Cell death and reactive oxygen species production have been suggested to be involved in neurodegeneration induced by the drugs of abuse. In this study we analyze the toxicity of the following drugs of abuse: heroin, morphine, d-amphetamine, and cocaine in undifferentiated PC12 cells, used as dopaminergic neuronal models. Our data show that opioid drugs (heroin and morphine) are more toxic than stimulant drugs (d-amphetamine and cocaine). Toxic effects induced by heroin are associated with a decrease in intracellular dopamine, an increase in DOPAC levels, and the formation of ROS, whereas toxic effects induced by amphetamine are associated with a decrease in intracellular dopamine and in ATP/ADP levels. In contrast with cocaine, both amphetamine and heroin induced features of apoptosis. The data suggest that the death of cultured PC12 cells induced by the drugs of abuse is correlated with a decrease in intracellular dopamine levels, which can be associated with an increased dopamine turnover and oxidative cell injury.

Repeated abuse of stimulant drugs, cocaine and amphetamine, is associated with extraneuronal dopamine accumulation in specific brain areas. Dopamine may be cytotoxic through the generation of reactive oxygen species, namely hydrogen peroxide (H2O2), resulting from dopamine oxidative metabolism. In this work, we studied the cytotoxicity in PC12 cells (a dopaminergic neuronal model) chronically and/or acutely exposed to cocaine or amphetamine, as compared to H2O2 exposure. Chronic cocaine treatment induced sensitization to acute cocaine insult and increased cocaine-evoked accumulation of extracellular dopamine, although no changes in dihydroxyphenylacetic acid (DOPAC) levels were observed. Moreover, dopamine was depleted in cells chronically exposed to amphetamine and acute amphetamine toxicity persisted in these cells, indicating that dopamine was not involved in amphetamine cytotoxicity. PC12 cells chronically treated with H2O2 were totally resistant to acute H2O2, but not to acute cocaine or amphetamine exposure, suggesting that the toxicity induced by these stimulant drugs is unrelated to adaptation to oxidative stress. Interestingly, chronic cocaine treatment largely, but not completely, protected the cells against a H2O2 challenge, whilst a decrement in intracellular ATP was observed. This study shows that chronic treatment of PC12 cells with cocaine or H2O2 modifies the cytotoxic response to an acute exposure to these agents.

This work evaluated in a population of heroin and heroin plus cocaine human addicts: 1. Norepinephrine (NE), epinephrine (Epi) and 3-methoxy-4-hydroxyphenylglycol (MHPG) (the principal metabolite of brain NE) plasma levels; 2. Monoamine oxidase (MAO) activity; and 3. 3H-imipramine specific binding to the amine carrier in platelets. NE plasma levels were significantly lower in the short-term heroin user groups (1-3 and 4-6 yr), a finding not observed in both long-term heroin user ( > 6 yr) and heroin plus cocaine user ( > 6 yr) groups. Epi levels changed in a similar manner, except that a significant increase was noted in heroin plus cocaine abusers. Conversely, dopamine and MHPG plasma levels increased with the duration of heroin use, and even more with cocaine abuse. Platelet MAO activity increased in all groups. Specific 3H-imipramine binding sites showed an increase after 3 yr of heroin abuse and in all heroin plus cocaine addicts. In conclusion, short-term use of heroin decreases NE or Epi release, but with prolonged use, a slow adaptation occurs. In contrast, cocaine inhibits the neuronal Epi uptake, even in a situation of long duration of abuse. Probably the amine levels additionally regulate the amine carrier, resulting in changes that show a different pattern from major depression. These drugs of abuse may also influence directly or indirectly related enzymatic systems.

In spite of recent theories about the aetiopathogenesis of migraine, serotonin continues to play a central role, explaining the efficacy of almost all migraine prophylactic drugs. In migraineurs with and without aura we measured (by HPLC-EC) the serum serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels between as well as during headache attacks. Between attacks of migraine with aura and at the beginning of attacks of both types of migraine the serum 5-HT and 5-HIAA concentration was significantly increased. These results were corroborated by 3H-spiperone binding to platelet membranes: in migraineurs with aura in the attack-free interval, there was a significant decrease in its Bmax, which suggests down-regulation of 5-HT2 receptors. In conclusion, we have verified that migraine with aura differs biochemically from migraine without aura.

Electrical stimulation-induced depolarization releases both dopamine (DA) and noradrenaline (NA) from sympathetic neurones of the human gastric and uterine arteries. The overflow of catecholamines elicited by electrical stimulation was measured by using high performance liquid chromatography with electrochemical detection. The addition of yohimbine (0.01-10 microM), an alpha2-adrenoceptor antagonist, to the perfusion fluid increased, in a concentration-dependent manner, the electrically-evoked DA and NA overflow from gastric and uterine arteries. In the presence of sulpiride (0.01-10 microM), a dopamine D2-type receptor antagonist, the overflow of both amines was found to be increased in the uterine artery, but not in the gastric artery. Apomorphine (0.1-10 microM), a dopamine receptor agonist, produced a dose-dependent inhibition in the amount of DA and NA released from gastric and uterine arteries. SCH 23390 (0.1-10 microM), a dopamine D1 receptor antagonist, had no effect on the release of both amines in both preparations. The inhibitory effect of apomorphine was blocked by sulpiride in the gastric and uterine arteries but not by SCH 23390. The results presented suggest the existence of dopamine D2-type receptors in the human gastric and uterine arteries. They seem to have, in each artery, a different physiological importance.