Melatonin reverses neurochemical alterations induced by 6-OHDA in rat striatum

The present work showed that the intrastriatal injection of 6-OHDA significantly decreases DA, DOPAC and HVA levels in that rat brain structure. Although there is also a decrease in 5-HT levels no changes were observed in 5-HIAA levels as compared to controls. On the other hand, melatonin (2, 5, 10 and 25 mg/kg. i.p., daily for 7 days) treatment starting 1 h after 6-OHDA lesions, partially reverses the decreases caused by 6-OHDA lesions on these neurotransmitter levels, and contents were brought to approximately 50% of that observed in the contralateral sides of controls or of melatonin treated group. Melatonin was more efficient at the doses of 5 and 10 mg/kg, i.p., and effects were similar between the lowest and highest doses characteristic of a bell-shaped type of response. The apomorphine-induced rotational behavior (3 mg/kg, i.p.) was blocked by 60, 89, 78 and 47% after the doses of 2, 5, 10 and 25 mg/kg, i.p., respectively. Similarly, in this case the doses of 5 and 10 mg/kg were also more efficient. Melatonin (5 mg/kg) produced an upregulation of D1 receptors associated with a decrease in Kd value. While no change was observed in maximum density of D2 receptors, the Kd value was also decreased.     

Effects of short- and long-acting dopamine agonists on sensitized dopaminergic neurotransmission in rats with unilateral 6-OHDA lesions

The effects of short and long-acting dopamine agonists on sensitized dopaminergic transmission in an animal model of Parkinson's disease were investigated. Rats with 6-hydroxydopamine (6-OHDA) lesions of the left nigrostriatal dopaminergic pathway were pre-exposed i.p. to 50 mg/kg methyl levodopa for 10 days. After a 7-day withdrawal period, these animals were treated with saline i.p., 0.05 mg/kg apomorphine s.c., or 0.5 mg/kg cabergoline i.p., once daily for 7 days. On the 8th day, rats in each treatment group received a challenge dose of 0.05 mg/kg apomorphine or saline s.c. The temporal changes in the number of rotations away from the 6-OHDA lesion side were evaluated after the challenge. The apomorphine challenge increased the number of rotations more markedly in the apomorphine pretreated rats than in the other pretreatment groups. In cabergoline pretreated rats, the number of rotations was significantly lower than that of saline-pretreated animals. Pretreatment with saline did not alter the apomorphine sensitivity of rotational behavior. These findings suggest that the repeated administration of long-acting dopamine agonists may reduce sensitized dopaminergic transmission in dopamine-depleted rats, whereas short-acting ones may further enhance sensitization of the transmission process.     

Increase in rat striatal acetylcholine content by d-fenfluramine, a serotonin releaser.

The anorectic agent, d-fenfluramine, maximally increased the acetylcholine content in the striatum by 50% at doses of 5–10 mg/kg. The action of the drug was completely prevented by treatments designed to interfere with serotonergic transmission (e.g., combined electrolytic lesion of the nucleus raphe medianus and dorsalis; pretreatments with methergoline, parachlorophenylalanine or fluoxetine). By contrast, interference with dopaminergic transmission (e.g., lesion of the nigrostriatal dopaminergic tract with 6-OHDA; pre-treatment with penfluridol) did not impede the action of d-fenfluramine. The administration of d-fenfluramine to animals given a supramaximal dose of apomorphine, 1.5 mg/kg, produced a summated increase in striatal acetylcholine. The data are consistent with the hypothesis that there may exist in the striatum different populations of cholinergic interneurons regulated by serotonin and dopamine, respectively.     

6-Hydroxydopamine infusions into the structures of mesolimbic dopaminergic system alter the memory enhancing effect of CK-8US and caerulein in rats

The influence of bilateral destruction of dopaminergic endings in the anterior and in the posterior part of nucleus accumbens (NAS) and in the nucleus septi lateralis (NSL), by 6-hydroxydopamine (6-OHDA) infusions, on the facilitatory effect of cholecystokinin-unsulfated octapeptide (CCK-8US) and caerulein (CER) on memory motivated affectively was investigated in male Wistar rats. CCK-8US and CER were given s.c. at the doses of 10 microg/kg and 0.5 microg/kg respectively, immediately after a single learning trial in a passive avoidance situation, ten days after bilateral 6-OHDA lesions (desipramine pre-treatment; 25 mg/kg, i.p.) of these structures. Bilateral 6-OHDA lesions to the anterior and to the posterior part of NAS totally abolished and significantly attenuated, respective, the facilitatory effect of CCK-8US and CER on retention of a passive avoidance behaviour evaluated 24 h later, while bilateral lesions to NSL did not have any influence on it. Moreover, neither, destruction of dopaminergic endings in lesioned structures, nor application of CCK-8US and CER changed the spontaneous psychomotor activity of rats estimated in an "open field" test. These results may indicate that dopaminergic projection to the anterior part of NAS is mainly responsible for the facilitatory effect of CCK-8US and CER on memory motivated affectively.     

