and turning behavior are positively modulated by D2 receptor stimulation and by blockade of N-methyl-D-aspartate (NMDA) or muscarinic receptors. Combined D1/D2 receptor stimulation by L-dopa activates c-fos in a manner not additive with muscarinic receptor blockade by scopolamine. On the other hand, blockade of NMDA receptors by MK 801 reduced c-fos expression induced by L-dopa while, depending on the dose of L-dopa, differentially affecting contralateral turning behavior. The results are interpreted to suggest that D2 receptor stimulation amplifies D1-receptor-mediated c-fos expression by two mechanisms differentially related to muscarinic and NMDA receptors.

Animals↗

PubMed1994

Modulatory functions of neurotransmitters in the striatum: ACh/dopamine/NMDA interactions.

The striatum is viewed as a structure performing fast neurotransmitter-mediated operations through somatotopically organized projections to medium-size spiny neurons. This view is contrasted with another view that depicts the striatum as a site of diffuse modulatory influences mediated by cholinergic interneurons and by dopamine and N-methyl-D-aspartate receptors. These two operational and organizational modes both contribute, through their mutual interaction, to the function of basal ganglia. Detailed knowledge of the neural mechanisms by which such interactions take place and are expressed into behaviour, can provide new insight into the physiopathology and new clues for therapy of disorders of basal ganglia.

Acetylcholine↗