Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis.

We show that cyclic AMP (cAMP) elevating agents protect blasts from patients with acute promyelocytic leukemia (APL) against death induced by first-line anti-leukemic anthracyclines like daunorubicin (DNR). The cAMP effect was reproduced in NB4 APL cells, and shown to depend on activation of the generally cytoplasmic cAMP-kinase type I (PKA-I) rather than the perinuclear PKA-II. The protection of both NB4 cells and APL blasts was associated with (inactivating) phosphorylation of PKA site Ser118 of pro-apoptotic Bad and (activating) phosphorylation of PKA site Ser133 of the AML oncogene CREB.

On the mechanisms of the development of tolerance to the muscular rigidity produced by morphine in rats.

The development of tolerance to the muscular rigidity produced by morphine was studied in rats. Saline-pretreated controls given a test dose of morphine (20 mg/kg i.p.

Individual and morphological differences in the behavioural response to apomorphine in rats.

The topography of stereotyped behaviour produced by apomorphine in rats was studied by using either a scoring system, based on observation in a wire cage, or by quantification of horizontal and vertical activities, and of the total distances run in an open field, using an automatic recording system. The latter design was combined with a classification of the type of stereotyped behaviour observed during recording. In addition, the reproducibility of the nature of the stereotyped behaviour and its dose-dependence in individual animals was evaluated.

Locomotor activity of rats after injection of various opioids into the nucleus accumbens and the septum mediale.

The possible role of the nucleus accumbens (ACB) and, in some experiments, the septum mediale (SM) in mediating alterations in locomotor activity, produced by various opioids, was evaluated in the rat, the drug being injected either into the left central part of the ACB or into the left SM. Morphine, predominantly acting at the mu-type receptors, given in larger doses (13 or 40 nmol into the ACB) produced depression of locomotor activity and catalepsy, whereas 2.5 nmol were ineffective.

Pharmacokinetics of morphine in striatum and nucleus accumbens: relationship to pharmacological actions.

The pharmacokinetics of morphine was compared with its ability to increase striatal dopamine turnover (estimated by an increase in DOPAC concentration) and to produce the development of a muscular rigidity (estimated as a tonic activity in the electromyogram). After systemic administration of morphine (15 mg/kg IP), the concentration of morphine in blood plasma, striatum and substantia nigra showed a parallel time course with a maximum after 30 min; in the striatum, in addition, normorphine was found in a lower concentration, but with a similar time course. The elevation of striatal DOPAC, in contrast, commenced very rapidly and lasted for about four hours.

Development of tolerance to the muscular rigidity produced by morphine and replacement by stereotypic behaviour.

After chronic treatment with morphine, the muscular rigidity mediated by opioid receptors in the striatum, was gradually replaced by stereotypic behaviour indicating an increased nigrostriatal dopaminergic activity. These results suggest that one behavioural pattern, originating in the striatum, was replaced by another one, which is antagonistic to the first one.

GABAergic mechanisms in mediating muscular rigidity, catalepsy and postural asymmetry in rats: differences between dorsal and ventral striatum.

In rats, the GABAergic agonist muscimol was injected unilaterally either into the mid ventroposterior striatum (ventral striatum) or into the mid dorsoposterior striatum (dorsal striatum), and the following parameters were estimated: (1) a tonic activity in the electromyogram (EMG) recorded from the gastrocnemius-soleus (GS) muscle, which appears to reflect a muscular rigidity; (2) catalepsy, and (3) asymmetries in posture. Injection of muscimol (25 or 50 ng) into the ventral striatum produced tonic EMG activity, catalepsy and ipsiversive posture; these signs were much less pronounced or not observed after injections into the dorsal striatum. Co-administration of bicuculline (500 ng) into the ventral striatum, or simultaneous injection of muscimol (25 ng) into the substantia nigra pars reticulata (SNR), antagonized both the tonic EMG activity and the catalepsy produced by injection of 50 ng muscimol into the ventral striatum.

Role of muscarinic cholinergic mechanisms in the substantia nigra pars reticulata in mediating muscular rigidity in rats.

Bethanechol chloride (5-25 micrograms), when injected into the substantia nigra pars reticulata (SNR) of rats, produced muscular rigidity in a dose-dependent way, and in addition, catalepsy and ipsilateral posture. The effects of bethanechol in the dose of 25 micrograms were prevented by co-administration of 10 micrograms scopolamine hydrochloride. Injections of 25 micrograms bethanechol or 10 micrograms scopolamine into the reticulata only slightly affected the muscular rigidity produced by 15 mg/kg i.

Opioid-specific recognition sites of the mu- and the delta-type in rat striatum after lesions with kainic acid.

The binding of 3H-dihydromorphine (3H-DHM) and of 3H-D-ala2, D-leu5-enkephalin (3H-DADL), which are regarded as relatively selective ligands for mu- or delta-type opioid receptors, respectively, was estimated in total particulate fraction of the striatum of rats in vitro, either in tissue of rats after striatal chemolesions with kainic acid or in control rats (not operated or saline injected into the striatum). Kainate lesions reduced the Bmax values of 3H-DHM by about 78 - 88% depending on the method of calculation, and of 3H-DADL by greater than 90%. Furthermore they lowered the Kd-values, suggesting an increase in affinity.

The role of the substantia nigra in motility of the rat. Muscular rigidity, body asymmetry and catalepsy after injection of morphine into the nigra.

Unilateral injection of morphine (1.0, 2.5 or 5.

Nigral GABAergic mechanisms and EMG activity in rats: differences between pars reticulata and pars compacta.