Turning in MFB-lesioned rats and antagonism of neuroleptic-induced catalepsy after lisuride and LSD.

The effects of lisuride, d-lysergic acid diethyl amide (LSD) and apomorphine were studied in rats with unilateral destruction of nigro-striatal nerve terminals either with 6-hydroxydopamine (6-OHDA) or 5, 6-dihydroxytryptamine (5,6-DHT). Lisuride at the dose of 50 μg kg^?1 i.p. induced contralateral turning for more than 4 hours while the circling induced by LSD (200 μg kg^?1) and apomorphine (1 mg kg^?1) persisted for only one hour. Lisuride, a compound stimulating both dopamine (DA) and 5-hydroxytryptamine (5-HT) receptors induced a more intense turning in 6-OHDA than in 5,6-DHT lesioned rats. This might indicate a modulation of 5-HT on rotational behavior. Haloperidol (1 mg kg^?1 i.p.) antagonized both lisuride- and LSD-induced turning. LSD, and much more persistently lisuride, counteracted the prochlorperazine-induced catalepsy. These findings correlate with the biochemical data indicating that lisuride is a very potent agonist at central dopaminergic receptors.     

Drug-induced circling preference in rats

Drugs of abuse, such as phencyclidine (PCP), methamphetamine (METH), and cocaine (COC) are known to affect several behaviors in rats, such as motor activity, stereotypy, and circling. In this study, we evaluated whether these drugs produce circling preferences in the presence or absence of unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the caudate nucleus. Adult male CD rats were lesioned with 10 μg 6-OHDA/site. Animals were dosed with PCP (15 mg/kg, ip), its congener, (+) MK-801 (0.15 mg/kg, ip), METH (2 mg/kg, ip), COC (60 mg/kg, ip), or apomorphine (0.2 mg/kg, ip). circling preference was recorded in control and lesioned rats for 2 h before animals were sacrificed to determine monoamine levels by HPLC/EC. In control animals, administration of these drugs produced 60–70% left circling. In, lesioned animals, these drugs produced 78–90% ipsilateral (toward the lesion) circling, except apomorphine, which produced 60–80% contralateral (away from the lesion) circling. Dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations significantly decreased ipsilaterally in lesioned caudate nucleus (CN) and substantia nigra (SN). However, no significant changes were observed in nucleus accumbens (NA) and olfactory tubercles (OT). These data demonstrate that drugs of abuse like PCP, its congener (+) MK-801, METH, and COC produce a greater preference to turn toward the left than the right, a finding similar to that found in human psychosis. Since 6-OHDA lesions enhanced the circling bias and depleted DA and its metabolites DOPAC and HVA, it also suggests that the dopaminergic system may be involved in the circling behavior.     

Differential effects of isoproterenol injections on the levels of pineal N-acetyltransferase, serum N-acetylserotonin and melatonin

Rats housed under diurnal lighting conditions were either injected with isoproterenol (ISO), 0.5 mg/kg subcutaneous (SC) and sacrificed at different times up to 180 minutes afterwards, or injected with different doses of ISO (0.2 mg/kg to 5.0 mg/kg intraperitoneally (IP] and sacrificed 120 minutes later. Pineal N-acetyltransferase (NATase), serum N-acetylserotonin (NAS) and serum melatonin (MT) levels were determined. It was found that both pineal NATase and serum MT responded to the injection with peak increase at 120 minutes after the injection. This increase in pineal NATase and serum MT levels were also found to be dose-dependent. It was also observed that at 30 minutes after ISO injection, the serum MT level already demonstrated a significant increase which preceeded any increase in the pineal NATase activity. The underlying mechanism for this observation remains undetermined. Unlike serum MT and pineal NATase, there were no changes in serum NAS levels after injections of ISO at all the doses tested or up to 180 minutes after injection of the drug at 0.5 mg/kg dose SC. This suggests that serum NAS level is neither regulated by pineal NATase activity nor is the pineal gland the major source of NAS in circulation. This also indicates that serum NAS level is not influenced by beta-adrenergic stimulation.     

