Dopamine deficiency

Genetic disruption of dopamine synthesis in mice lacking TH shows that dopamine is not essential for development. However, dopamine deficient mice do not survive long after weaning unless treated with l-DOPA. These mice display severe aphagia and adipsia and loss of motor function. While these mice have a major reduction in dopamine levels some residual dopamine can be detected that is generated through the action of tyrosinases. 

Chen, L. and Zhuang, X. Transgenic mouse models of dopamine deficiency. Ann. Neurol. 54(Suppl. 6) S91-S102,2003. 

These findings suggest that dopamine deficiencies arising from MB-COMT promoter hypomethylation (i.e., increased expression) may influence promoter methylation and expression of RELN, DRD2, DRDl, and potentially other genes via coordinated epigenetic events that may aggravate disease symptoms (see Fig. 9.1). 

Parkinson s disease (shaking palsy) and its syndromal forms are caused by a degeneration of nigrostriatal dopamine neurons. The resulting striatal dopamine deficiency leads to overactivity of choUnergic intemeurons and imbalance of striopallidal output pathways, manifested by poverty of movement (akinesia), muscle stiffness (rigidity), tremor at rest, postural instability, and gait disturbance. 

As dopamine deficiency of the nigrostriatal tract, resulting in an overactivity of cholinergic interneurons, is considered to be the fundamental pathophysiological mechanism for Parkinson s disease two approaches for pharmacological intervention seem rational. 

Robertson, Matthew W., Catherine A. Leslie, and James P. Bennett. 1991. "Apparent Synaptic Dopamine Deficiency Induced by Withdrawal from Chronic Cocaine Treatment." Brain Research 538 337-39. 

The cause of RLS is still unknown, but likely involves a deficiency in the neurotransmitter dopamine. Scientists suspect a dopamine deficiency is to blame because the most widely prescribed medication for treating RLS is levadopa (also called L-dopa), which the body turns into dopamine. Other medications that seem to alleviate symptoms are opiate drugs such as codeine and oxycodone, but these must only be administered occasionally since they are prone to cause addiction. Finally, some benzodiazepines (discussed in Chapter 6) also help the RLS sufferer get a better night s rest. 

PLMS occurs mostly in older people, with an estimated 35% or more of elderly people suffering from the disorder. It can also occur in younger people and seems to affect males and females equally. Occasionally, PLMS has been associated with other medical problems such as kidney disease or diabetes. The cause of PLMS is unknown, but like RLS it may involve a dopamine deficiency. PLMS is usually treated with the same types of medications as for RLS (see above). 

In this formulation of negative and cognitive symptoms of schizophrenia as a dopamine deficiency state of mesocortical dopamine neurons, the deficiency could... 

FIGURE 10—11. Several different causes of dopamine deficiency may result in negative and cognitive symptoms. In schizophrenia itself, there may be a primary dopamine (DA) deficiency or a DA deficiency secondary to blockade of postsynaptic D2 dopamine receptor by an antipsychotic drug. If serotonin is hyperactive, this may also cause a relative DA deficiency by inhibiting DA release. Either primary or secondary DA deficiency in this pathway may cause cognitive blunting, social isolation, indifference, apathy, and anhedonia. 

FIGURE 11—10. This figure shows what happens to acetylcholine activity when dopamine receptors are blocked. As dopamine normally suppresses acetylcholine activity, removal of dopamine inhibition causes an increase in acetylcholine activity. Thus, if dopamine receptors are blocked, acetylcholine becomes overly active. This is associated with the production of extrapyramidal symptoms (EPS). The pharmacological mechanism of EPS therefore seems to be a relative dopamine deficiency and an acetylcholine excess. 

FIGURE 11—27. The mesocortical dopamine pathway may mediate deficits in cognitive functioning and negative symptoms in schizophrenia because of a relative deficiency in dopamine, due either to a primary deficiency or to various secondary causes, such as serotonin excess. In either case, blockade of 5HT2A receptors with an atypical antipsychotic should lead to dopamine release, which could compensate for the dopamine deficiency and improve negative and cognitive symptoms. 

Drug Levodopa Mechanism of Action Resolves dopamine deficiency by being converted to dopamine after crossing blood-brain barrier. Special Comments Still the best drug for resolving parkinsonian symptoms long-term use limited by side effects and decreased efficacy. 

