Dopamine release

Youngren KD, Inglis FM, Pivirotto PJ et al (1999) Clozapine preferentially increases dopamine release in the rhesus monkey prefrontal cortex compared with the caudate nucleus. Neuropsychopharmacology 20 403-12... 

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. 

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

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). 

At low doses, both psychostimulants could theoretically stimulate tonic, extracellular levels of monoamines, and the small increase in steady state levels would produce feedback inhibition of further release by stimulating presynaptic autoreceptors. While this mechanism is clearly an important one for the normal regulation of monoamine neurotransmission, there is no direct evidence to support the notion that the doses used clinically to treat ADHD are low enough to have primarily presynaptic effects. However, alterations in phasic dopamine release could produce net reductions in dopamine release under putatively altered tonic dopaminergic conditions that might occur in ADHD and that might explain the beneficial effects of methylphenidate in ADHD. 

It has been suggested that modafinil increases wakefulness by activating ai noradrenergic receptors or hypothalamic cells that contain the peptide hypocre-tin [3], or that it may act by modulating the GABAergic tone that might lead to an increased dopamine release in the nucleus accumbens. On the other hand, modafinil does not have any effect in DAT knockout mice. 

An important clinical clue connected with the difference between tonic and phasic dopamine release is the so-called rate dependence of psychostimulant action. That means, it depends on the actual dopaminergic state (tonic and phasic) how an individual will react to psychostimulants. Figure 3 illustrates this rule by some examples [2]. The arrows represent the response of each component to methylphenidate for each of the classes of subjects tested, with the horizontal dashed line representing the baseline tonic andphasic levels present in control individuals. Summarizing, methylphenidate tends to normalize dopamine transmission regardless what the baseline rate is. 

FIGURE 4-23 Experimental setup for monitoring dopamine release by exocytosis, from a cell body. The microelectrode and glass capillary (containing the chemical stimulant) are micromanipulated up to the cell body. (Reproduced with permission from reference 82.)... 

Swartz CM, Breen K, Leone F Serum prolactin levels during extended cocaine abstinence. AmJ Psychiatry 147 777—779, 1990 Sziraki I, Sershen H, Hashim A, et al Receptors in the ventral tegmental area mediating nicotine-induced dopamine release in the nucleus accumbens. Neurochem Res 27 253-261, 2002... 

Howard SG, Feigenbaum JJ Effect of gamma-hydroxybutyrate on central dopamine release in vivo a microdialysis study in awake and anesthetized animals. Biochem Pharmacol 33 103-110, 1997... 

There are few reports on the effects of nitrous oxide on dopaminergic neurotransmission. A study in mice showed that nitrous oxide inhalation produced a significant increase in locomotor activity that was antagonized in a dose-dependent fashion by the dopamine synthesis inhibitor a-methyl-/)-tyrosine (Hynes and Berkowitz 1983). Moreover, administration of the D2 antagonist haloperidol also reduced the locomotor activity induced by nitrous oxide (Hynes and Berkowitz 1983). These results suggest that excitatory effects induced by nitrous oxide may be also mediated by dopaminergic neurotransmission. However, other studies have reported that exposure to nitrous oxide resulted in decreased dopamine release by neurons in the striatum (Balon et al. 2002 Turle et al. 1998). 

Piccini, P, Brooks, DJ, Bjorklund, A, Grmn, RN, Grasby, PM, Ornella, R, Brundin, P, Hagell, P, Rehnerona, S, Widner, H and Lindvall, O (1999) Dopamine release from nigral transplants visualised in vivo in a Parkinsonian patient. Nat. Neurosci. 2 1137-1140. 

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. 

Johnson, M.P. Hoffman, A.J. and Nichols, DE. Effects of the enantiomers of MDA, MDMA and related analogs on [ H] serotonin and [ H] dopamine release from superfused rat brain sliees. Eur J Pharmacol 132 269-276, 1986. 

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. 

The affinity (Kj values) observed for [ H]MDA and [ HJMDMA binding were similar to the effective doses (i.e., ED50 or K] values) of MDA and MDMA reported for various pre- and postsynaptic monoamine markers, such as serotonin and dopamine release (Johnson et al. 1986), monoamine transport (Steele et al. 1987), and multiple brain, ligand binding sites (Battaglia et al. 1988). 

Reid, M. Herrera-Marschitz, M. Hokfelt, T. Terenius, L. and Ungerstedt, U. Differential modulation of striatal dopamine release by intranigral injection of gamma-aminobutyric acid (GABA), dynorphin A and substance P. Eur J Pharmacol 147 411-420, 1988. 

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