Dual effects of L-3,4-dihydroxyphenylalanine on aromatic L-amino acid decarboxylase, dopamine release and motor stimulation in the reserpine-treated rat: evidence that behaviour is dopamine independent

The comparative effects of L-3,4-dihydroxphenylalanine (L-DOPA) on dopamine synthesis, release and behaviour were studied in the reserpine-treated rat. Acute administration of L-DOPA (25-200 mg/kg) dose-dependently inhibited the activity of aromatic L-amino acid decarboxylase (AADC) in the substantia nigra and corpus striatum. The antiparkinsonian drugs budipine (10 mg/kg) and amantadine (40 mg/kg) enhanced AADC activity in these regions, and prevented or reversed AADC inhibition by L-DOPA. Dual probe dialysis revealed that low doses of L-DOPA (25-50 mg/kg) dose-dependently stimulated the release of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in nigra and striatum, whilst high doses of L-DOPA (100-200 mg/kg) completely suppressed the release of dopamine, but not DOPAC. Sulpiride (50 microM) administered via the probes antagonized dopamine release in response to 25 mg/kg L-DOPA, but greatly facilitated release by 200 mg/kg L-DOPA. Dopamine release was blocked by the centrally acting AADC inhibitor NSD 1015, but facilitated by the central AADC activator budipine. In behavioural tests L-DOPA (plus benserazide, 50 mg/kg) only reversed akinesia at 200 mg/kg, and not at 25-100 mg/kg. Pretreatment with either NSD 1015 (100 mg/kg) or budipine (10 mg/kg) markedly potentiated the motor stimulant action of a threshold dose of L-DOPA (100 mg/kg). A combination of NSD 1015 (100 mg/kg) and benserazide (50 mg/kg) potentiated L-DOPA behaviour more effectively than either inhibitor alone. NSD 1015-facilitated L-DOPA behaviour was antagonized by sulpiride (100 mg/kg) and not by SCH 23390 (1 mg/kg), whereas budipine-facilitated L-DOPA behaviour was fully antagonized by SCH 23390 and only partially by sulpiride. These results show that behaviourally active doses of L-DOPA in the reserpinized rat are not accompanied by significant increases in extracellular dopamine and are therefore probably not dopamine mediated. We propose that L-DOPA is capable of directly stimulating dopamine D2 and possibly non-dopamine receptors, thereby inhibiting dopamine efflux presynaptically and promoting motor activation postsynaptically. A stimulant action of L-DOPA on motor behaviour, preferentially mediated by D1 > D2 receptors, suggests that L-DOPA may also be capable of yielding a dopamine-like response in the absence of detectable dopamine release. These findings are incorporated into a new model of L-DOPA's actions in the reserpinized rat, and their possible implications for our understanding of L-DOPA in Parkinson's disease are discussed.     

Blockade of D-1 dopamine receptors by SCH 23390 prevents EEG and behavioral activation induced by L-dopa

Administration of L-DOPA, a precursor of dopamine, induced EEG activation, arousal and signs of behavioral excitation in the rabbit. The effects were fully prevented by pretreatment with minute doses (0.01 mg/kg i.v.) of the selective D-1 antagonist SCH 23390. Conversely, its S-enantiomer SCH 23388, which has weak actions on D-1 receptors, displayed relatively low inhibition of L-DOPA effects. (-)-Sulpiride (12.5 mg/kg), a selective D-2 antagonist, and haloperidol (0.1-0.3 mg/kg), a neuroleptic that interacts preferentially with D-2 receptors, both inhibited behavioral effects but failed to block EEG activation. The data indicate that D-1 receptors play an essential role in mediating EEG activation induced by L-DOPA.     

