Contralateral Circling Behaviour Induced by Intranigral Injection of Taurine in Rats

Abstract A study was made of the effect of unilateral injection of taurine into the substantia nigra on the behaviour of rats. Taurine (10–200 μg) induced a dose-dependent contralateral circling behaviour. The maximum intensity of circling after doses of 100–200 μg of taurine was reached within 10 min. and the circling lasted for about 4–5 hrs. There was neither ipsilateral circling nor stereotyped behaviour. Intranigral injection of isethionic acid, a metabolite of taurine, induced weak ipsilateral circling of short duration. Pretreatment with bicuculline (3 mg/kg intraperitoneally) or strychnine (0.25 mg/kg intraperitoneally) significantly inhibited the taurine-induced circling. A dose of 1 mg/kg but not of 0.5 mg/kg of haloperidol (subcutaneously) significantly decreased the intensity of the taurine-induced circling. Pretreatment with atropine (10 mg/kg intraperitoneally) had no significant effect on the circling behaviour. Besides the dopaminergic nigrostriatal pathway, the non-dopaminergic nigral output pathways also seem to be involved in the taurine-induced circling behaviour. The results show that taurine may play some role in the function of the substantia nigra.     

Effect of Nicotinic and Muscarinic Drugs on Amphetamine- and Apomorphine-induced Circling Behaviour in Rats

Abstract: The effect of drugs modulating the activity of nicotinic or muscarinic cholinergic receptors on the circling behaviour induced by amphetamine and apomorphine in rats with unilateral 6-hydroxydopamine lesion of nigrostriatal dopaminergic pathway was studied. Nicotine (0.2 mg/kg subcutaneously) significantly increased amphetamine-induced circling behaviour and tended to inhibit apomorphine-induced circling behaviour. Mecamylamine and pempidine (both 2 mg/kg intraperitoneally) slightly but significantly depressed the intensity of circling behaviour induced by amphetamine, but failed to modify that induced by apomorphine. Pilocarpine (10 mg/kg intraperitoneally) clearly inhibited both amphetamine- and apomorphine-induced circling behaviour. Unlike pilocarpine, atropine (10 mg/kg intraperitoneally) significantly increased the intensity of the circling behaviour induced by amphetamine and also to some extent that induced by apomorphine. Neither hexamethonium (5 mg/kg intraperitoneally) nor methylatropine (1 mg/kg subcutaneously) modified the circling behaviour induced by either amphetamine or apomorphine. The results show that stimulation of central nicotinic and muscarinic receptors may have some opposite effects on the dopamine-dependent circling behaviour. The presynaptic nicotinic cholinergic receptors on the terminals of the nigrostriatal dopaminergic neurones, stimulation of which may increase the release of dopamine, might be involved in the action of nicotinic drugs. The muscarinic cholinergic receptors in the striatum and/or in the substantia nigra might be involved in the action of muscarinic drugs.     

Circling behavior induced by intranigral injections of GABA and muscimol in rats

Circling behavior induced by unilateral intranigral injections of GABA or muscimol was studied in rats. Both GABA (10–400 g) and muscimol (1–100 ng) evoked the same kind of contralateral circling behavior dose-dependently when injected into the substantia nigra. Muscimol was much more potent than GABA and its effect lasted longer. Neither GABA nor muscimol induced any ipsilateral circling. Pretreatment with bicuculline (3 mg/kg IP) significantly attenuated the intensity of circling behavior induced by intranigral injections of GABA or muscimol. Pretreatment with haloperidol (0.5 and 1.0 mg/kg SC) also significantly antagonized the circling behavior induced by GABA and muscimol. Pretreatment with atropine (10 mg/kg IP) significantly increased the intensity of circling behavior induced by intranigral injections of muscimol and tended to increase the intensity of circling behavior induced by intranigral injections of GABA. Pretreatment with strychnine (0.25 mg/kg IP) did not modify circling behavior induced by GABA, but did to some extent increase that induced by muscimol. These results indicate that the contralateral circling behavior induced by intranigral injections of GABA and muscimol seems to be dependent both on the activation of the dopaminergic nigrostriatal system and on the nondopaminergic nigral output system.     

