Methamphetamine dosing

Few studies have examined the effects of delta opioids on abuse-related effects of other psychostimulants. Naltrindole and naltriben, but not BNTX, attenuated both methamphetamine-induced place preferences and the discriminative stimulus effects of low methamphetamine doses in rats however, naltrindole did not alter the discriminative stimulus effects of a higher dose of methamphetamine [140,142], A single dose of 3 mg/kg naltrindole was also reported to block facilitation of electrical brain stimulation by a single dose of methylenedioxymethamphetamine (MDMA) [143]. Finally, a recent study found that both morphine and TAN-67 prevented mecamylamine-induced place aversions in rats chronically-treated with nicotine. These results were interpreted to suggest that both mu and delta agonists may attenuate some aversive effects associated with nicotine withdrawal [144]. 

Crowley, T.J. Dose-dependent facilitation or suppression of rat fighting by methamphetamine, phenobarbital, or imipramine. Psychopharmacologia 27 213-222, 1972. 

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. 

In eontrast to methamphetamine, where we are dealing with behaviorally effeetive doses that are in the range of 1 to 4 mg/kg, toxieity doses are in the range of 50 to 100. 

Hotchkiss, A.J. Morgan, M.E. and Gibb, J.W. The long-term effects of multiple doses of methamphetamine on neostriatal tryptophan hydroxylase, tyrosine hydroxylase, choline acetyltransferase and glutamate decarboxylase activities. Life Sci 25 1373-1378. 1979. 

Commins et al. (1987) have also reported the formation of 5,6-dihydroxy-tryptamine in rat hippocampus after a single, high doses of methamphetamine. They suggested that the formahon of 5,6-dihydroxytryptamine, a known neurotoxie substance, may mediate the neurotoxie effects of methamphetamine toward serotonergic nerve terminals. 

Cook, C.E., Jeffcoat, A.R., Sadler, B.M. et al. Pharmacokinetics of oral methamphetamine and effects of repeated daily dosing in humans. Drug Metab. Dispos. 20 856, 1992. 

Kovachich, G.B., Aronson, C.E., Brunswick, D.J. Effects of high-dose methamphetamine administration on serotonin uptake sites in rat brain measured using [3H]cyanoimipramine autoradiography. Brain Res. 505 123, 1989. 

Brunswick, D.J., Benmansour, S., Tejani-Butt, S.M., Hauptmann, M. Effects of high-dose methamphetamine on monoamine uptake sites in rat brain measured by quantitative autoradiography. Synapse. 11 287, 1992. 

Villemagne, V., Yuan, J., Wong, D.F. et al. Brain dopamine neurotoxicity in baboons treated with doses of methamphetamine comparable to those recreationally abused by humans evidence from [llC]WIN-35,428 positron emission tomography studies and direct in vitro determinations. J. Neu-rosci. 18 419, 1998. 

Frey, K., Kilboum, M., Robinson, T. Reduced striatal vesicular monoamine transporters after neurotoxic but not after behaviorally-sensitizing doses of methamphetamine. Eur. J. Pharmacol. 334 273, 1997. 

Cass, W.A., Manning, M.W. Recovery of presynaptic dopaminergic functioning in rats treated with neurotoxic doses of methamphetamine. J. Neurosci. 19 7653, 1999. 

Methamphetamine was widely used by soldiers in World War II because its potent stimulant effects kept them awake and alert for longer periods of time and increased their physical endurance. One infamous user of methamphetamine during wartime was one of the most evil men of the twentieth century—Adolf Hitler. Hitler started receiving daily injections of methamphetamine from his personal physician Dr. T. Morrell in 1942, and it was reported he could not function without his daily doses. Hitler also took many other drugs (perhaps over two dozen), including Cola-Dalmann tablets that contained caffeine. Hitler also dispensed methamphetamine to his troops so they could fight for days on end without sleep or food and outlast the endurance of enemy troops. 

Substance-Induced Anxiety Disorder. Numerous medicines and drugs of abuse can produce panic attacks. Panic attacks can be triggered by central nervous system stimulants such as cocaine, methamphetamine, caffeine, over-the-counter herbal stimulants such as ephedra, or any of the medications commonly used to treat narcolepsy and ADHD, including psychostimulants and modafinil. Thyroid supplementation with thyroxine (Synthroid) or triiodothyronine (Cytomel) can rarely produce panic attacks. Abrupt withdrawal from central nervous system depressants such as alcohol, barbiturates, and benzodiazepines can cause panic attacks as well. This can be especially problematic with short-acting benzodiazepines such as alprazolam (Xanax), which is an effective treatment for panic disorder but which has been associated with between dose withdrawal symptoms. 

Fludeprenyl (7) also has methamphetamine-like discriminative-stimulus properties in squirrel monkeys that appear at twofold higher doses than the L-deprenyl-induced response [35]. These behavioral activities were ascribed to formation of the metabolites, p-fluoroamphetamine and p-fluorometamphetamine. 

Dopaminergic activity. Smoke was administered intranasally to mice for 20 minutes twice daily for 3 days before methamphet-amine treatment. The treatment significantly attenuated the neurotoxicity as judged by a lesser depletion of dopamine, dihydrophenylacetic acid, and homovanillic acid. The lesser effect of methamphetamine on the content of serotonin level was unaltered by prior inhalation of smoke h Tobacco glycoside, administered to mice, increased behavior via dopamine 2 neuronal activity but not dopamine 1 activity in a dose-dependent manner. The results indicated that smoking can affect the human brain function via not only the nicotinic cholinergic neuron but also the dopamine 2 neuron . 

---