Dual effects of l-3,4-dihydroxyphenylalanine on aromatic l-amino acid decarboxylase,dopamine release and motor stimulation in the reserpine-treated rat: evidence that behaviour is dopamine independent

The comparative effects of l-3,4-dihydroxphenylalanine (L-DOPA) on dopamine synthesis, release and behaviour were studied in the reserpine-treated rat. Acute administration of L-DOPA (25–200 mg/kg) dose-dependently inhibited the activity of aromatic l-amino acid decarboxylase (AADC) in the substantia nigra and corpus striatum. The antiparkinsonian drugs budipine (10 mg/kg) and amantadine (40 mg/kg) enhanced AADC activity in these regions, and prevented or reversed AADC inhibition by L-DOPA. Dual probe dialysis revealed that low doses of L-DOPA (25–50 mg/kg) dose-dependently stimulated the release of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in nigra and striatum, whilst high doses of L-DOPA (100–200 mg/kg) completely suppressed the release of dopamine, but not DOPAC. Sulpiride (50 μM) administered via the probes antagonized dopamine release in response to 25 mg/kg L-DOPA, but greatly facilitated release by 200 mg/kg L-DOPA. Dopamine release was blocked by the centrally acting AADC inhibitor NSD 1015, but facilitated by the central AADC activator budipine. In behavioural tests L-DOPA (plus benserazide, 50 mg/kg) only reversed akinesia at 200 mg/kg, and not at 25–100 mg/kg. Pretreatment with either NSD 1015 (100 mg/kg) or budipine (10 mg/kg) markedly potentiated the motor stimulant action of a threshold dose of L-DOPA (100 mg/kg). A combination of NSD 1015 (100 mg/kg) and benserazide (50 mg/kg) potentiated L-DOPA behaviour more effectively than either inhibitor alone. NSD 1015-facilitated L-DOPA behaviour was antagonized by sulpiride (100 mg/kg) and not by SCH 23390 (1 mg/kg), whereas budipine-facilitated L-DOPA behaviour was fully antagonized by SCH 23390 and only partially by sulpiride.These results show that behaviourally active doses of L-DOPA in the reserpinized rat are not accompanied by significant increases in extracellular dopamine and are therefore probably not dopamine mediated. We propose that L-DOPA is capable of directly stimulating dopamine D₂ and possibly non-dopamine receptors, thereby inhibiting dopamine efflux presynaptically and promoting motor activation postsynaptically. A stimulant action of L-DOPA on motor behaviour, preferentially mediated by D₁>D₂ receptors, suggests that L-DOPA may also be capable of yielding a dopamine-like response in the absence of detectable dopamine release. These findings are incorporated into a new model of L-DOPA's actions in the reserpinized rat, and their possible implications for our understanding of L-DOPA in Parkinson's disease are discussed.     

Regional central serotonin receptor binding in rats treated chronically with high-dose 5-hydroxy-L-tryptophan

Summary The serotonin (5-HT) precursor 5-hydroxy-L-tryptophan (L-5-HTP) exerted differential regional effects on central 5-HT receptors in rats treated chronically by intraperitoneal injections of large incremental doses (50–200 mg/kg). There were significant reductions in B_max of agonist-labelled (-35%) and antagonist-labelled (-20%) 5-HT₂ sites in cortex but no changes in brainstem. K_d and n_H were unaffected by L-5-HTP. B_max of 5-HT₁ sites (unsubtyped) was reduced 16% in cortex and 18% in spinal cord, but the changes were not significant. Brainstem 5-HT₁ sites were unaffected. Studies at a single isotope concentration in other regions revealed significant reductions of antagonist-labelled 5-HT₂ specific binding in diencephalon (-26%) but not septum, and of 5-HT₁ binding in diencephalon (-25%) and cerebellum (-30%) but not in hippocampus or striatum. Absence of L-5-HTP-evoked changes in 5-HT receptors in brainstem may have implications for L-5-HTP-responsive and brainstem-mediated human myoclonic disorders.     