Effects of morphine and met-enkephalin analogue on gastric lesions induced by indomethacin

The effects of morphine HCl and a synthetic met-enkephalin analogue [D-Ala2,MePhe4,Met(O)5ol]enkephalin (FK 33-824) on gastric damage produced by the intraperitoneal administration of indomethacin (10 mg/kg i.p.) have been investigated. Rats intraperitoneally pretreated with morphine HCl (10 mg/kg i.p.) and FK 33-824 (1 mg/kg i.p.) showed a statistically significant reduction both of the number and intensity of lesions induced by indomethacin. This protection was reversed by naloxone HCl (2 mg/kg i.p.). The protective effect was not related to a reduction of gastric secretion since the antisecretory drug cimetidine (25 mg/kg i.p.) and methscopolamine bromide (10 mg/kg i.p.) did not significantly prevent mucosal damage under the same experimental conditions.     

Some behavioural effects of quinine in mice

The effects of quinine on motor activity, pentobarbitone-induced sleep and gross behaviour were examined in mice. Low doses of quinine (0.1-0.5 mg/kg intraperitoneally) increased locomotor activity in mice; this effect was potentiated by L-dopa (25 mg/kg sub cutaneously), L-dopa (25 mg/kg subcutaneously) plus benserazide (12.5 mg/kg subcutaneously) and pargyline (50 mg/kg intraperitoneally) and antagonized by α-methyl- p-tyrosine (50 mg/kg intraperitoneally), pimozide (0.2 mg/kg intraperitoneally), L-sulpiride (40 mg/kg intraperitoneally) and SCH 23390 (0.2 mg/kg subcutaneously). Similarly, D-amphet amine (2.5 mg/kg intraperitoneally)-induced locomotor activity in mice was blocked by pimo zide (0.2 mg/kg intraperitoneally). On the other hand, pimozide (0.2 mg/kg intraperitoneally), L-sulpiride (40 mg/kg intraperitoneally and SCH 23390 (0.2 mg/kg subcutaneously) potentiated the locomotor depressant effect of high doses of quinine (1-5 mg/kg) intraperitoneally). Furthermore, the onset and duration of pentobarbitone (30 mg/kg intraperitoneally)-induced sleep were respectively shortened and prolonged in a dose-dependent manner. D-Amphet amine (25 mg/kg intraperitoneally) significantly delayed the onset and shortened the duration of sleep induced by the interaction of quinine (100 mg/kg intraperitoneally) with pen tobarbitone (30 mg/kg intraperitoneally). L-sulpiride (40 mg/kg intraperitoneally) and pimozide (4 mg/kg intraperitoneally), on the other hand, significantly shortened the onset and prolonged the duration of sleep resulting from the interaction of quinine with pentobarbitone. The antagonism of pentobarbitone (30 mg/kg intraperitoneally)-induced sleep by D-amphetamine (2.5 mg/kg intraperitoneally) was prevented by pimozide (4 mg/kg intraperitoneally). Quinine (0.1 mg/kg intraperitoneally) desynchronized the EEG and antagonized pentobarbitone (20 mg/kg intraperitoneally)-induced EEG synchronization while 100 mg/kg intraperitoneally of quinine desynchronized the hyperstriatum with marked decrease in EMG activity in chicks and potentiated pentobarbitone (20 mg/kg intraperitoneally)-induced EEG synchronization with profound reduction in EMG activity. Quinine (0.01-5 mg/kg intraperitoneally) exhibited a biphasic dose-related increase in circling. The stereotyped circling induced by D-amphetamine (4 mg/kg intraperitoneally) was dose-dependently reduced by quinine (0.5-25 mg/kg intra peritoneally) while 0.05-0.1 mg/kg intraperitoneally of quinine weakly potentiated this activity. Pimozide (4 mg/kg intraperitoneally) and L-sulpiride (40 mg/kg intraperitoneally) antagonized both the circling and increase in locomotor activity induced by quinine (0.1 mg/kg intra peritoneally) and D-amphetamine (4 mg/kg intraperitoneally) respectively. These results indi cate that quinine exhibits both excitatory and inhibitory effects on the gross behaviour of mice; these biphasic effects were dose-related. Since pimozide, L-sulpiride and SCH 23390 influenced both effects, both D( 1) and D(2) receptors may be involved in the behavioural effects of quinine.     

Circling behavior induced by microinjection of serotonin reuptake inhibitors in the substantia nigra.