Brain mast cells and therapeutic potential of vasoactive intestinal peptide in a Parkinson's disease model in rats: brain microdialysis, behavior, and microscopy

In the present study, the effect of systemically administered vasoactive intestinal peptide (VIP) (25 ng/kg i.p.) was investigated on drug-induced rotational behavior, extra-cellular dopamine levels and histology of corpus striatum in a 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. After 15 days of 6-OHDA lesion, apomorphine-induced (0.05 mg/kg s.c.) rotational behavior of the animals significantly increased and extra-cellular dopamine levels of corpus striatum were significantly reduced. VIP reversed the rotational deficits but did not alter the decrease in striatal dopamine levels. On the other hand, histological data indicate that VIP significantly reduced neuronal death and demyelination. Electron microscopic appearance of mast cells showed ultra-structural variety between VIP-treated and 6-OHDA lesioned groups. VIP activates mast cells without any evidence of typical exocytosis, and possibly mast cells could participate in neuroprotection. Our results suggest that systemically administered VIP can attenuate the motor response changes, neuronal cell death, and myelin sheet loss characteristically associated with 12 microg 6-OHDA administration into the rat striatum. Brain mast cells seem to participate in neuronal protection. Possibly, protective cues could be produced by brain mast cells.     

神经节苷脂对6-OHDA损毁交感神经末梢的对抗作用

单次6-OHDA (15mg/kg.i.p.)注射后24h,可使雌性成年小鼠颌下腺内儿茶酚胺荧光神经末梢几乎完全消失;同时用 HPLC 测得腺体内去甲肾上腺素(NA)和多巴胺(DA)的含量下降至正常值的3—4%以下。随着受损交感神经末梢再生过程,NA 和 DA 水平有缓慢的恢复。在损毁2周时 NA 和 DA 含量分别达到正常水平的50%和28%,且在4周时完全恢复。在注射6-OHDA 的同时,和在损伤后12h 内给动物注射4次神经节苷脂(每次50mg/kg.i.p.)并在其后的一周內每天注射一次,可使颌下腺内 NA 含量维持在正常水平;在损毁后4h 及损毁前4d 开始施用神经节苷脂,也可不同程度地对抗交感神经末梢损伤,但作用强度不如前者。实验结果提示:(1)神经节苷脂通过减弱6-OHDA 及其代谢产物的损伤效应能够保护交感神经末梢膜,它可能还有促损伤末梢再生性长芽的作用;(2)损伤后神经节苷脂处理得越早,其效果越好。     

The characterization of central neuromediation in rats fed with magnesium-deprived diet before and after magnesium replenishment

Magnesium (Mg) has been proposed to take part in biochemical dysregulation contributing to psychiatric disorders. The aims of this study was to estimate acute behavioural responses to clonidine (0.1 mg/kg i.p.), d-amphetamine (5 mg/kg, i.p), arecoline (15 mg/kg i.p), nicotine (6 mg/kg i.p.), apomorphine (1.5 mg/kg i.p.) and L-5-hydroxytryptophan (300 mg/kg i.p.) in rats fed with Mg-deprivated diet for 49 days and then treated with organic and inorganic Mg salts (50 mg Mg per kg) ether alone or in combination with pyridoxine (5 mg vitamin B6 per kg). In our study Mg-deficient rats were more sensitive to d-amphetamine-induced motor stereotypes compared with control rats; time of onset of the stereotypies insignificantly decreased by 14.89% and duration of the stereotypies significantly increased by 19.44% (320.36 +/- 19.90 vs. 268.23 +/- 8.17 minutes; p = 0.043). Mg deficiency did not modulate sensitivity to nicotine-induced seizure. The time between nicotine injection and emergence of clonic seizure (seizure latency) in the controls and Mg-deficient rats were 0.80 +/- 0.26 and 0.96 +/- 0.21 minutes respectively. Duration of the seizures in the controls and Mg-deficient rats were 64.93 +/- 7.20 and 79.32 +/- 8.13 minutes. In our study, Mg deficiency did not affect on clonidine- and apomorphine-induced hypothermia. Clonidine produced similar decreases in rectal temperature in controls and Mg-deficient group. In experiments using apomorphine, values of hypothermia were similar to those observed with clonidine. Mg deficiency antagonized 5-hydroxytryptophan-induced head-twitch response. The number of head twitches produced by 5-hydroxytryptophan was significantly (p = 0.49) decreased: twofold in magnesium-deficient rats (1.23 +/- 0.44 per minute) as compared with controls (2.42 +/- 0.52 per minute). Arecoline-induced tremor was comparably less expressed in Mg-deficient rats than in controls. The time between arecoline injection and time of onset of the tremor in the controls and Mg-deficient rats were 92.75 +/- 19.35 and 245.17 +/- 121.86 seconds respectively (p < or = 0.035). Duration of the tremors in the controls and Mg-deficient rats were 1175.58 +/- 127.87 and 703.83 +/- 89.33 seconds (p = 0.015). Magnesium salts (Mg chloride, Mg L-aspartate alone and in combination with B6) were administered through gastric tube during twenty days up to complete compensation oferythrocyte and plasma Mg levels in all experimental groups. In our study administration of Mg salts resulted in normalization of acute behavioural responses in Mg-deficient rats to d-amphetamine, arecoline, and L-5-hydroxytryptophan. Behavioural responses in rats treated with both Mg chloride and Mg L-aspartate in combinations with B6 were comparable with those observed in MagneB6 treatment.     