Synergistic activation of the central pattern generator for locomotion by l-beta-3,4-dihydroxyphenylalanine and quipazine in adult paraplegic mice

L-beta-3,4-Dihydroxyphenylalanine (L-DOPA) and quipazine, respectively dopamine/noradrenaline precursor and serotonergic (5-HT(2)) receptor agonist, were injected intraperitoneally in low-thoracic spinal mice at 7 days post-spinalization. In mice pre-treated with decarboxylase and monoamine oxydase inhibitors, L-DOPA (30-100 mg/kg) was found not to induce air-stepping. On the other hand, L-DOPA (40 mg/kg) consistently triggered locomotor-like movements if combined with low doses of quipazine (0.4-0.7 mg/kg) or if mice were placed on a motor-driven treadmill running at low speed. However, twitches, spasms, and other non-locomotor movements were also induced, especially on the treadmill. These results suggest that (1) spinal catecholaminergic and serotonergic receptors interact synergistically to generate locomotor-like movements in chronic spinal mice, and that (2) hindlimb afferent inputs associated with the treadmill conditions contribute to the genesis of locomotor-like and non-locomotor movements induced by these drugs.     

The effect of chronic L-dopa treatment on the recovery of motor function in 6-hydroxydopamine-lesioned rats receiving ventral mesencephalic grafts

The effect of treatment for 5 weeks with L-DOPA (200 mg/kg/24 h) plus carbidopa (25 mg/kg/24 h) on the behavioral recovery produced by rat fetal ventral mesencephalon grafts implanted into the striatum of 6-hydroxydopamine-lesioned rats was assessed. Animals with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway and a sham graft (Group A) showed persistent high rates of rotation in response to the administration of apomorphine (0.5 mg/kg, s.c.) (contralateral rotation) or (+)-amphetamine (5 mg/kg, i.p.) (ipsilateral rotation). Treatment of sham-grafted animals with L-DOPA plus carbidopa had no effect on the rate of rotation to apomorphine or (+)-amphetamine (Group B). The proportion of animals showing marked stereotypy following apomorphine administration was greater in sham-grafted animals receiving L-DOPA and carbidopa than in sham-grafted animals alone. Animals receiving unilateral 6-hydroxydopamine lesions followed by a fetal graft (Group C) showed a reduction in apomorphine-induced contralateral rotation and a complete reversal of (+)-amphetamine-induced ipsilateral rotation when assessed 6 weeks later. The reductions in apomorphine- and (+)-amphetamine-induced rotational behaviour produced by the fetal graft in animals with a 6-hydroxydopamine lesion were not altered by treatment with L-DOPA plus carbidopa (Group D). The proportion of animals showing marked apomorphine-induced stereotypy did not change significantly in either group over time. In rats with a unilateral 6-hydroxydopamine lesion receiving fetal dopamine grafts, treatment with high doses of L-DOPA and carbidopa for 5 weeks does not have a detrimental effect on the functional activity of the grafts as assessed by reduction of apomorphine- and (+)-amphetamine-induced motor asymmetry. The continuation of L-DOPA therapy may not adversely affect fetal graft survival and growth in patients with Parkinson's disease.     

Further studies on catecholamine-containing specific endothelial granules in carp cerebral veins. A fluorescence histochemical and electron microscopy study

The effects of noradrenaline (NA), L-3, 4-dihydroxyphenylalanine (L-DOPA), 5-hydroxydopamine (5-OHDA), 6-hydroxydopamine (6-OHDA), and reserpine (RES) on the uptake, accumulation, and release of amines in cate-cholamine-containing specific endothelial granules (SEG) of carp cerebral veins and their mode of formation were examined by fluorescence histochemistry and electron microscopy. The intramuscular injection of NA (4 mg/kg) or L-DOPA (200 mg/kg) resulted in an increase in both the fluorescence and electron density of SEG. After the administration of false neurotransmitters, 5-OHDA (190 mg/kg) or 6-OHDA (200 mg/kg), the venous endothelia fluorescence almost completely disappeared but the SEG electron density increased. Following the injection of RES (15 mg/kg), the fluorescence intensity and SEG electron density showed no sign of decrease, as was expected, but in fact increased. It is suggested that the SEG are able to take up and accumulate exogeneous amines and that these mechanisms are RES-resistant. The electron density of SEG increased in proportion to the amount of amines in the SEG. The swelling and fragmentation of rough endoplasmic reticulum cisternae and the accumulation of dense material within the cisternae suggests the possible participation of these organelles in SEG formation.     