The nigrostriatal dopaminergic neurons of the substantia nigra pars compacta (SNc) and the nondopaminergic neurons of the substantia nigra pars reticulata (SNr) receive a dense synaptic input from the serotonergic neurons of the raphe nuclei. To assess whether serotonin [5-hydroxytryptamine (5-HT)] spontaneously released at the substantia nigra could modulate motor activity, the 5-HT reuptake inhibitors (SRIs), duloxetine (6-12 nmol) and clomipramine (12 nmol), were unilaterally microinjected either into the SNc or the SNr of freely moving rats, and the circling behavior was counted with an automated rotometer. In the SNc, the main effect of the SRIs was a contraversive circling behavior that was not observed when applied at distances > or = 0.2 mm above the SNc. The circling induced by clomipramine was blocked by microinjection of haloperidol (53 nmol) into the ipsilateral neostriatum, suggesting that the circling elicited by microinjection of the SRIs into the SNc depends on an intact striatal dopaminergic transmission. Microinjection of 5-HT (21 nmol) only produced a significant contraversive circling response when it was coinjected with the SRIs. Pretreatment with methysergide (1 mg/kg ip), a nonselective 5-HT(2) antagonist, did not block the circling elicited by microinjection of clomipramine into the SNc, either alone or in combination with 5-HT. However, microinjection of the 5-HT(2) antagonist mianserin (2 nmol) into the SNc partially inhibited the circling induced by duloxetine (6 nmol), alone or coinjected with 5-HT. Since current theories of circling behavior hypothesize that the animal turns away from the cerebral hemisphere where dopamine neurotransmission predominates, these results suggest that the contraversive circling induced by the unilateral microinjection of SRIs into the SNc could be mediated by a 5-HT-induced increase of firing frequency of nigrostriatal dopaminergic neurons. When applied into the SNr, clomipramine and duloxetine also elicited a contraversive circling behavior and enhanced the circling induced by 5-HT. Systemic methysergide (1 mg/kg i.p.), but not intranigral mianserin (2 nmol), blocked the circling elicited by microinjection of clomipramine into the SNr, either alone or in combination with 5-HT. These results suggest that 5-HT(2)-like receptors are involved in the contraversive circling induced by enhancement of serotonergic transmission in the SNr.     

Potentiation of morphine-elicited circling by dopaminergic uptake blockade

Contraversive circling induced by unilateral infusions of morphine (7.5 nanomoles or 5 μg) into the ventral tegmental area was studied under conditions of dopamine uptake inhibition. Dopamine uptake blockade with either nomifensine (2.5 mg/kg) or GBR 13069 (2.0 mg/kg) resulted in a 3-fold increase in the rate of circling. Naloxone (1.5 mg/kg) attenuated but did not completely block the potentiated circling. These data are consistent with the hypothesis that morphine causes contraversive circling through local activation or disinhibition of dopaminergic cell firing.     

Extreme hyperthermia induced in cats by the enkephalin analog FK 33-824

FK 33-824 [H₂N-Tyr-D-Ala-Gly-MePhe-Met(O)-OH] was injected into the third cerebral ventricle of unrestrained cats. Doses of 0.25–4 μg induced dose-related increases in body temperature. Hyperthermic responses to 1 μg of the peptide were greater the warmer the environment. Naloxone given intraventricularly 1 hr after FK 33-824 (1 μg) reduced the hyperthermia. In 12 tests with six cats FK 33-824 (1–25 μg) increased temperature 4.2–4.7°C. These marked responses were also inhibited by naloxone, but two cats died when administration of antagonist was delayed for 80 min to 3 hr after attainment of maximal body temperature. Larger doses of FK 33-824 (50–250 μg) evoked little increase in temperature, indicative of a separate action to depress thermoregulation. Although responses to FK 33-824 were antagonized by naloxone, this peptide, like another enkephalin analog D-Ala²-Met-enkephalinamide, must act on receptors which are not affected by morphine since (1) the hyperthermic response to FK 33-824 varied with environmental temperature, whereas the response to morphine does not, and (2) high doses of FK 33-824 depressed thermoregulation, an activity not shared by morphine in the cat. Furthermore, the maximal increases in temperature after FK 33-824 injection were greater than those evoked by either morphine or D-Ala²-Met-enkephalinamide. This observation provides evidence for an additional subset of naloxone-sensitive, ν, receptors, stimulation of which can influence thermoregulation in the cat.     