The effects of GABAergic drugs, injected unilaterally either into the substantia nigra pars compacta (SNC) or pars reticulata (SNR) of rats, on motility (tonic activity in the gastrocnemius-soleus muscle, turning behaviour, catalepsy) were studied. Administration of the GABAergic antagonist bicuculline (12.5-50 ng) into the SNR produced tonic activity in the EMG, catalepsy and an ipsiversive posture.

Motility, rigidity and turnover of dopamine in the striatum after administration of morphine to rats: a re-evaluation of their mechanisms.

Whether the delayed behavioural activation and the increase in dopamine (DA) turnover in the striatum reflect signs of rebound effects or of counter-regulatory processes directed against locomotor depression and/or muscular rigidity was studied in rats. Administration of a large dose of morphine (30 mg/kg i.p.

Reversal of the muscle relaxant effect of diazepam by the specific benzodiazepine antagonist Ro 15-1788: an electromyographic study in morphine model of muscular rigidity in rats.

The effects of the benzodiazepines diazepam and midazolam on the rigidity produced by systemic administration of morphine (15 mg/kg i.p.) were studied in rats.

The effects of D-ala2, D-Leu5-enkephalin injections into the nucleus accumbens on the motility of rats.

Previous studies suggested that the nucleus accumbens (ACB) is relevant for mediating morphine-induced akinesia and catalepsy. In the present study, the effects of unilateral injections of D-ala2, D-leu5-enkephalin (DADL) into the ACB were evaluated. Compared with saline-injected controls, 0.

Disinhibition of nigral GABA output neurons mediates muscular rigidity elicited by striatal opioid receptor stimulation.

Unilateral injection of bicuculline (12.5-50 ng) into the substantia nigra pars reticulata (SNR) dose-dependently produced a tonic activity in the electromyogram (EMG), which was antagonized by coadministered muscimol. Bilateral lesions of the caudate nucleus with kainic acid failed to affect the EMG activity produced by unilateral injection of bicuculline into the SNR.

Role of opioid receptors in the substantia nigra in morphine-induced muscular rigidity.

Uni- or bilateral injection of morphine (MO) (3-13 nmoles) into the substantia nigra pars reticulata (SNR) produced tonic activity in the electromyogram (EMG) recorded from the gastrocnemius-soleus (GS) muscle of non-anesthesized rats. This activity was antagonized by naloxone (NAL) (10 nmoles) coadministered with MO into the SNR. Bilateral lesion of the caudate nucleus (CN) with kainic acid did not prevent the tonic EMG activity occurring after the injection of MO into the SNR.

On the possible role of excitatory amino acids in the striatum in mediating morphine-induced muscular rigidity.

The possible role of excitatory amino acids in the striatum in mediating tonic activity in the electromyogram (EMG) was studied. Glutamate diethylester (GDEE) (100-400 nmoles) induced a tonic activity in the EMG in a dose-dependent way when injected into the striatum. This effect was well antagonized by intrastriatal injection of quisqualic acid (5 and 25 nmoles), less by kainic acid (5 nmoles) and not significantly by N-methyl-D-aspartate (NMDA) (30 nmoles).

Is morphine-induced akinesia related to inhibition of reflex activation of flexor alpha-motoneurones? Role of the nucleus accumbens.

Unilateral injections of morphine (5-15 micrograms) into the nucleus accumbens of non-anesthetized rats produces a decrease of locomotor activity and a catalepsy. In a similar dose-response relationship, injections of morphine into this area inhibited the reflex activation of alpha-motoneurones by mild tetanic stimulation of the ipsilateral peroneal nerve (flexor alpha-motoneurones) in halothane-anesthetized rats. All these effects were antagonized by systemic administration of naloxone.

Evidence that opioid receptors in the substantia nigra pars reticulata are relevant in regulating the function of striatal efferent pathways.

A tonic activity in the electromyogram (EMG) was induced in conscious rats by injections of morphine either systemically or into the caudate nucleus. This activity was antagonized by injections of naloxone into the substantia nigra pars reticulata. These findings suggest that opioid receptors in this brain area are relevant in regulating the function of striatal efferent pathways.

Role of GABAergic mechanisms in the substantia nigra pars reticulata in modulating morphine-induced muscular rigidity in rats.

Systemic administration of morphine (15 mg/kg i.p.) induced a muscular rigidity in rats, which was recorded from the gastrocnemius-soleus muscle as tonic activity in the electromyogram (EMG).

Unilateral injection of morphine into the nucleus accumbens induces akinesia and catalepsy, but no spontaneous muscular rigidity in rats.

The role of the nucleus accumbens in the generation of the signs of morphine-induced "catatonia" namely akinesia, catalepsy and muscular rigidity, was studied in rats. Morphine was injected into the nucleus accumbens and either spontaneous locomotor activity or catalepsy or activity in the electromyogram of the gastrocnemius-soleus muscle, signalling the appearance of rigidity, were recorded. Unilateral injections of 5 micrograms of morphine induced a decrease of locomotor activity and weak catalepsy; 15 micrograms of morphine completely abolished locomotor activity (akinesia) and produced a very pronounced catalepsy.

Neurochemical aspects of the opioid-induced 'catatonia'.

In this review, the symptoms contributing to the opioid-induced 'catatonia' are presented in detail, and efforts are made to relate these symptoms to opioid-induced alterations in neurotransmitter metabolism in several parts of brain, in particular in the basal ganglia. One important symptom is the muscular rigidity, which is, at least to a great part, mediated by opioid receptors in the striatum. This effect is probably not due to an action on opioid receptors located on endings of nigro-striatal dopaminergic neurones (localization I in Fig.