Mechanisms of the effects of exogenous levodopa on the dopamine-denervated striatum

The efficacy of exogenous levodopa (L-DOPA) is attributed to its conversion to dopamine by the enzyme aromatic L-amino-acid decarboxylase in striatal dopaminergic terminals. However, there is controversy about the mechanisms underlying the therapeutic and adverse effects of L-DOPA after almost all striatal dopaminergic afferents have disappeared (i.e. in the later stages of Parkinson's disease). After administration of 30mg/kg or 100mg/kg of L-DOPA, rats subjected to unilateral dopaminergic denervation showed intense contraversive rotation and a high density of Fos-immunoreactive nuclei throughout the denervated striatum, with no significant induction of Fos in the intact striatum. Injection of the central aromatic L-amino-acid decarboxylase inhibitor NSD-1015 30min before and 15min after the injection of L-DOPA suppressed the rotational behavior and the striatal induction of Fos. Comparison of results obtained in rats subjected to unilateral and bilateral dopaminergic denervation indicated that the presence of contralateral dopaminergic innervation does not significantly modulate the effects of L-DOPA on the denervated striatum. Serotonergic denervation led to slight and statistically non-significant decrease in the rotational behavior and Fos expression induced by high doses of L-DOPA (100mg/kg) in the dopamine-denervated striatum, but totally suppressed the rotational behavior and Fos expression induced by low doses of L-DOPA (30mg/kg).The present data indicate that the major effects observed after administration of exogenous L-DOPA are not due to a direct action of L-DOPA on dopamine receptors, or to extrastriatal release of dopamine, but to conversion of L-DOPA to dopamine by serotonergic terminals and probably some intrastriatal cells. Given that serotonergic neurons appear to play an important role in the action of L-DOPA in the later stages of Parkinson's disease, strategies targeting the serotonergic system should be considered for the treatment of Parkinson's disease and for combating undesirable side effects of L-DOPA therapy.     

Effect of serotonin on the chemiluminescence response of rat peripheral blood leucocytes

Serotonin (5-HT) has been shown to exert various immunomodulatory effects. In this study, the effects of 5-HT, 5-hydroxy-DL-tryptophan (5-HTP) and dl-p-chlorophenylalanine (PCPA) on the chemiluminescence (CL) responses of rat peripheral blood leucocytes (PBL) activated by phorbol myristate acetate (PMA), opsonized zymosan or latex beads were assessed. The CL responses were measured following in vitro treatment with 0.01-100 μM 5-HT, and either 1 h after the last i.p. administration of 5-HT (0.05, 0.5, 1, 2.5, 5 or 10 mg/kg for 4 days), 5-HTP (25 or 100 mg/kg for 4 days) or PCPA (200 mg/kg for 4 days, n = 5), or 48 h after a single 200 mg/kg PCPA injection. A concentration-dependent decrease in CL responses was noted following in vitro 5-HT treatment. In vivo treatment of rats with 5-HT produced a reverse bell-curve inhibiting effects on the CL response with a maximal inhibition in rats receiving 1 mg/kg/day 5-HT and a weaker response of PMA-activated PBL. In vivo treatment with high-dose 5-HTP increased CL response of opsonized zymosan-activated PBL, while low-dose 5-HTP decreased CL response of opsonized zymosan and latex beads-activated PBL. No effect was observed in PMA-activated PBL from rats treated with 5-HTP. By contrast, in vivo treatment with PCPA increased CL responses induced by PMA or latex beads, whereas CL responses using opsonized zymosan were not significantly affected. These results suggest that 5-HT modulates the CL response of rat leucocytes to particulate stimuli.     