Ethanol induces rotational behavior in 6-hydroxydopamine lesioned mice

Mice with unilateral striatal lesions created by 6-hydroxydopamine (6HDA) injection were screened for rotational (circling) behavior in response to injection of amphetamine and apomorphine. Those that rotated ipsilaterally in response to amphetamine and contralaterally in response to apomorphine were subsequently challenged with 1 to 3 g/kg (i.p.) ethanol. Surprisingly, ethanol induced dose related contralateral (apomorphine-like) rotation which, despite gross intoxication, was quite marked in most animals. No significant correlation was found between the number of turns made following ethanol and made after apomorphine or amphetamine.     

Depletion of epinephrine in rat hypothalamus by a dopamine agonist,pergolide

The i.p. injection of pergolide mesylate, a dopamine agonist, at doses of 0.3–0.6 mg/kg led to a decrease in epinephrine concentration in rat hypothalamus. After a 0.6 mg/kg dose of pergolide mesylate, epinephrine concentration in hypothalamus decreased within 2 hr, reached a minimum concentration at about 8 hrs, and then returned toward control values. Norepinephrine N-methyltransferase activity was not decreased after pergolide injection in vivo nor was it inhibited by pergolide added in vitro at concentrations as high as 10^–3 M. Higher i.p. doses of less potent dopamine agonists, apomorphine (10 mg/kg) and lergotrile (3 mg/kg), also decreased epinephrine concentration in hypothalamus. The pergolideinduced decrease in hypothalamic epinephrine concentration was prevented by pretreatment with haloperidol or spiperone., antagonists of dopamine receptors. Activation of dopamine receptors appears to result in a decrease in epinephrine concentration in rat brain, possibly due to, enhanced release of epinephrine.     

Evidence that the stimulus properties of apomorphine are mediated by both D1 and D2 receptor activation

Male and female rats were trained to discriminate between the stimulus properties of apomorphine (0.16 mg/kg i.p.) and saline in a two-lever, food-motivated operant procedure. Apomorphine, at doses different than the training dose, produced a similar dose-dependent relationship in both sexes. Consistent with the hypothesis that the behavioral effects of apomorphine are mediated by D2 activation, the apomorphine interoceptive cue generalized to bromocriptine, a drug considered to be a preferential D2 agonist. In addition, the dose-response curve after 5-15 mg/kg bromocriptine administration was parallel to that of apomorphine. Consistent with the biochemical evidence that apomorphine's effects are mediated, to a lesser extent, by D1 activation, the apomorphine cue partially generalized to the selective D1 agonist SKF 38393. Furthermore, the apomorphine cue was not blocked by the selective D1 antagonist SCH 23390. Somewhat surprising was the partial generalization of the apomorphine cue to SCH 23390. However, this is not the first time that the administration of SCH 23390 has resulted in unexpected behavioral responses. Other novel findings include the lack of sex differences in acquisition training to the apomorphine cue and in the generalization tests to the selective agonists. The behavioral results are consistent with previous biochemical evidence that the effects of apomorphine are mediated by both D1 and D2 activation and is further behavioral support that apomorphine's effects are not the result of D2 activation alone, as previously hypothesized.     

Concomitant D1 dopamine receptor activation (SKF 38393) unmasks D2 dopaminergic actions of B-HT 920 in mice.

