Dopamine release stimulators

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... 

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. 

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. 

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.)... 

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. 

Benkirane, S. Arbilla, S. and hanger, S.Z. A functional response to D1 dopamine receptor stimulation in the central nervous system Inhibition of the release of [ H]-serotonin from the rat substantia nigra. Naunyn-Schmiedebergs Arch Pharmacol 335 502-507, 1987. 

Vickroy, T.W., and Johnson, K.M. In vivo administration of phencyclidine inhibits 3H-dopamine accumulation by rat brain striatal slices. Subst Alcohol Actions Misuse 1 351-354, 1980. Vickroy, T.W.,and Johnson, K.M. Similar dopamine-releasing effects of phencyclidine and nonamphetamine stimulants in striatal slices. J. Pharmacol Fxp Ther 223 669-674, 1982. 

Devoto P., Flore G., Saba P Fa M., Gessa G. (2005). Stimulation of the locus coeruleus elicits noradrenaline and dopamine release in the medial prefrontal and parietal cortex. J. Neurochem. 92, 368-74. 

Di Chiara, G. and Imperato, A., Ethanol preferentially stimulates dopamine release in the nucleus accumbens of freely moving rats, Pur. J. Pharmacol., 115, 131, 1985. 

Weiss, F., Lorang, M.T., Bloom, F.E., and Koob, G.F., Oral alcohol self-administration stimulates dopamine release in the nucleus accumbens genetic and motivational determinants, J. Pharmacol. Exp. Ther., 267, 250, 1993. 

Kulak, J.M., Nguyen, T.A., Olivera, B.M., McIntosh, J.M. alpha-Conotoxin MB blocks nicotine-stimulated dopamine release in rat striatal synaptosomes. J. Neurosci. 17 5263, 1997. 

Grady, S.R., Marks, M.J., Collins, A.C. Desensitization of nicotine-stimulated [3H]dopamine release from mouse striatal synaptosomes. J. Neurochem. 62 1390, 1994. 

Grady, S.R., Meinerz, N.M., Cao, J. et al. Nicotinic agonists stimulate acetylcholine release from mouse interpeduncular nucleus a function mediated by a different nAChR than dopamine release from striatum. J. Neurochem. 76 258, 2001. 

Fiorino DF, Coury A, Fibiger HC and Phillips AG (1993). Electrical stimulation of reward sites in the ventral tegmental area increases dopamine release in the nucleus accumbens of the rat. Behavioral Brain Research, 55, 131-141. 

Drugs stimulate receptors on the cell bodies of dopaminergic neurons causing dopamine release and stimulating postsynaptic dopamine receptors in the nucleus accumbens, supposedly resulting in the perception of pleasure [1]. Other hypotheses suggest that these mesolimbic dopaminergic pathways are necessary for the... 

If these changes are also present in central dopaminergic reward pathways, it may be that the allele is linked to impaired perception of reward. It has been suggested that an inherited dopamine deficit could be overcome by nicotine, which stimulates dopamine release thereby restoring dopamine function to normal levels [17]. In this way the polymorphism could confer susceptibility to tobacco use. 

The reinforcing effects of opiate drugs involve a number of neuronal pathways [21]. In the VTA, opiates stimulate p-opioid receptors on GABA neurons that synapse on dopamine neurons. This inhibits the GABA neurons, leading to disinhibition of the dopamine neurons and enhanced dopamine release in the nucleus accumbens and other target areas (Fig. 56-3). Opiates also exert dopamine-independent effects in the nucleus accumbens by activating... 

Patel, J. et al., Biphasic inhibition of stimulated endogenous dopamine release by 7-Oh-Dpat in slices of rat nucleus-accumbens, Brit. J. Pharmacol., 115, 421, 1995. 

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