Visual evoked responses in ethambutol induced optic neuritis

Pattern evoked responses were recorded in 46 patients of tuberculosis on ethambutol and 16 healthy subjects. Deterioration in visual acuity was documented in two patients (4.3%). P100 latency was delayed in 16 cases (34.8%), while in 12 patients (26.1%) both latency and amplitude were affected. A cut off latency value of > or = 140 ms was associated with ophthalmological findings. The incidence of subclinical toxicity as detected by visual evoked response (VER) was higher in older subjects, patients on higher doses of ethambutol (> or = 20 mg/kg/day) and longer duration of treatment. Of two cases with objective ocular signs, one who reported for follow up after two months had recovered completely after stopping ethambutol. Recording of VER is an extremely useful objective test for subclinical optic nerve damage.     

Serotonin uptake inhibition: in vivo effect of sertraline in rats.

Sertraline, a potent and selective serotonin uptake inhibitor, was used to analyze the changes occurring in the serotonin system after uptake inhibition in vivo. Sertraline (11 mg/kg) lowered extracellular 5-hydroxyindolacetic acid (5-HIAA), measured in rat hippocampus by in vivo voltammetry, for about 3 h. The interaction between sertraline and drugs known to interfere with the release or uptake of serotonin (L-5-hydroxytryptophan (5-HTP), d-norfenfluramine and tianeptine) was then studied. The sertraline-induced decrease in extracellular 5-HIAA was related to the inhibition of uptake.     

The maturational onset of the 5-HT mediated head twitch in mice

The effect of elevated brain serotonin (5-hydroxytryptamine, 5-HT) on the head twitch was examined to determine an age of onset in mice for this 5-HT mediated motor activity. Two different treatments were used to elevate 5-HT: 100 mg/kg L-tryptophan with 100 mg/kg pargyline; and 100 mg/kg 5-HTP with 25 mg/kg carbidopa. Mice from ages 14 to 42 days postpartum were examined. Both treatments showed an onset of the head twitch at 15 days. Juvenile mice of 15-18 days appeared to differ in their response to the two treatments. Although 5-HTP and carbidopa stimulated head twitches, 5-HTP alone had a greater stimulatory effect at these ages, while in the other experiment only those animals receiving the combined tryptophan and pargyline treatment showed significant responses.     

The α2-adrenoceptor antagonist idazoxan is an agonist at 5-HT1A autoreceptors modulating serotonin synthesis in the rat brain in vivo

The in vivo effects of the α₂-adrenoceptor antagonists idazoxan, rauwolscine and phentolamine on α₂-auto/heteroreceptors and 5-HT_1A autoreceptors modulating the synthesis of dopa/noradrenaline and 5-HTP/serotonin were assessed in rats, using the accumulation of dopa and 5-HTP after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation. The acute administration of idazoxan (0.1–40 mg/kg) induced a pronounced dose-dependent increase in the synthesis of dopa in the cerebral cortex (22–86%) and hippocampus (8–80%), as a consequence of the powerful blockade of α₂-autoreceptors. However, idazoxan did not increase the synthesis of 5-HTP in these brain regions, as it would have been expected by the concurrent blockade of α₂-heteroreceptors on serotonergic terminals. Instead, idazoxan decreased the synthesis of 5-HTP in the cerebral cortex (13–33%) and hippocampus (25–48%), suggesting that these inhibitory effects were mediated through activation of 5-HT_1A autoreceptors. Similar results were obtained for rauwolscine. Pre-treatment of rats with the selective 5-HT_1A receptor antagonist WAY100135 (10 mg/kg) fully antagonized the inhibitory effects of idazoxan (10 mg/kg) on 5-HTP synthesis, but it did not prevent the stimulatory effects of idazoxan on dopa synthesis. The results indicate that idazoxan is a potent and specific agonist at 5-HT_1A autoreceptors modulating brain serotonin synthesis in vivo.     