The present study attempts to demonstrate D1/D2 dopamine (DA) receptor interactions during stereotyped behaviour in mice. B-HT 920 [2-amino-6-allyl-5, 6, 7, 8-tetrahydro-4H-thiazolo-(4, 5-d)-azepine] (0.05-1.0 mg/kg), a selective D2-DA agonist, induced mild per se stereotypy consisting mainly of sniffing and rearing responses. Apomorphine, a mixed D1/D2 agonist, also produced typical stereotypic response in mice. The stereotypic response of B-HT 920 was blocked by D2-DA antagonist, sulpiride (50 mg/kg). The effect of apomorphine was not influenced by co-treatment with SKF 38393. Simultaneous administration of B-HT 920 (0.1-0.5 mg/kg) with SKF 38393 (5 mg/kg), a selective D1-DA agonist, elicited dramatic increase in stereotyped behaviours in naive as well as in 24 hr reserpinised (2 mg/kg) mice. Co-treatment of apomorphine (0.5 mg/kg) with B-HT 920 (0.1, 0.25 mg/kg) also resulted in a clearly synergistic effect on stereotyped behaviour. These potentiated responses were reduced or blocked by haloperidol, a D2-DA antagonist. The data suggest that in presence of concomitant stimulation of D1-DA receptors. B-HT 920 exhibits full expression of postsynaptic D2-DA receptor mediated behavioural effects.     

Effects of chronic administration of phencyclidine on stereotyped and ataxic behaviors in the rat

After chronic administration of Phencyclidine (PCP) to rats, a high test dose (15 mg/kg) of PCP produced increases in stereotypic and ataxic behaviors, and a lower test dose of PCP (5 mg/kg) produced decreases in these behaviors, compared to behavioral responses of control rats. Rearing behavior in rats chronically administered PCP was increased at all test doses of the drug. Rats treated chronically with 15 mg/kg PCP for 9 days showed marked increases in most of these behaviors, whereas, rats receiving 5 mg/kg PCP for 9 days showed less change in several stereotypic and ataxic behaviors. Rats receiving 10 mg/kg PCP on a once-weekly schedule also exhibited more rearing and ataxic behavioral responses after the 3rd or 4th weekly PCP injection. Chronic PCP rats did not show more stereotypic or ataxic behavior after administration of apomorphine or amphetamine than control rats. These results suggest that chronic administration of PCP augments sensitivity to the stereotypic inducing effects of high doses, and decreases sensitivity to low doses of PCP.     

神经生长因子在6－OHDA化学性去交感神经中的保护作用

本实验用６－ＯＨＤＡ造成成年小白鼠领下腺化学性去交感神经,观察了神经生长因子对该神经的保护作用。６－ＯＨＤＡ（１５ｍｇ／ｋｇｉｐ）处理后２４ｈ腺体内去甲肾上腺素（ＮＥ）含量降至正常水平的２％以下。若在６－ＯＨＤＡ处理同时开始多次给予神经生长因子（ＮＧＦ）,则ＮＥ残留量明显提高。减小６－ＯＨＤＡ剂量至１０ｍｇ／ｋｇ,ＮＥ残留量增加,同时ＮＧＦ的作用亦较用６－ＯＨＤＡ１５ｍｇ／ｋｇ时更为显著。若提前２４ｈ给予ＮＧＦ,尽管仍显著提高ＮＥ残留量,但程度却显然低于与６－ＯＨＤＡ同时给予者。以上结果表明外源性ＮＧＦ对６－ＯＨＤＡ造成交感神经化学性损毁有保护作用,此作用与神经受损的严重程度以及ＮＧＦ处理时间有关。     