Central and peripheral sites of action for the protective effect of opioids of the rat stomach

Rats exposed to combined cold and restraint exhibited a reduced intensity of gastric damage when pre-treated intraperitoneally with morphine HCl or with the synthetic enkephalin analog [D-Ala2, MePhe4, Met(0)5ol]enkephalin (FK 33-824). Morphine HCl and FK 33-824 prevented some of the indices of the lesion also when injected intracerebroventricularly; morphine methyliodide, quaternary derivative of morphine with does not cross the blood brain barrier, was fully effective, by intraperitoneal route, in preventing the gastric damage. Both peripheral and central mechanisms seem, therefore, involved in the protective effect of opioids on rat gastric mucosa. Morphine HCl and FK 33-824 reduced significantly gastric acid secretion when administered intracerebroventricularly or intraperitoneally; in addition, a concomitant increase of prostaglandin production was observed in rat gastric mucosa after i.p. administration of both opioids. Both these events might contribute to the protective action of opioids on the stomach.     

Morphine-6-glucuronide-Induced Locomotor Stimulation in Mice: Role of Opioid Receptors

Abstract: Morphine-6β-glucuronide is a major metabolite of morphine with potent analgesic actions. To explore the importance of this opiate when administered as a drug by its own or in morphine action, we studied the locomotor activity response to morphine and morphine-6-glucuronide in drug-naive C57 BL/6JBom mice. The effects of administration of the two opiates on a battery of 7 different locomotor activities were studied and compared to saline controls. A dose of 20 μmol/kg morphine-6-glucuronide resulted in more locomotion than the same dose of morphine, while at higher doses (up to 120 umol/kg), similar increases for most locomotor behaviours were recorded for both drugs. Pretreatment with naltrindole indicated that the S-receptors play an equivalent but minor role in mediating both morphinc-6-glucuronide and morphine hyperlocomotion. Administration of high naltrexone doses (10 mg/kg) completely abolished the locomotor stimulation induced by both opiates. However, at intermediate naltrexone doses of 0.25 and 0.5 mg/kg, morphine-induced behaviours was completely inhibited while morphine-6-glueuronide induced behaviours demonstrated partial resistance to naltrexone inhibition. The μ₁-specifie receptor antagonist naloxonazine caused 75% reduction of morphine induced behaviours and only 50% inhibition of morphine-6-glucuronide induced behaviors. Taken together our observations indicated general similarity but also marked differences between morphine and morphine-6-glucuronide with respect to opiate receptors mediating the locomotor stimulatory effect.     

Inhibition of PGE1 induced intestinal secretion by the synthetic enkephalin analogue FK 33-824

1. The effects of the enkephalin analogue, FK 33-824 were compared with those of morphine and naloxone on the prostaglandin E1-induced increase in intestinal fluid volume and unanaesthetized and pithed rats. 2. FK 33-824 inhibits the prostaglandin E1-induced increase in intestinal fluid volume both in unanaesthetized and pithed rats. 3. Naloxone abolished the inhibitory effect of FK 33-824 in both experimental models. 4. It can be concluded from the experiments in pithed rats that the inhibitory effect of FK 33-824, like that of morphine, on prostaglandin E1-induced secretion is caused by a peripheral action. 5. It is assumed that endogenous enkephalins protect against prostaglandin-mediated loss of fluid into the gut lumen. This protective effect can be mimicked by an enkephalin analogue and blocked by naloxone.     

Ceruletide inhibits water intake in deprived mice: comparison with morphine and the enkephalin analogue, FK 33-824

Subcutaneous injections of ceruletide (caerulein diethylammonium hydrate, CER) reduced dose-dependently the water intake in male NMRI mice deprived of water for 18 h. The ED50 for this effect was 5.5 (3.70-7.94) nmol/kg, which is 3.7 times more than the corresponding food intake inhibiting dose. Also inhibitory but much less potent than CER were (in decreasing order) FK 33-824, morphine and naloxone. Naloxone was an antagonist to both FK 33-824 and morphine but not to CER, thereby separating CER from the opioids. When water intake reducing doses of CER (15 nmol/kg) and FK 33-824 (850 nmol/kg) were combined, the two peptides were not additive but antagonized each other. Together, the present and previous results suggest that pharmacological inhibition of food and water intake have different characteristics.     

