Amphetamine, dopamine release

The patty drug MDMA (3,4-methylene-dioxymetham-phetamine) as well as amphetamine causes efflux of all monoamine neurotransmitters. The effects of MDMA are described as psychostimulant and hallucinogenic and are judged differently from those of amphetamine. This difference is due to the stronger inhibition of SERT by MDMA as compared with amphetamine, which is a more potent dopamine releaser and moreaddictivethan MDMA. 

The nucleus accumbens is part of the limbic system. It receives dopaminergic input through the mesolimbic system that originates from cell bodies in the ventral segmental area (A 10 cell group). This mesolimbic dopaminergic pathway is part of the reward pathways. Drugs of abuse (cocaine, amphetamine, opiates or nicotine) have been shown to increase the level of dopamine release in these neurons. 

Mild increases in tonic dopamine release - as a consequence of the administration of both methylphenidate and amphetamine - could have important impact on subsequent phasic release by feedback mechanisms (lowering the concentration). 

We are routinely screening compounds for ability to displace 1-125 DOI from frontal cortex homogenates. As far as the CNS stimulant effects, differentiating from psychostimulants, the present model we are using is substitution in amphetamine-trained rats, in drug discrimination. We have used synaptosomes and looked at their effect on dopamine release and reuptake. But basically they are correlative models. 

COMMENT I would favor the view that lethargy and fatigue of postamphetamine withdrawal during the withdrawal phase would be consistent with the shutting off of the dopamine neuron. Still, it is hard to imagine how that would be. First, the amphetamine-induced release is not regulated by the autoreceptor. And, as you say, if it would be impulse related, however weak, it would be regulated. But we do know that after a period of amphetamine intoxication, an individual is supersensitive behaviorally. 

Accumulation of amphetamine and / -chloroamphetamine into synaptosomes of rat brain. J Pharm Pharmacol 24 171-173, 1972. Yamamoto. B.K., and Spanos, L.J. The acute effects of methylenedioxymethamphetamine on dopamine release in the awake-behaving rat. Eur J Pharmacol 148 195, 203, 1988. 

Ventura R., Cabib S., Alcaro A., Orsini C., Puglisi-AUegra S. (2003). Norepinephrine in the prefrontal cortex is critical for amphetamine-induced reward and mesoaccumbens dopamine release. J. Neurosci. 23, 1879-85. 

Ungerstedt, U., Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behavior, Acta Physiol. Scand, 367, 49, 1971. 

Masuoka, D.T., Alcaraz, A.R, and Schott, H.F., [3H]Dopamine release by d-amphetamine from striatal synaptosomes of reserpinized rats, Biochem. Pharmacol., 31, 1969, 1982. 

Bowyer, J.F., Spuler, K.P., and Weiner, N., Effects of phencyclidine, amphetamine and related compounds on dopamine release from and uptake into striatal synaptosomes, J. Pharmacol. Exp. Ther., 229, 671, 1984. 

Laruelle, M., Abi-Dargham, A., van Dyck, C. H. etal. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc. Natl Acad. Sci. USA 93 9235-9240,1996. 

Villemagne, V. L., Wong, D. F., Yokoi, F. et al. GBR12909 attenuates amphetamine-induced striatal dopamine release as measured by C raclopride continuous infusion PET scans. Synapse 33 268-273,1999. 

Vickroy, T. W., and Johnson, K. M. (1982) Similar dopamine-releasing effects of phencyclidine and non-amphetamine stimulants in striatal slices. J. Pharmacol. Exp. Ther., 223 669-674. 

Sakurai Y, Takano Y, Kohjimoto Y, Honda K, Kamiya HO. (1982). Enhancement of [3H]dopamine release and its [3H]metabolites in rat striatum by nicotinic drugs. Brain Res. 242(1) 99-106. Schechter MD. (1990). Rats become acutely tolerant to cathine after amphetamine or cathinone administration. Psychopharmacology (Berlin). 101(1) 126-31. 

Hamamura T, Fibiger HC. 1993. Enhanced stress-induced dopamine release in the prefrontal cortex of amphetamine-sensitized rats. Eur J Pharmacol 237(1) 65-71. 

Becker IB, Beer ME, et al (1984) Striatal dopamine release stimulated by amphetamine or potassium influence of ovarian hormones and the light-dark cycle. Brain Res 311(1) 157-160 Becker IB, Molenda H, et al (2001) Gender differences in the behavioral responses to cocaine and amphetamine. Implications for mechanisms mediating gender differences in drug abuse. Ann N Y Acad Sci 937 172-187... 

Dluzen DE, Anderson LI (1997) Estrogen differentially modulates nicotine-evoked dopamine release from the striatum of male and female rats. Neurosci Lett 230(2) 140-142 Dluzen DE, Ramirez VD (1990) In vitro progesterone modulation of amphetamine-stimulated dopamine release from the corpus striatum of ovariectomized estrogen-treated female rats response characteristics. Brain Res 517(1-2) 117-122 Donny EC, Caggiula AR, et al (2000) Nicotine self-administration in rats estrous cycle effects, sex differences and nicotinic receptor binding. Psychopharmacology 151(4) 392-405... 

Rossetti ZL, Pani L, Kuzmin A, et al Dihydropyridine calcium antagonists prevent cocaine-, but not amphetamine-, induced dopamine release and motor activity in rats. Acta Physiol Hung 75 (suppl) 249-250, 1990 Rossetti ZL, Lai M, Hmaidan Y, et al Depletion of mesohmbic dopamine during behavioural despair partial reversal by chronic imipramine. Eur J Pharmacol 242 313-315, 1993... 

Russell V, de Villiers A, Sagvolden T, et al Differences between electrically, Ritalin-, and D-amphetamine-stimulated release of pH]dopamine from brain slices suggest impaired vesicular storage of dopamine in an animal model of attention-deficit hyperactivity disorder. Behav Brain Res 94 163-171, 1998... 

The storage and release of DA can be modified irreversibly by reserpine (3.1), just as in vesicles containing other catecholamines and serotonin. Dopamine release can be blocked specifically by y-hydroxybutyrate (4.78) or its precursor, butyrolactone, which can cross the blood-brain barrier. High doses of amphetamines do deplete the storage vesicles, but this is not their principal mode of action. Apparently, amantadine (4.79), an antiviral drug that is likewise beneficial in parkinsonism (and also perhaps to relieve fatigue in multiple sclerosis), may also act by releasing DA. 

Imaging studies have shown increased amphetamine-induced striatal dopamine release, increased baseline occupancy of striatal D2 receptors by extracellular dopamine, and other measures consistent with increased striatal dopamine synthesis and release. 

Rossetti, Zvani L., Yousef Hmaidan, and Gian L. Gessa. 1992. "Marked Inhibition of Mesolimbic Dopamine Release A Common Feature of Ethanol, Morphine, Cocaine, and Amphetamine Abstinence in Rats." European Journal of Pharmacology 221 227-34. 

Wolf, Marina E, Francis J. White, Richard Nassar, Richard J. Brooderson, and Mohamed R. Khansa. 1993. "Differential Development of Autoreceptor Subsensitivity and Enhanced Dopamine Release During Amphetamine... 

The most obvious hypothesis is that in mania, as in dream psychosis with elation and grandiosity, it is possible to raise to very high levels the general activation of the brain and the specific activation of the positive emotion generator in the medial septum and other limbic regions. Because this effect can be artificially accomplished by taking amphetamines, it is reasonable to propose that excessive endogenous dopamine release (or increased receptor sensitivity) may be involved. 

---