N. Dourmap

Association of DNA polymorphism in the first intron of the tyrosine hydroxylase gene with disturbances of the catecholaminergic system in schizophrenia

We examined whether there are clinical or biological differences in chronic schizophrenic patients sharing a rare variant allele (a perfect ten tetranucleotide repeats allele of the human TH01 microsatellite) in the tyrosine hydroxylase (TH) gene. For that purpose, clinical parameters (PANSS subscores) and plasma measurements (homovanillic acid and 3-methoxy-4-hydroxy-phenylglycol (MHPG)) were analyzed in five schizophrenic patients sharing the rare allele and 19 schizophrenic patients who did not possess this allele. The mean concentration of plasma HVA and plasma MHPG were significantly lower in the group of schizophrenic patients sharing the rare allele. No other group differences were observed between both groups. These results suggest that this TH gene polymorphism may be associated with disturbances of the catecholaminergic pathway.

Plasma 3-Methoxy-4-Hydroxyphenylglycol and Homovanillic Acid Measurements in Deficit and Nondeficit Forms of Schizophrenia

BACKGROUND Discrepancies in the biochemical research on negative symptoms in schizophrenia may be ascribed to the lack of differentiation into primary and secondary negative symptoms. We have used Carpenters criteria to define the deficit syndrome of schizophrenia as the presence of enduring and primary negative symptoms and measured catecholaminergic parameters in deficit as compared with nondeficit schizophrenics. METHODS We have investigated plasma homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG) concentrations in 34 DSM-III-R neuroleptic-treated schizophrenic patients who were classified into deficit (n = 14) and nondeficit (n = 20) forms of schizophrenia. All these patients were in a stable clinical and therapeutic status for the preceding 12 months. RESULTS The 14 deficit schizophrenic patients had lower plasma levels of pHVA and higher plasma concentrations of pMHPG from 9 AM to 12 AM as compared with the 20 nondeficit schizophrenic patients. The two groups did not differ on any demographic, therapeutic, or clinical variable considered. CONCLUSIONS Our data are consistent with the postulated distinct pathophysiological basis for the deficit syndrome of schizophrenia and suggest that opposite alterations in the pHVA or pMHPG levels may reflect specific changes in noradrenergic and dopaminergic functions in these deficit patients.

Differential Effect of Intrastriatal Kainic Acid on the Modulation of Dopamine Release by μ‐ and δ‐Opioid Peptides: A Microdialysis Study

Abstract: The present study investigated the effects of a striatal lesion induced by kainic acid on the striatal modulation of dopamine (DA) release by μ‐ and δ‐opioid peptides. The effects of [d‐Pen2, d‐Pen5]‐enkephalin (DPDPE) and [d‐Ala2,N‐Me‐Phe4,Gly5‐ol]‐enkephalin (DAGO), two highly selective δ‐ and μ‐opioid agonists, respectively, were studied by microdialysis in anesthetized rats. In control animals both opioid peptides, administered locally, significantly increased extracellular DA levels. The effects of DPDPE were also observed in animals whose striatum had been previously lesioned with kainic acid. In contrast to the effects of the δ agonist, the significant increase induced by DAGO was no longer observed in lesioned animals. These results suggest that δ‐opioid receptors modulating the striatal DA release, in contrast to μ receptors, are not located on neurons that may be lesioned by kainic acid.

MU and delta opioid receptors control differently the horizontal and vertical components of locomotor activity in mice

The present study investigated the role of mu and delta opioid receptors in the control of the horizontal and vertical components of locomotion. Mice received intracerebroventricularly (i.c.v.) enkephalin analogs specific for either the mu or delta opioid receptors. The administration of the specific mu agonist [D-Ala2-NMePhe4-Gly5(ol)] enkephalin (DAGO) induced a dose-dependent increase in horizontal activity and a decrease in vertical activity. The specific delta agonist [D-Pen2,D-Pen5] enkephalin (DPDPE) increased both components of motor activity. The opiate antagonist naltrexone reversed the effects of DAGO, but did not influence the effects of DPDPE on motor activity. The pretreatment with the delta opiate antagonist ICI 154, 129 completely reversed the effects of DPDPE on locomotion but antagonized only partially the effects of DAGO on locomotion. These results indicate that the two components of locomotor activity--horizontal and vertical activity--are modulated differently by the stimulation of mu or delta opioid receptors.