Behavioural effects and supersensitivity in the rat following intranigral MPTP and MPP+ administration

Unilateral intranigral injections of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP+ (1-methyl-4-phenylpyridine) were given to young rats and unilateral intranigral injections of MPTP were given to old rats. MPTP in old rats and MPP+ in young rats induced ipsiversive circling for at least one week after injection and contraversive circling after the systemic administration of apomorphine; the number of D-2 receptors (Bmax) in the striatum of the injected hemisphere increased compared with that of control rats. MPTP in young rats induced only short-lasting ipsiversive circling and no contraversive circling after apomorphine; the number of striatal D-2 receptors did not increase. These results suggest that the neurotoxicity of MPTP is age-dependent in the rat, and that MPTP has neurotoxic effects on the nigrostriatal dopaminergic system in old rats and induces dopamine receptor supersensitivity in the denervated striatum.     

Effects of serotonergic activity in nucleus accumbens septi on drug-induced circling

The effects of injections of 5-hydroxytryptamine (5-HT) into the nucleus accumbens and lesions of the nucleus accumbens induced by 5,7-dihydroxytryptamine (5,7-DHT) on drug-induced circling were investigated in rats with unilateral nigrostriatal lesions induced by 6-hydroxydopamine (6-OHDA). Injections of 5-HT (60-120 micrograms in 1 microliter; 1 microliter/min) into the nucleus accumbens caused a significant decrease in the circling response to 5.0 mg/kg of d-amphetamine (s.c.). The distribution of radioactivity after intracerebral injections of [3H]5-HT using these parameters showed that although much of the injected material was retained in the nucleus accumbens there was also considerable spread to the frontal cortex. However, in further behavioural experiments, using an injection procedure (0.5 microliter; 0.11 microliter/min) which caused much greater retention of injected material in the nucleus accumbens, with minimal spread to the frontal cortex, the ability of 5-HT injected into the accumbens to block amphetamine-induced circling was not diminished. Moreover, injections of 5-HT into the frontal cortex did not have any effect on amphetamine-induced circling. Lesions of the nucleus accumbens induced by 5,7-DHT caused a significant enhancement of the contralateral circling response to 1.0 mg/kg of apomorphine and a similar but non-significant tendency to increase the circling responses to several other doses of apomorphine and amphetamine. The results provide evidence that serotonergic mechanisms in the nucleus accumbens inhibit circling behaviour generated by unilateral activation of nigrostriatal dopaminergic mechanisms.     

Phencyclidine-induced rotational behavior in rats with nigrostriatal lesions and its modulation by dopaminergic and cholinergic agents.

The peripheral administration of the psychotomimetic drug phencyclidine (1-(phenylcyclohexyl) piperidine hydrochloride) (PCP) induces a dose-related ipsilateral rotation in unilateral substantia nigra electrolytically-lesioned rats. The intensity of this rotation can be modulated by administration of various dopaminergic and cholinergic agents. Injection of alpha-methylparatyrosine methylester (125 mg/kg) or haloperidol (1 mg/kg) inhibited the ipsilateral circling behavior. Pimozide (1 mg/kg) also inhibitied the rotation, but to a lesser extent. The injection of the anticholinergic agent trihexyphenidyl (5 mg/kg) potentiated, and the cholinomimetic drug arecoline (5 mg/kg), depressed the rotation induced by PCP (7.5 mg/kg), It is probable that PCP possesses significant dopaminergic and anticholinergic properties. The capacity of PCP to induce rotation in this model may be related to its effects on dopaminergic and cholingergic neurons in the rat striatum. Thus, PCP may induce rotational behavior by potentiating dopaminergic transmission, by blocking cholinergic activity, or both; both of these effects have been demonstrated to be important in the generation of circling behavior in rats with nigrostriatal lesions.     

Effects of Anticonvulsants on Local Anaesthetic‐Induced Neurotoxicity in Rats

Abstract: The effects of various anticonvulsants on local anaesthetics procaine‐ and lidocaine‐induced convulsions were investigated in rats. Pretreatment with diazepam (2.5–5 mg/kg, intraperitoneally) and clonazepam (5–10 mg/kg, intraperitoneally) completely protected the rats against both local anaesthetic‐induced convulsions. Phenobarbital (12.5–50 mg/kg, subcutaneously) also significantly decreased the incidence of both convulsions and prolonged their latencies. Carbabazepine (10–40 mg/kg, intraperitoneally) did not completely repress both convulsions, but it prolonged their latencies. Phenytoin (5–20 mg/kg, intraperitoneally) and primidone (30–60 mg/kg, intraperitoneally) markedly enhanced both local anaesthetic‐induced convulsions, as shown by shortening of latency and increase in mortality. Valproate (100–200 mg/kg, intraperitoneally) produced a protective effect against procaine‐induced convulsions, while it strongly enhanced lidocaine‐induced convulsions. These results suggest that the benzodiazepines are effective drugs to prevent neurotoxicity induced by local anaesthetics, while phenytoin and primidone potentiate them.     

