Methamphetamine dopamine

The reinforeing properties of psychomotor stimulants have also been linked to the aetivation of eentral dopamine neurons and their postsynaptie reeep-tors. When the synthesis of eatecholamines is inhibited by administering alpha-methyl-para-tyrosine, an attenuation of the subjective effeets of euphoria assoeiated with psyehomotor stimulants oeeurs in man (Jonsson et al. 1971), and a bloekade of the reinforeing effects of methamphetamine occurs in animals (Pickens et al. 1968). Furthermore, low doses of dopamine antagonists will increase response rates for intravenous injections of h-amphetamine (Risner and Jones 1976 Yokel and Wise 1975 Yokel and Wise 1976). 

In view of this neurotoxicity, we will review some data relevant to this process. First, we will review data showing that methamphetamine (METH), a prototypic psychomotor stimulant, which has been widely used for nonmedical purposes at doses often a good deal higher than therapeutie doses, is neurotoxic to dopamine (DA) and serotonin (5-hydroxytryptamine (5-HI)) systems. Second, we will examine the evidence that other substituted phenethylamines are also neurotoxic to certain transmitter systems. Last, we will examine the behavioral and pharmacological consequences of neurotoxicity that result from exposure to some of these amphetamine-related drugs. 

In other words, we do not have them self-administering these toxic doses. We have done it with some rhesus monkeys that were self-administering methamphetamine. If you give them a regime that depletes the dopamine and serotonin, and then see what alterations there are in self-administration, it does go down, but we have not looked at that. 

COMMENT You have presented some evidence that dopamine may be involved in the neurotoxic action of methamphetamine in terms of dopaminergic neurons, and you presented evidence suggesting that it may be involved in not only the dopamine system but also the serotonin system. 

Kogan, F.J., and Gibb, J.W. Influence of dopamine synthesis on methamphetamine-induced changes in striatal and adrenal tyrosine hydroxylase activity. N-S Arch Pharmacol 310 185-187, 1979. 

ANSWER Yes, 6-hydroxydopamine by itself elevates neurotensin levels. When you combine it with methamphetamine, you do not get any additivity. It is just a 6-hydroxydopamine action. It is a bit complicated to interpret, but it appears that it is still the nigral striatal dopamine pathway that is mediating the methamphetamine effect. 

Wagner, G.C. Ricaurte, G.A. Seiden, L.S. Schuster, C.R Miller, RJ. and Westley, J. Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine. Brain Res 181 151-160, 1980. 

During the 1970s, evidence accumulated that amphetamine and methamphet-amine could also be neurotoxic (Ellison et al. 1978 Hotchkiss and Gibb 1980 Wagner et al. 1980). The effects of amphetamine seem mostly limited to dopamine neurons, whereas methamphetamine affects dopamine and serotonin neurons (Warren et al. 1984). Most recently, MDMA and MDA have been shown to produce neurotoxicity toward brain serotonin neurons much like that of the halogenated amphetamines (Ricaurte et al. 1985 Stone et al. 1986). 

Rats that have lost dopamine and/or serotonin terminals following treatment with amphetamine, methamphetamine, MDMA, MDA, / -chloroamphetamine, or fenfluramine show little in the way of overt ehanges in appearanee or behavior. Dr. Rieaurte (this volume) emphasized the need for more studies in primates, since MPTP-treated miee also show little in the way of observable functional changes, whereas MPTP-treated monkeys show marked neurologie deficits. It may be neeessary to do more detailed analysis of speeifie behaviors and other funetional outputs that are influeneed by dopamine and/or serotonin neurons, to detect functional deficits induced by some neurotoxic drugs. For instance, specific behaviors sueh as appetite-eontrolled behavior (Leibowitz and Shor-Posner 1986), murieidal behavior (Katz 1980), and sexual behavior (Tucker and File 1983) elieited by drugs... 

Role of dopamine in the neurotoxic effects of methamphetamine. J Pharmacol Exp Ther 233 539-544, 1985. 

Schmidt, C.J. and Gibb, J.W., Role of the dopamine uptake carrier in the neurochemical response to methamphetamine effects of amfonelic acid, Eur. J. Pharmacol., 109, 73, 1985. 

Kashihara, K., Hamamura, T., Okumura, K., Otsuki, S. Methamphetamine-induced dopamine release in the medial frontal cortex of freely moving rats. Jpn. J. Psychiatry Neurol. 45 677, 1991. 

Baumann, M.H., Ayestas, M.A., Sharpe, L.G., et al. Persistent antagonism of methamphetamine-induced dopamine release in rats pretreated with GBR12909 decanoate. J. Pharmacol. Exp. Ther. 301 1190, 2002. 

Cubells, J.F., Rayport, S., Raygendran, G., Sulzer, D. Methamphetamine neurotoxicity involves vac-uolation of endocytic organelles and dopamine-dependent intracellular oxidative stress. J. Neurosci. 14 2260, 1994. 

Uramura, K., Yada, T., Muroya, S. et al. Methamphetamine induces cytosolic Ca2+ oscillations in the VTA dopamine neurons. NeuroReport 11 1057, 2000. 

Higashi, H., Inanaga, K., Nishi, S., Uchimura, N. Enhancement of dopamine actions on rat nucleus accumbens neurones in vitro after methamphetamine pre-treatment. J. Physiol. 408 587, 1989. 

LaVoie, M.J., Hastings, T.G. Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine evidence against a role for extracellular dopamine. J. Neurosci. 19 1484, 1999. 

Kokoshka, J.M., Vaughan, R.A., Hanson, G.R., Fleckenstein, A.E. Nature of methamphetamine-induced rapid and reversible changes in dopamine transporters. Eur. J. Pharmacol. 361 269, 1998. 

Metzger, R.R., Haughey, H.M., Wilkins, D.G. et al. Methamphetamine-induced rapid decrease in dopamine transporter function role of dopamine and hyperthermia. J. Pharmacol. Exp. Ther. 295 1077, 2000. 

Broening, H.W., Morford, L.L., Vorhees, C.V. Interactions of dopamine D, and D2 receptor antagonists with D-methamphetamine-induced hyperthermia and striatal dopamine and serotonin reductions. Synapse. 56 84, 2005. 

Brown, J.M., Riddle, E.L., Sandoval, V. et al. A single methamphetamine administration rapidly decreases vesicular dopamine uptake. J. Pharmacol. Exp. Ther. 302 497, 2002. 

Kuczenski, R., Segal, D.S., Cho, A.K., Melega, W. Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine. J. Neurosci. 15 1308, 1995. 

Holtzman, S.G. Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine. Psychopharmacology. 155 180, 2001. 

Munzar, R, Tanda, G., Justinova, Z., Goldberg, S.R. Histamine h3 receptor antagonists potentiate methamphetamine self-administration and methamphetamine-induced accumbal dopamine release. Neuropsychopharmacology. 29 705, 2004. 

---