Anticholinergics (see Table 10-2) Inhibit excessive acetylcholine influence caused by dopamine deficiency. Use in Parkinson disease limited by frequent side effects. 

The etiology of progressive death of dopaminergic neurons in substantia nigra of Parkinson s disease brains remains unclear. Dopamine deficiency in Parkinson s disease is commonly treated with L-dopa and carbidopa, a periphera dopa decarboxylase inhibitor (Sinemet). Since its introduction, L-dopa has been shown to be effective in treating Parkinson s disease. However, high concentrations of L-dopa produce side effects such as psychosis, on-off effects, abnormal involuntary movements, and akinetic crisis. 

Levodopa (L-dopa) is a natural intermediate in the biosynthesis of catecholamines in the brain and peripheral adrenergic nerve terminals. In the biologic sequence of events it is converted to dopamine, which in turn serves as a substrate of the neurotransmitter norepinephrine. Levodopa is used successfully in the treatment of Parkinson s syndrome, a disease characterized by dopamine deficiency. When levodopa is administered to an individual with this syndrome, the symptoms of Parkinson s disease are ameliorated, presumably because the drug is converted to dopamine and thereby counteracts the deficiency. Individuals treated with levodopa, especially older men, have been observed to experience a sexual rejuvenation. This effect has led to the belief that levodopa stimulates sexual powers. Consequently, studies with younger men complaining of decreased erectile ability have shown that levodopa increases libido and the incidence of penile erections. Overall, however, these effects are short lived and do not reflect continued satisfactory sexual function and potency. Thus, levodopa is not a true aphrodisiac. The increased sexual activity experienced by parkinsonian patients treated with levodopa may reflect improved well-being and partial recovery of normal sexual functions that were impaired by Parkinson s disease. 

This book shows how Eastern physicians used belladonna alkaloid for Parkinson s disease but also provides evidence that belladonna alkaloid contains anticholinergic drugs, which counterbalance the dopamine deficiency syndrome seen in Parkinson s disease. 

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. 

In the normal state, the putamen receives afferents from the motor and somatosensory cortical areas and communicates with the GPi/SNr through a direct inhibitory pathway and though a multisynaptic (GPe, STN) indirect pathway. In PD, dopamine deficiency leads to increased inhibitory activity from the putamen onto the GPe and disinhibition of the STN. STN hyperactivity by virtue of its gluta-matergic action produces excessive excitation of the GPi/SNr neurons, which overinhibit the thalamocortical and brain stem motor centers. 

Parkinson s disease Neurological disorder accompanied by dopamine deficiency. Patients exhibit extrapyramidal symptoms. 

We know that dopamine deficiency is the cause of parkinsonism and that many RBD patients will develop this condition. Beyond that, it is not clear what is going on, although it is clear that prolonged use of a group of antidepressants known as the selective serotonin reuptake inhibitors (SSRIs) can lead to RBD. This suggests that serotonin, which is known to be a potent inhibitor of REM, may interact with brain dopamine systems and upset the balance between inhibition and excitation of the motor systems in sleep. 

Burns RS, LeWitt PA, Ebert MH, Pakkenberg H, Kopin IJ (1985) The clinical syndrome of striatal dopamine deficiency. Parkinsonism induced by l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP). New Engl J Med 372 1418-1421. 

Jinnah HA, Wojcik BE, Hunt M, Narang N, Lee KY, Goldstein M, Wamsley JK, Langlais PJ, Friedmann T (1994) Dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease. J Neurosci 74 1164-1175. 

Kim DS, Szezypka MS, Palmiter RD (2000a) Dopamine-deficient mice are hypersensitive to dopamine receptor agonists. J Neurosci 20 4405-4413. 

Schmidt MJ, Sawyer BD, Perry KW, Fuller RW, Foreman MM, Ghetti B (1982) Dopamine deficiency in the weaver mutant mouse. J Neurosci 2 376-380. 

Stotz EH, Triarhou LC, Ghetti B, Simon JR (1993) Serotonin content is elevated in the dopamine deficient striatum of the weaver mutant mouse. Brain Res 606 261-212. 

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