Inhibition of locus coeruleus neuronal activity by beta-phenylethylamine

The effect of beta-phenylethylamine (PEA) on brain noradrenaline (NA) neurons in the rat locus coeruleus (LC) was analyzed using single unit recording techniques including microiontophoretic methodology. Systemic injection of low doses of PEA consistently produced an instantaneous and dose-dependent inhibition of firing rate of the LC neurons. The effect was strongly antagonized by administration of the alpha 2-receptor antagonist yohimbine (1 mg/kg, i.v.) or by depletion of endogenous stores of NA by pretreatment with reserpine (10 mg/kg, i.p., 6 h), but unaffected by inhibition of tyrosine hydroxylase (alpha-met-hyl-p-tyrosine (alpha-MT), 250 mg/kg, i.p., 30 min). In contrast, the inhibitory effect of PEA on the LC neurons was strongly potentiated by pretreatment with the selective monoamine oxidase (MAO) - B inhibitor pargyline (2 mg/kg, i.p., 1 h), but, unexpectedly, also by pretreatment with the MAO-A selective inhibitors clorgyline (2 mg/kg, i.p., 1 h) or FLA 336 (2 mg/kg, i.p., 1 h). When microiontophoretically applied directly onto the LC neurons, PEA produced inhibition of a majority of the NA neurons. This action was prevented by intravenous injection of yohimbine (2.5 mg/kg). The results suggests that the action of PEA on NA neurons in the LC is an indirect effect, requiring availability of a reserpine-sensitive storage pool of NA, and mediated via activation of central alpha 2-receptors within the LC.     

In vivo 6-OHDA-induced neurodegeneration and nigral autophagic markers expression

Numerous reports suggest the involvement of oxidative stress in the pathogenesis of Parkinson's disease (PD), however, the crucial mechanism of the degenerative process remain unclear. Emerging evidence supports a critical role for autophagy in the pathogenic process of dopaminergic neurodegeneration. However, the definitive in vivo proof of it is currently lacking. Due to the relevance oxidative stress and chaperone-mediated autophagy (CMA) in PD pathogenesis, we investigated the expression of nigral CMA markers in 6-OHDA-lesioned hemiparkinsonian rats. Male Sprague-Dawley rats received a 6-OHDA injection (8 μg in 4 μl of saline with 0.02% ascorbate over 8 min) into the left medial forebrain bundle by means of a Harvard infusion pump. Following a three-week recovery period, rats exhibiting a vigorous rotational response (>100 total turns) to apomorphine (0.05 mg/kg, sc) were selected for further study. Western blotting analyses showed a decrease by 88% in TH expression levels in the striatum ipsilateral to 6-OHDA lesion (p<0.01) associated to an increase in nigral lysosomal membrane protein receptor type 2A (LAMP2A, p<0.01) and heat shock protein 90 (HSP90, p<0.01). The present results provide in vivo evidence of CMA activation in the animal model of parkinsonism in rats with a unilateral lesion of the nigrostriatal pathway induced by 6-OHDA. This widely used model offers great potential for future studies regarding new potential treatments for neurodegenerative conditions and in the investigation of signaling pathways regulating autophagy.     

Evaluation of antipyretic potential of Clitoria ternatea L. extract in rats.

The methanol extract of Clitoria ternatea L. root (MECTR) blue flowered variety (Family: Fabaceae), was evaluated for its anti-pyretic potential on normal body temperature and yeast-induced pyrexia in albino rats. Yeast suspension (10 ml/kg body wt.) increased rectal temperature after 19 hours of subcutaneous injection. The extract, at doses of 200, 300 and 400 mg/kg body wt., p.o., produced significant reduction in normal body temperature and yeast-provoked elevated temperature in a dose-dependent manner. The effect extended up to 5 hours after the drug administration. The anti-pyretic effect of the extract was comparable to that of paracetamol (150 mg/kg body wt., p.o.), a standard anti-pyretic agent.     

Neurotoxic action of 6-hydroxydopamine on the nigrostriatal dopaminergic pathway in rats sensitized with D-amphetamine.

To determine whether behavioral sensitization produced by prolonged D-amphetamine administration affects susceptibility of nigrostriatal dopaminergic neurons to the neurotoxic actions of 6-hydroxydopamine (6-OHDA), rats were treated daily from the 23 rd day after birth for 11 consecutive days with D-amphetamine (1.0 mg/kg s.c.) or saline. On the last day of treatment, one group primed with D-amphetamine and one control group of rats were tested to confirm behavioral sensitization development. The remaining animals were additionally treated on the 34 th day (one day after the last D-amphetamine injection) with 6-OHDA HBr (300 microg in 10 microl i.c.v., salt form, half in each lateral ventricle) or its vehicle. Four weeks later the levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-metoxytyramine (3-MT), as well as 5-hydroxytrypatmine (5-HT) and its metabolite 5-hydroxyindoleacteic acid (5-HIAA) were assayed in the striatum, by HPLC/ED. In rats with behavioral sensitization, 6-OHDA reduced endogenous dopamine and its metabolites content to a comparable degree in comparison to controls. This finding indicates that presumed up-regulation of the dopamine transporter in the behaviorially sensitized rats did not increase the neurotoxicity of a high dose of 6-OHDA.