Decreased protein synthesis in hypothalamic nuclei following L-5-hydroxytryptophan in intact and p-chlorophenylalanine-pretreated rats.

The rate of protein synthesis was estimated in individual hypothalamic nuclei by a quantitative autoradiographic technique with L-[35S]methionine. The i.v. administration of 60 mg/kg L-5-hydroxytryptophan (40 min before) resulted in a 45-55% decrease of overall protein synthesis rate in all the hypothalamic nuclei examined. In rats pretreated (42 h before) with a single i.v. injection of 280 mg/kg p-chlorophenylalanine, a drug which is known to deplete brain serotonin concentration, the administration of 60 mg/kg L-5-hydroxytryptophan resulted in a 50-75% decrease of protein synthesis rates in the hypothalamic nuclei. These results suggest that the systemic administration of large doses of L-5-hydroxytryptophan may inhibit protein synthesis in hypothalamic nuclei directly or indirectly after the conversion of this compound to serotonin.     

Effect of the COX-2 Selective Inhibitor L-745,337 on Inflammation and Organ Prostaglandin E2 (PGE2) Levels in Adjuvant Arthritic Rats

The anti-inflammatory activity of the cyclooxygenase-2 inhibitor, L745,337, was assessed in adjuvant arthritic rats (AA). The relationship between PGE₂ organ levels and drug activity or adverse effects was determined. Arthritic rats were orally treated for two weeks with L-745,337 (0.1, 1 and 5 mg/kg/day), indomethacin (1 mg/kg/day) or vehicle and paw swelling was determined. At the end of the study, samples from paw, stomach (wall and mucosa) and kidney were obtained from rats with or without treatment at high doses of L-745,337 or indomethacin and PGE₂ levels were determined. The L-745,337 anti-inflammatory effective-dose-50 was 0.4 mg/kg. Maximal anti-inflammation was obtained with L-745,337 or indomethacin at doses of 5 and 1 mg/kg respectively. L-745,337 showed anti-arthritic activity. No stomach ulcers appeared in either untreated or treated arthritic and healthy control rats. In AA rats, PGE₂ increased in paw, stomach wall, gastric mucosa and kidney. These levels were lower in all organs after both drugs but not below PGE₂ control levels.     

Inhibition of adjuvant arthritis by intraperitoneal administration of low doses of silica

Daily intraperitoneal administration from day 3 to day 10 post-adjuvant of crystalline silica in doses 1.5–3.1 mg/kg per day or of amorphous silica in doses of 12.5 mg/kg per day inhibited the development of adjuvant arthritis mostly suppressing the swelling of the non-injected paw. These doses of silica did not impair the carbon elearance. Higher doses of silica (25 mg/kg per day of the crystalline form and 50 mg/kg of the amorphous form) administered from day 17 to day 24 post-adjuvant had no effect on the already established disease.     

Antidepressant potentiation of 5-hydroxytryptophan by L-deprenil in affective illness

In an open trial study, L-Deprenil, an irreversible selective MAO-B inhibitor without 'chesse effect' was given to 14 patients with unipolar and bipolar depression receiving L-5-Hydroxytryptophan (L-5-HTP) and benzerazide. Ten out of 14 patients showed a good response to the combination of drugs and a correlation was found between the degree of platelet MAO inhibition and clinical response. In a double-blind controlled study, 18 affectively ill patients were randomly allocated to L-Deprenil plus L-5-HTP and benzerazide, 21 patients were treated with L-5-HTP and benzerazide and 19 patients with placebo only. Patients treated with the combination of L-Deprenil and L-5-HTP showed a significantly greater clinical improvement than placebo patients but this was not the case for patients treated with 5-HTP alone. A positive relationship was demonstrated between mood improvement and degree of platelet MAO inhibition in patients treated with L-Deprenil.     