Role of endogenous enkephalins in locomotion and nociception studied with peptidase inhibitors in two inbred strains of mice (C57BL/6J AND DBA/2J)

Acetorphan, a parenterally active enkephalinase inhibitor, induced dose-dependently a naloxone-reversible analgesia on the hot-plate jump test in DBA/2J (DBA2) mice but was devoid of effects in C57BL/6J (C57) mice. By contrast, acetorphan increased locomotion in both strains; however, the DBA2 strain was much more sensitive than C57 mice to the locomotor stimulant effect. The increased locomotion was antagonized by naloxone in both strains. These data suggest that endogenous enkephalins modulate nociception and locomotion in the two inbred strains differently.

Role of delta opioid receptors in the effects of inhibitors of enkephalin-degrading peptidases on the horizontal and vertical components of locomotion in mice

In the present study we report the effects of inhibitors of enkephalin-degrading peptidases on spontaneous locomotion in mice and the involvement of delta opioid receptors in these effects. Animals received intracerebroventricularly (i.c.v.) or intravenously (i.v.) enkephalinase inhibitors (thiorphan and acetorphan), aminopeptidase inhibitors (bestatin and carbaphethiol) or mixed peptidase inhibitors (kelatorphan). The i.c.v. co-administration of bestatin and thiorphan (50 micrograms + 50 micrograms) induced an increase in both the horizontal and vertical components of locomotion. A similar pattern was observed after the i.c.v. administration of kelatorphan (8.5-50 micrograms) or the i.v. co-administration of acetorphan and carbaphethiol (5 mg/kg + 10 mg/kg). The opiate antagonist naltrexone (1 mg/kg, s.c.) failed to reverse the excitolocomotor effects of kelatorphan or of bestatin and thiorphan and antagonized only partially the effects of acetorphan and carbaphethiol. Naloxone (2 mg/kg-10 mg/kg, s.c.) partially reversed the increase in locomotion elicited by bestatin and thiorphan. The pretreatment with the delta opioid antagonists ICI 154,129 (20 micrograms, i.c.v.) or ICI 174,864 (2-4 micrograms, i.c.v.) strongly decreased the effects of all the peptidase inhibitors we tested. These results suggest that endogenous enkephalins may control via delta opioid receptors the horizontal and vertical components of locomotor activity in mice.

Acute interactions between l-DOPA and the neurotoxic effects of 1-methyl-4-phenylpyridinium or 6-hydroxydopamine in mice

We have compared the effects of an i.p. pretreatment with L-DOPA (200 mg/kg) associated with benserazide (25 mg/kg) on neurotoxic effects of either 6-hydroxydopamine (6-OHDA) (50 microg, 10 microl per mouse) or 1-methyl-4-phenylpyridinium (MPP+) (17.5 microg, 10 microl per mouse). The striatal dopamine (DA) content, the vesicular monoamine transporter (VMAT2) density, as well as the hypothalamic norepinephrine (NE) content were measured 8 days after treatments. The L-DOPA-benserazide pretreatment worsened by 65% the 6-OHDA-induced depletion in striatal DA. On the contrary, it reduced by 42% the MPP+-induced depletion in striatal DA and by 54% the MPP+-induced decrease in VMAT2 density. It was noticed that the L-DOPA-benserazide pretreatment did not modify the marked decrease in hypothalamic NE content induced by 6-OHDA.

Semi-chronic increase in striatal level of 3,4-dihydroxyphenylacetaldehyde does not result in alteration of nigrostriatal dopaminergic neurones.

