Dopamine Clonidine

Opioids, benzodiazepines, barbiturates, corticosteroids, dopamine agonists (e.g., amantadine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole), H2-receptor antagonists, anticholinergics (e.g., diphenhydramine, trihexylphenidyl), P-adrenergic blockers, clonidine, methyldopa, carbamazepine, phenytoin, baclofen, cyclobenzaprine, lithium, antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors), and interleukin-2... 

A host of medications have been nsed to treat TD including medications that block norepinephrine activity (clonidine and propranolol), dopamine-activating medications (bromocriptine), benzodiazepines, acetylcholine-activating medications, calcium channel blockers, and monoamine oxidase inhibitors. In addition, vitamin E supplementation and atypical antipsychotics including clozapine have been used to treat TD. 

Methyldopa (dopa = dihydroxy-phenylalanine), as an amino acid, is transported across the blood-brain barrier, decarboxylated in the brain to a-methyldopamine, and then hydroxylat-ed to a-methyl-NE The decarboxylation of methyldopa competes for a portion of the available enzymatic activity, so that the rate of conversion of L-dopa to NE (via dopamine) is decreased. The false transmitter a-methyl-NE can be stored however, unlike the endogenous mediator, it has a higher affinity for a2- than for ai-receptors and therefore produces effects similar to those of clonidine. The same events take place in peripheral adrenergic neurons. 

Methyldopa is an false substrate for the dopamine-/ -hydroxylase resulting in a-methylnor-adrenaline. This metabolite is an a2-adrenoceptor agonist an induce, like clonidine, a centrally mediated reduction of sympathetic tonus. 

Catecholamines also appear to modulate this cortex (reviewed in Coull et ak, 2001). Studies in both monkeys and humans have found that clonidine, but not guanfacine, can impair alerting abilities in the Posner task, likely because of reducing NE release. Dopamine receptor blockade also impairs performance. 

Grenhoff, J. and Svensson, T.H. (1989) Clonidine modulates dopamine cell firing in rat ventral tegmental area. Eur J Pharmacol 165 11-18. 

Cervo L, Rossi C, Samanin R The role of serotonin and dopamine in brain in the antidepressant-like effect of clonidine in the forced swimming test. Neuropharmacology 31 331-335, 1992... 

Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants, particularly the older tricyclic antidepressants can inhibit norepinephrine and serotonin reuptake to different degrees. This may lead to orthostatic tachycardia as a side effect. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking 04 receptors, but the mechanism remains unclear. 

If these measures fail, clonidine, fluphenazine, clonazepam, or carbamazepine should be tried. The pharmacologic properties of these drugs are discussed elsewhere in this book. Clonidine reduces motor or vocal tics in about 50% of children so treated. It may act by reducing activity in noradrenergic neurons in the locus coeruleus. It is introduced at a dose of 2-3 mcg/kg/d, increasing after 2 weeks to 4 mcg/kg/d and then, if required, to 5 mcg/kg/d. It may cause an initial transient fall in blood pressure. The most common adverse effect is sedation other adverse effects include reduced or excessive salivation and diarrhea. Phenothiazines such as fluphenazine sometimes help the tics, as do dopamine... 

Dopamine Microdialysis in the Nucleus Accumbens During Acute and Chronic Morphine, Naloxone-Precipitated Withdrawal and Clonidine Treatment." Brain Research 566 348-50. 

In this chapter, we have looked at two topics in cognitive enhancement attention and memory. We have first reviewed the role of dopamine and norepinephrine/ noradrenaline in the neuropharmacology of attention, and then the syndrome of attention deficit disorder as a common problem associated with a disorder of attention. We then discussed the use of stimulants for improving attention, primarily in attention deficit disorder, and reviewed the pharmacological mechanisms of action of methylphenidate, d and 1 amphetamine, pemoline, and secondary therapies such as clonidine and guanfacine. 

When making a choice of test situations, some investigators are biased by the effects of the tested substance in adulthood. Based on this knowledge, it is possible to formulate and test a specific hypothesis about aspects of brain and behavioral development that are expected to be affected. For instance, haloperidol can be expected to alter development of the dopamine system and motor activity, whereas clonidine can be expected to affect development of the catecholamine system and REM sleep. 

Pothos E, Rada P, Mark GP, Hoebel BG (1991) Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone-precipitated withdrawal and clonidine treatment. Brain Res 566 348-350. 

Amineptine increases the release and reduces the reuptake of dopamine, and it is therefore not surprising that an amphetamine-like drug dependence has been reported (3-5). A withdrawal syndrome occurs and can be improved by clonidine (SEDA-16, 8). 

Another dmg closely similar to DOPA but used for different applications is a-methyl-DOPA (Figure 10.19a). This molecule acts in the peripheral autonomous system but also enters the brain, by the same route as DOPA. It is converted by DOPA decarboxylase to the false transmitter a-methyl-dopamine. Like dopamine or norepinephrine, a-methyl-dopamine is accumulated inside the transmitter vesicles, and released in response to action potentials. While it has no strong effect on postsynaptic a,-receptors, it does activate 0C2-receptors. It will therefore inhibit the further release of transmitter without stimulating the postsynaptic neuron. The effect of methyl-DOPA is augmented by the fact that it is fairly resistant to monoamine oxidase. Its mode of action resembles that of clonidine (which accomplishes the same in a less roundabout manner). 

Whenever symptoms are severe enough to impair the child s ability to function, drug therapy should be initiated. Haloperi-dol and pimozide (dopamine [D2] receptor antagonists) are approved by the FDA and are highly effective with a relatively rapid onset. Clonidine is significantly less effective but has no risk of extrapyra-midal side effects. Psychotherapy and behavioral treatment are useful adjuncts. " ... 

Solutions of drugs were prepared in 145 mM aqueous NaCl, from which a dose series was prepared. dl-Octopamine, dl-synephrine, dopamine, tolazoline, clonidine, yohimbine, cyproheptadine, gramine, chlorpromazine, promethazine, propranolol, metoclopramide, and 3-isobutyl-l-methylxanthine were obtained from Sigma Chemical Co. naphazoline from Aldrich Chemical Co. chlordimeform and phentolamine from Ciba Geigy mianserin from Research Biochemicals Inc. and lofexidine, XAMI, and tramazoline were gifts from Dr. R. Hollingworth, Purdue Univ. 

Our agonist studies were designed to further document the effect of lower doses of OA on male sensitivity to pheromone (as shown in Figure 1), and to provide a pharmacological profile that could be compared with data from other published studies on OA receptors (12-14). The compounds included 1) the phenylethylamines synephrine and dopamine, 2) the formamidine chlordimeform, and 3) the substituted imidazolines naphazoline (2-[ 1-naphthylmethyl] imidazoline ), lofexidine (2-[ l-(2,6-dichlorophenoxy)ethyl]-2-imidazoline), XAMI (2,3-xylylaminomethyl-2-imidazoline), clonidine (2-(2,6-dichloro-anilino)-2-imidazoline), tolazoline (2-benzyl-2-imidazoline), and tramazoline (2-[5,6,7,8-tetrahydro-1-naphthyl]amino-2-imidazoline) ... 

The agonists were found to vary considerably in their potency, with peak response in chlordimeform and XAMI treated insects occurring at 1 pg/g vs 100 pg/g for OA (Figure 2). The dose-response curves also show that males treated with chlordimeform, XAMI, lofexidine naphazoline, and synephrine exhibited levels of response to 0.01 mg pheromone that were equal to those of OA-treated (100 pg/g) males, but that clonidine, tolazoline, and tramazoline were much less effective, and that dopamine was without effect on male sensitivity. 

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