Effect of imipramine-like antidepressants on head twitching in mice induced by 5-hydroxytryptophan

When headtwitching (HT) in mice in response to administration of 5-hydroxytryptophan (5-HTP) was used as a serotoninergic model the antidepressants chlorimipramine and imipramine, and also chlorpheniramine (suprastin), exhibited a serotonin-positive action in doses of 1.0, 5.0, and 1.0 mg/kg respectively. Quipazine had a serotoninomimetic action, desipramine an ambivalent action in doses of 1–20 mg/kg, whereas iprindole and morphaphen were ineffective in doses of up to 20 mg/kg. Amitryptiline, noveril (dibenzepine), melitracene, trimeprimine (trimipramine), and ludiomil (maprotiline) exhibited an antiserotonin action in doses of 0.5, 1.0, 20.0, and 20.0 mg/kg respectively. The results are discussed in the light of the concept of a complex spectrum of mediator activity of the imipramine-like antidepressant.Laboratory of Psychopharmacology, V. M. Bekhterev Leningrad Psychoneurological Research Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR S. V. Anichkov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 86, No. 9, pp. 304–306, September, 1978.     

Increased striatal expression of glutamate decarboxylase 67 after priming of 6-hydroxydopamine-lesioned rats.

Previous single exposure (priming) to a dopamine receptor agonist greatly enhances the contralateral turning behaviour elicited by dopamine D1 receptor agonists in unilaterally 6-hydroxydopamine lesioned rats. In the present study we have investigated the levels of glutamate decarboxylase 67 and glutamate decarboxylase 65 messenger RNA in the striatum of 6-hydroxydopamine-lesioned rats primed with L-3,4-dihydroxyphenylalanine (L-DOPA) and challenged with the D1 receptor agonist SKF 38393, three days thereafter. As previously reported, levels of glutamate decarboxylase 67 messenger RNA increased in the striatum denervated by the 6-hydroxydopamine lesion as compared with the intact one. Striatal glutamate decarboxylase 67 messenger RNA levels, measured three days after priming with L-DOPA (50 mg/kg), further increased in the lesioned striatum while were not modified in the intact one. Administration of SKF 38393 (3 mg/kg) elicited a more intense contralateral turning behaviour in primed than in drug-naive 6-hydroxydopamine-lesioned rats but did not induce any change in striatal glutamate decarboxylase 67 messenger RNA. In contrast, striatal levels of glutamate decarboxylase 65 messenger RNA were not modified by either 6-hydroxydopamine lesions or priming with L-DOPA. The results show that priming with L-DOPA induces long-lasting changes in GABAergic neurons of the 6-hydroxydopamine-lesioned striatum. These changes might play a role in the increased behavioural response of striatal D1 receptors induced by priming.     

In Vivo Susceptibility of Cryptococcus neoformans to Hamycin, Amphotericin B, and 5-Fluorocytosine

Previous investigations have shown that hamycin is 5 to 10 times more active in vitro than amphotericin B against Cryptococcus neoformans, whereas 5-fluorocytosine is approximately 15 times less active. Present studies are concerned with a comparison of these drugs in vivo. Three strains of C. neoformans which varied in both their virulence for mice and their susceptibilities to the antifungal agents were studied. Acute experimental infections were established in mice by using inocula containing approximately 4 × 10⁶ cells. The mice were treated by gastric intubation for 28 days; daily dosages of the three drugs ranged from 12.5 to 250 mg/kg. The polyenes were suspended in 5% dimethyl sulfoxide, whereas 5-fluorocytosine was suspended in saline. Amphotericin B was the most effective drug, with almost complete absence of toxic deaths in control mice and increased survival in mice infected with two of the three strains and treated with 25 mg/kg per day or more. 5-Fluorocytosine was nontoxic but provided protection against only one strain. Hamycin was both the least effective and the most toxic compound, providing only slight protection at doses of 12.5 or 25 mg/kg per day and causing toxic deaths in over 50% of uninfected mice at doses above 25 mg/kg per day.