The possible cross-tolerance between morphine- and nicotine-induced hypothermia in mice

In the present study, cross-tolerance between hypothermia induced by morphine and nicotine in mice has been investigated. Different doses of morphine or nicotine induced dose-dependent hypothermia. The sub-maximal doses of both drugs were used for interaction studies. Administration of mecamylamine either intracerebroventricularly (2-6 microg/animal icv) or intraperitoneally (0.5 and 1 mg/kg ip) decreased both morphine- or nicotine-induced hypothermia. Naloxone either intracerebroventricularly (2-6 microg/animal) or intraperitoneally (1 and 2 mg/kg) reduced the response to morphine, but not nicotine's response. Hexamethonium (5 and 10 mg/kg ip) caused a slight decrease in morphine's hypothermia, but not that of nicotine. Nicotine's response was decreased in the animals which were made tolerant to hypothermic effect of morphine. Pre-treatment of the animals with low doses of morphine (12.5 or 25 mg/kg), once daily for 3 days, did not cause significant tolerance to the hypothermic response to morphine or nicotine. However, the administration of low doses of morphine (12.5 or 25 mg/kg) plus nicotine (2 mg/kg), once daily for 3 days, increased levels of tolerance to hypothermia induced by either drug. It is concluded that nicotinic receptor mechanism may play a role in morphine-induced hypothermia and there is cross-tolerance between the two drugs.     

Effect of a synthetic enkephalin analogue on spinal nociceptive messages in humans

The effects of a single dose (1.0 mg. i.v.) of a synthetic methionine enkephalin, FK 33-824 (FK) on spinal nociceptive pathways were studied in 3 normal subjects and in 3 paraplegic patients. In normal patients, FK 33-824 produced an increased threshold of a nociceptive flexor reflex of the lower limb as well as a decrease in the slope of the recruitment curve of this reflex as a function of stimulus intensity. The inhibition of a monosynaptic reflex induced by conditioning noxious cutaneous stimulation was also reduced by FK 33-824. In patients, administration of FK 33-824 resulted in marked depression of supraliminal nociceptive reflexes, showing a direct spinal effect of this opioid. In all subjects, FK 33-824 also produced severe side effects. All these effects were naloxone-reversible (0.03 mg/kg. i.v.). The clinical implications of these data are discussed.     

The immunophilin ligand FK506 protects against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum

Repeated use of methamphetamine (MAP) is known to cause neurotoxicity in the dopaminergic neurons of the striatum. Recently, we reported that FK506, a calcineurin inhibitor and immunosuppressive agent, could attenuate acute behavioral changes and the development of sensitization after administration of MAP. In this study, we investigated the effects of FK506 on the neurotoxicity in the dopaminergic neurons induced by repeated administration of MAP. BALB/c mice were injected subcutaneously (s.c.) with vehicle (10 ml/kg) or MAP (4 mg/kg) four times every 2h. Vehicle (10 ml/kg) or FK506 (0.1, 0.3, 1 or 3 mg/kg i.p.) was administered 15 min before the first MAP administration. Three days later, we assessed the contents of dopamine (DA) and its major metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the mouse striatum using high-performance liquid chromatography (HPLC). We also examined the immunohistochemistry of dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the mouse brain. Repeated administration of MAP decreased significantly the contents of DA and DOPAC in the mouse striatum, and pretreatment with FK506 inhibited significantly the reduction of DA and DOPAC in the mouse brain by repeated administration of MAP. Furthermore, repeated administration of MAP decreased significantly the immunoreactivity of DAT and TH in the striatum as compared to controls. Pretreatment with FK506 (3 mg/kg) attenuated significantly the reduction of DAT and TH immunoreactivity after repeated administration of MAP. These results suggest that FK506 shows protective effects on the MAP-induced neurotoxicity in the dopaminergic neurons of the mouse striatum.