Dopamine Transmission

ADHD because cognitive functions known to be affected in this disorder, namely working memory and inhibitory control, are sensitive to manipulations of D1 receptor-mediated dopamine transmission [1]. Thus, the tonic component might be more critical for the behavioral functions of the FC. 

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. 

A simple decrease in striatal dopamine transmission produced by even low clinical doses of the dtugs according to current data seems an untenable... 

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. 

Fiorino, DF, Coury, A, Fibiger, HC and Phillips, AG (1993) Electrical stimulation of reward sites in the ventral tegmentum area increases dopamine transmission in the nucleus acumbers of the rat. Behav. Brain Res. 55 131-141. 

Floresco S. B., West A. R., Ash B Moore H., Grace A. A. (2003). Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nat. Neurosci. 6(9), 968-73. 

Jaber M., Jones S., Giros B., Caron M. G. (1997). The dopamine transporter a crucial component regulating dopamine transmission. Mov. Disord. 12(5), 629-33. 

Laviolette, S.R., van der Kooy, D. Blockade of mesolimbic dopamine transmission dramatically increases sensitivity to the rewarding effects of nicotine in the ventral tegmental area. Mol. Psychiatry. 8 50, 2003. 

Neurotensin NT, (NTS1) Human cDNA Anorexia, thermoregulation, inflammation, pain, Parkinson s disease, schizophrenia, diabetes, Alzheimer s disease Modulation of dopamine transmission, inhibition of gastric acid secretion, modulation of gastric motility, hypothermia... 

Neuroleptic malignant syndrome is an acute iatrogenic condition caused by neuroleptics, characterized by tremor, catatonia, fluctuating consciousness, hyperthermia, and cardiovascular instability. It is relatively uncommon, occuring in 1-1.5% of patients but is fatal in 11-38%, most often due to cardiovascular collapse (Jahan et al. 1992). The pathogenesis of neuroleptic malignant syndrome is poorly understood, but it is believed to result from altered dopamine and serotonin transmission in the hypothalamus, spinal cord, and striatum. Treatment includes discontinuation of neuroleptics and administration of drugs that increase dopamine transmission bromocriptine or L-dopa (Jahan etal. 1992 Baldessarini 1996). 

Talhout R, Opperhuizen A, van Amsterdam JG (2007) Role of acetaldehyde in tobacco smoke addiction, Eur Neuropsychopharmacol 17 627-636 Tanda G, Pontieii FE, Di Chiara G (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mul opioid receptor mechanism. Science 276 2048-2050 Taylor JR, Robbins TW (1984) Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens. Psychopharmacology 84 405 12... 

Marks Ml, Stitzel lA, et al (1985) Time course study of the effects of chronic nicotine infusion on drug response and brain receptors. 1 Pharmacol Exp Ther 235(3) 619-628 Marshall DL, Redfem PH, et al (1997) Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis comparison of naive and chronic nicotine-treated rats. 1 Neurochem 68(4) 1511-1519 Martinez D, Gil R, et al (2005) Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry 58(10) 779-786 McClernon El, Kozink RV, Rose IE (2007) Individual differences in nicotine dependence, withdrawal symptoms, and sex predict transient fMRl-BOLD responses to smoking cues. Neuropsychopharmacology 33(9) 2148-2147... 

CS291 Rodriguez De Fonseca, F., M. A. Gorriti, A. Bilbao et al. Role of the endogenous cannabinoid system as a modulator of dopamine transmission implications for Parkinson s disease and schizophrenia. Neurotox Res 2001 3(1) 23-35. 

Stimulant), act directly on dopamine transmission. Both cocaine and amphetamine block reuptake of dopamine, which means that more dopamine is available to activate postsynaptic receptors. Due to the links between excessive dopamine and schizophrenia, it comes as no surprise that the use of cocaine, amphetamine, and similar drugs such as crack (a form of cocaine) often lead to symptoms strongly resembling schizophrenia. 

They also cause blockade of postsynap-tic monoaminergic (including 5-HT, noradrenaline and dopamine) transmission in the brain resulting in decrease in central sympathetic activity. 

The antidepressant effect of agents that enhance dopamine transmission... 

Acquas, Elio, and Gaetano Di Chiara. 1992. "Depression of Mesolimbic Dopamine Transmission and Sensitization to Morphine During Opiate Abstinence." Journal of Neurochemistry 58 1620-25. 

Richardson, Nicole R., and Alain Gratton. 1996. "Behavior-Relevant Changes in Nucleus Accumbens Dopamine Transmission Elicited by Food Reinforcement An Electrochemical Study in the Rat." 1996. Journal of Neuroscience 16 8160-69. 

As with Thorazine, this discovery was both serendipitous and perspicacious. And, as with Thorazine, LSD s mechanism of action turned out to be related to the neuromodulators. In this case it was serotonin that was blocked, but dopamine transmission was also affected. The prominent effect on dopamine was activation. Recent work on serotonin-dopamine interaction suggests that serotonin may inhibit dopamine function such that a decrease in serotonin efficacy leads indirectly to dopamine enhancement. This combination of serotonin blockade and dopaminergic enhancement is interesting because it mimics the chemistry of REM sleep in which normal dreaming occurs. 

By 1980, the time that Hofmann wrote up his experiences, the role of the neuromodulators serotonin and dopamine in controlling conscious states was well established. Hofmann knew from the work of Gaddum and others that LSD blocked serotonin and enhanced dopamine transmission in the brains of animals, yet Hofmann stopped short of speculating about the possible brain mechanisms of his experience that he could have derived from that knowledge. 

Kalivas, P.W. and Stewart, J. Dopamine transmission in drug- and stress-induced behavioral sensitization, Brain Res. Rev. 1991, 16, 223-244. 

FIGURE 8-1 Effects of antipsychotic drugs on dopamine synapses. Antipsychotics act as postsynaptic receptor antagonists to block the effects of overactive dopamine transmission. 

---