This work was carried out to evaluate the potential in vivo toxicity of 3,4‐dihydroxyphenylacetaldehyde (DOPAL), an aldehyde formed from dopamine by monoamine oxidase (MAO) that is oxidised mainly to 3,4‐dihydroxyphenylacetic acid (DOPAC) by brain aldehyde dehydrogenases (ALDH). In this study, male Sprague‐Dawley rats were treated with levodopa (L‐dopa)‐benserazide, which increases DOPAL production by MAO, and disulfiram, an irreversible inhibitor of ALDH, which reduces the formation of DOPAC from DOPAL. An acute systemic intraperitoneal (i.p.) injection of 100 mg/kg disulfiram and L‐dopa‐benserazide (100 mg/kg + 25 mg/kg, 24 hr later) significantly increased DOPAL striatal level. A 30‐day treatment with disulfiram (100 mg/kg i.p., once every 2 days) and L‐dopa‐benserazide (100 mg/kg + 25 mg/kg, two times/day) did not affect either indexes used to assess integrity of the nigrostriatal dopaminergic neurones (i.e., the striatal content in dopamine and binding to the vesicular monoamine transporter on striatal membranes). These results do not evidence any deleterious effect of DOPAL and argue against toxicity of L‐dopa therapy.

Acetorphan, an Enkephalinase Inhibitor, Modulates Dopaminergic Transmission in Rat Olfactory Tubercle, but not in the Nucleus Accumbens and Striatum

The present study focused on the effects of acetorphan, a parenterally active enkephalinase inhibitor, on dopaminergic transmission in rat olfactory tubercle, nucleus accumbens and striatum. Acetorphan was administered i.v. (10 mg/kg) 15 min before measurement of the in vivo specific binding of [3H]N‐propyl‐norapomorphine ([3H]NPA) or measurement of the levels of dopamine (DA) and its metabolites 3‐methoxytyramine‐homovanillic acid (3MT‐HVA) in the three areas. Acetorphan decreased the in vivo specific binding of [3H]NPA in the olfactory tubercle, this effect being antagonized by naloxone 1.5 mg/kg s.c. DA release in this brain structure was also significantly increased by acetorphan 10 mg/kg, as indicated by the 3MT:DA and HVA:DA ratios. Neither the specific binding of [3H]NPA nor DA metabolism and release were modified by the inhibitor in the striatum and the nucleus accumbens. The stimulant effect of acetorphan was significantly decreased in rats in which a bilateral lesion of dopaminergic endings in the olfactory tubercle had been produced by 6‐hydroxydopamine (6‐OHDA). These results suggest that dopaminergic transmissions in the olfactory tubercle are particularly sensitive to the modulation exerted by endogenous enkephalins, this modulation being at least partly involved in the increased locomotion induced by the enkephalinase inhibitor.

Rapid and long lasting reduction of the hypothermic effect of a D2 dopamine agonist after an intracerebroventricular injection of 6-hydroxydopamine

In mice pretreated intracerebroventricularly (i.c.v.) with 6-hydroxydopamine (6OHDA) (50 micrograms per mouse), as soon as the hypothermia elicited by the neurotoxin had vanished (3 hr), the hypothermic effect induced by the direct D2 dopamine receptor agonist RU 24926 (1 mg/kg, s.c.), was almost completely suppressed. This reduction in hypothermic effect was observed more than 1 month after the 6OHDA injection. On the 3rd day after 6OHDA injection, this reduction was observed for all tested doses of RU 24926 (0.25-2 mg/kg). It was prevented when an i.p. administration of the norepinephrine uptake inhibitor desipramine (20 mg/kg) was performed 30 min before the 6OHDA i.c.v. injection. It was not modified when an i.p. administration of the dopamine uptake inhibitor GBR 12783 (20 mg/kg) was performed 30 min before the 6OHDA i.c.v. injection. The 6OHDA i.c.v. injection modified significantly neither the dopamine nor the serotonin hypothalamic contents. On the contrary it resulted in a marked decrease (-73%) of the norepinephrine hypothalamic content, which was unchanged by the administration of GBR 12783 (20 mg/kg, i.p.) 30 min before 6OHDA, but completely prevented by desipramine (20 mg/kg, i.p.) 30 min before 6OHDA i.c.v. injection. It is concluded that the hypothermic effect resulting from the stimulation of D2 dopamine receptors involves a central norepinephrine transmission, which is very rapidly altered after 6OHDA administration.