Dopamine excess

Circunstantial evidence directly implicating dopamine in the pathogenesis of duodenal ulcer in man is the unusual incidence of peptic ulcer disease in dopamine-deficient disorders. From purely descriptive clinical and epidemiologic studies we know that patients with Parkinson s disease, before the introduction of dopamine therapy, had an excess of ulcer disease (72). One report even comments on the curiosity that after initiation of L-DOPA administration the ulcer symptoms have virtually disappeared (72 ). On the other hand, less clearly, schizophrenia which is associated with dopamine excess and/or receptor hyperactivity is accompanied by virtual lack, or decreased prevalence, of peptic ulcer (73-76). Schizophrenia associated with ulcer disease has been viewed as a reportable curiosity in medical literature (75). At present, possibly because of the widespread therapeutic application of neuroleptics, the lack of peptic ulcer disease in schizophrenics is less striking than in the past. On the other hand, we recently observed in our autopsy series perforated duodenal ulcers in two schizophrenic patients who had been on large doses of haloperidol therapy (Szabo, unpublished observation). Thus, even in man, dopamine may indeed be implicated in the pathogenesis of duodenal ulcer disease. 

There have been several theories behind the brain circuits involved in the development of deficit symptoms. One, published in 1987 by Daniel Weinberger, attempted to explain the seemingly paradoxical concurrent hyperdopaminergic state of psychosis and hypodopaminergic state of negative symptoms. He postulated that an early developmental insult to mesocortical dopamine afferents would simultaneously deprive the dorsolateral prefrontal cortex of dopamine and lead to dysregulation/dopamine excess in mesolimbic projections. This is supported by what Pycock et al. (1980) had found in rats a lesion of the dopaminergic afferents in the prefrontal cortex led to subcortical dopamine overactivity. 

Tourette s syndrome (TS) is a hyperkinetic movement disorder with symptoms of sudden, rapid and brief, recurrent, stereotyped motor movements or sounds (tics) and can range from mild to severe. TS is commonly treated with dopamine antagonists such as haloperidol, which may be effective but has significant adverse side effects and is ineffective in up to 30% of cases. While the etiology is not known it is proposed that, unlike PD, TS represents a disorder of excess dopamine transmission in the striatum (Shapiro et al., 1989 Wolf et al., 1996), either through dopamine excess or receptor hypersensitivity. 

The actions of neurotransmitters are mediated mostly through their interactions with receptors located either at presynaptic or postsynaptic sites. These receptors function in a coordinated fashion to elicit excitation (depolarization) or inhibition (hyperpolarization) within and between neuronal subsystems. A basic inadequacy in this interplay is believed to lead to pathologic states such as Parkinson s disease (dopamine deficiency), Huntington s disease (dopamine excess), endogenous depression (catecholamine deficiency), or mania (catecholamine excess). 

IF YOU SUFFER FROM A NOREPINEPHRINE/ DOPAMINE EXCESS EATING TO LOWER YOURNOREPI/DOPA LEVELS... 

Interestingly, the instability of vata energies in Ayurveda corresponds with the Western scientific notion that a serotonin deficiency is the most common problem associated with depression. Just as vata energies can become unbalanced even in pitta and kapha types, so can serotonin become deficient even in people with other types of brain chemical imbalances, such as norepinephrine/dopamine excess or deficiency. So when people have either vata imbalances or serotonin deficiencies, I usually try to treat those first, no matter what other problems they re experiencing. 

Pitta imbalance, in my view, corresponds remarkably well with the Western category of norepinephrine/dopamine excess, or agitated de-... 

Entacapone and tolcapone increase the AUC of levodopa given with benserazide or carbidopa. This may require a reduction in the levodopa dose to avoid symptoms of dopamine excess when first starting the COMT inhibitor. Tolcapone increases the levels of benserazide, but neither entacapone nor tolcapone alters carbidopa pharmacokinetics. 

The COMT inhibitors should not be administered with the monoamine oxidase (MAO) inhibitors (see Chap. 31) because there is an increased risk of toxicity. If the COMT inhibitors are administered with norepinephrine, dopamine, dobutamine, methyldopa, or epinephrine, there is a risk of increased heart rate, arrhythmias, and excessive blood pressure changes. 

Silylation-amination of 4(lH)-quinohnone 255 with a twofold excess of dopamine hydrochloride 256 as amine and an acidic catalyst affords, on heating with excess HMDS 2 for 21 h at 145 °C and subsequent transsilylation in excess boihng methanol, 75% of the crystalline hydrate of 257 (Scheme 4.28). The silylation-amination of 2-thio-6-azauracil 258 with homoveratrylamine 259, HMDS 2, and SnCLj as catalyst for 48 h at 145 °C furnishes 63% of the diamine 260, and MesSiOSiMes 7 and Me3SiSH or Me3SiSSiMe3 601 as leaving groups. 

The behavioral effects of PCP have been associated with excessive release of a wide variety of neurotransmitters in particular, a massive dopamine release may underlie some of the most prominent symptoms of PCP intoxication (Rappolt et al. 1980). Our results readily explain the genesis of such an effect, because activation of presynaptic K channels is one of the primary factors that influences Ca entry into nerve terminals and Ca-dependent transmitter release by limiting action-potential duration and regulating excitabi1ity. 

Levodopa, a dopamine precursor, is the most effective agent for PD. Patients experience a 40% to 50% improvement in motor function. It is absorbed in the small intestine and peaks in the plasma in 30 to 120 minutes. A stomach with excess acid, food, or anticholinergic medications will delay gastric emptying time and decrease the amount of levodopa absorbed. Antacids decrease stomach acidity and improve levodopa absorption. Levodopa requires active transport by a large, neutral amino acid transporter protein from the small intestine into the plasma and from the plasma across the blood-brain barrier into the brain (Fig. 29-2). Levodopa competes with other amino acids, such as those contained in food, for this transport mechanism. Thus, in advanced disease, adjusting the timing of protein-rich meals in relationship to levodopa doses may be helpful. Levodopa also binds to iron supplements and administration of these should be spaced by at least 2 hours from the levodopa dose.1,8,16,25... 

FIGURE 38-1. Primary assessment and initial treatment for complaint of excessive daytime sleepiness. RLS, restless-legs syndrome NPSG, nocturnal polysomnography OSA, obstructive sleep apnea DA, dopamine agonist MSLT, multiple sleep latency test BZDRA, benzodiazepine receptor agonist SNRI, serotonin and norepinephrine reuptake inhibitor TCA, tricyclic antidepressant CPAP, continuous positive airway pressure. 

Additional studies in rats in vivo and in rat tissues or cells in vitro have focused on potential relationships between the effects of lead on neurotransmitter systems and neurobehavioral function. Lead exposure decreased dopamine binding sites, suggesting excess dopamine availability. The decreased dopamine binding was localized in the nucleus accumbens (mesolimbic dopamine system) but not the dorsal... 

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