Extrapyramidal system

Basal ganglia are a group of subcortical nuclei which are essential for the coordination of movements (so-called extrapyramidal system). They include the caudate nucleus, putamen, globus pallidus, and lenti-form nucleus. Damage of the basal ganglia results in involuntary movements, as are observed in Parkinson s disease and Huntington s chorea. 

This chapter discusses the responses of these extrapyramidal neuropeptide systems to the amphetamine analogs methamphetamine (METH), methylene dioxyamphetamine (MDA), and methylenedioxymethamphetamine (MDMA). These dmgs were selected for this study because they represent somewhat diverse mechanisms of action. While all three agents are able to enhance extrapyramidal serotonergic activity (Schmidt et al. 1987). only METH has been characterized as a substantial stimulant of the DA system. The effects of MDA and MDMA on extrapyramidal DA systems have not been well elucidated. Thus, evaluating and comparing the responses of the SP, NT, and Dyn extrapyramidal systems to these dmgs will help to determine the nature of the DA responses to METH, MDA, and MDMA administrations. 

FIGURE 29-1. Anatomy of the extrapyramidal system. The extrapyramidal motor system controls muscle movement through a system of pathways and nerve tracts that connect the cerebral cortex, basal ganglia, thalamus, cerebellum, reticular formation, and spinal neurons. Patients with Parkinson s disease have a loss of dopamine neurons in the substantia nigra in the brain stem that leads to depletion of dopamine in the corpus striatum. The corpus striatum is made up of the caudate nucleus and the lentiform nuclei that are made up of the putamen and the globus pallidus. 

Patients who have received neuroleptics for long periods of time may develop a hyperkinetic disorder of the extrapyramidal system characterized by involuntary, purposeless movements affecting many parts of the body. This is known as tardive dyskinesia. Most commonly, these are manifested in a syndrome involving abnormal movements of the tongue, mouth and masticatory muscles. There are also choreoathetoid movements of the extremities. The mechanism by which these symptoms develop remains unknown. 

Drags that exhibit central anticholinergic properties are used in treating Parkinsonism. It is believed that they do not affect the synthesis, release, or hydrolysis of acetylcholine. Their medicinal efficacy is manifest by the rednction or removal of motor disturbances cansed by damage to the extrapyramidal system. They reduce rigidity, and to a somewhat lesser degree, akinesia, and they have little effect on tremors. 

Since the main clinical use for antisympathotonics is in the treatment of essential hypertension, such drugs will be discussed in Chapter 20 in more detail. The alkaloid reserpine from Rauwolfia serpentina was the first drug used clinically to reduce sympathetic tone. Reserpine reduce the ability of storage and release of various transmitters (adrenaline, noradrenaline, serotonine and dopamine) by an irreversible destruction of the axonal vesicle membranes. The duration of the reserpine effect is actually determined by the de novo synthesis of these structure. Beside various central side effects like sedation, depression, lassitude and nightmares the pattern of unwanted effects of reserpine is determined by the shift of the autonomic balance towards the parasympathetic branch myosis, congested nostrils, an altered saliva production, increased gastric acid production, bardycardia and diarrhea. As a consequence of the inhibition of central dopamine release, reserpine infrequently shows Parkinson-like disturbances of the extrapyramidal system. 

Lateral efferents of the MPOA innervate septum, amygdala, other hypothalamic regions, ventral tegmental area (VTA) of the midbrain, and midbrain central gray matter (Numan, 1986). Studies have shown that the MPOA-VTA-basal ganglia (BG) circuit is believed to be of importance in maternal behavior because the BG is a major component of the extrapyramidal system (EPS) (Numan, 1986). Perhaps MPOA neurons relevant to maternal behavior via the BG to EPS promote the somatic-motor processes underlying maternal responsiveness (Numan, 1986). 

Current research is directed toward discovering atypical antipsychotic compounds that are either more selective for the mesolimbic system (to reduce their effects on the extrapyramidal system) or have effects on central neurotransmitter receptors—such as those for acetylcholine and excitatory amino acids—that have been proposed as new targets for antipsychotic action. 

Effects, below. Newer antipsychotics such as olanzapine, quetiapine, and aripiprazole cause no or minimal increases of prolactin and reduced risks of extrapyramidal system dysfunction and tardive dyskinesia, reflecting their diminished D2 antagonism. 

Benzisoxazole Risperidone Broad efficacy little or no extrapyramidal system dysfunction at low doses Extrapyramidal system dysfunction and hypotension with higher doses... 

Thienobenzodiazepine Olanzapine Effective against negative as well as positive symptoms little or no extrapyramidal system dysfunction Weight gain dose-related lowering of seizure threshold... 

Figure 30-12 Diagram illustrating some of the major interconnections of the "extrapyramidal system" of the brain. Arrows indicate major direction of projections. The nigrostriatal (substantia nigra to striatum) and related neuronal pathways are indicated with dashed lines. After Nohack and Demarest,405 pp. 182 and 183.

One of the more serious problems occurring from the use of antipsychotics is the production of abnormal movement patterns.36,44 Many of these aberrant movements are similar to those seen in patients with lesions of the extrapyramidal system and are often referred to as extrapyramidal side effects. The basic reason that these motor problems occur is because dopamine is an important neurotransmitter in motor pathways, especially in the integration of motor function that takes place in the basal ganglia. Because antipsychotic drugs block CNS dopamine receptors, it makes sense that... 

Because of the rather nonspecific blockade of dopaminergic receptors, antipsychotics are associated with several adverse side effects. The most serious of these are abnormal movement patterns that resemble tardive dyskinesia, Parkinson disease, and other lesions associated with the extrapyramidal system. In some cases, these aberrant motor activi-... 

Laudanosine (6,7,3, 4 -tetramethoxy-1 -benzyltetrahydroisoquinoline) was isolated for the first time by Hesse (371) from opium. Intravenous administration of this substance to rabbits reduced the intraocular pressure (372). The whole effect manifested itself by motor restlessness, convulsions, disorders in coordination of movements, salivation, etc., which indicated an involvement of the extrapyramidal system and the mesencephalon. The effect produced by synthetic racemic laudanosine on rabbits was similar to that of the (+) form, but it was more toxic (373). The pharmacological properties of laudanosine have also been described (374). 

The most well known of the naturally occurring phenethylamine derivatives (Table I) are the transmitters of the sympathetic nervous system, epinephrine, norepinephrine, and dopamine. All these compounds are 3,4-dioxygenated in the aromatic nucleus and are collectively known as the catecholamines. Norepinephrine is the transmitter of most sympathetic postganglionic fibers, dopamine is the predominant transmitter of the mammalian extrapyramidal system and of several mesocortical and mesolimbic neuronal pathways, and epinephrine is the major hormone of the adrenal medulla (363). The literature that has accumulated on the action of these compounds in higher animals is enormous. Metanephrine and normetanephrine are known from animals as deactivated metabolites of epinephrine and norepinephrine that result from the action of the enzyme catechol O-methyltransferase (364). 

Overall the effects of atypical antipsychotics appear more difficult to characterise. Some are probably similar in nature to the older neuroleptics, but they tend to be used at lower doses that are less problematic in terms of effects on the extrapyramidal system. Some, such as olanzapine... 

Most of the neurological disorders associated with the neuroleptics fall into the category of extrapyramidal reactions or extrapyramidal symptoms, and are often designated EPS. The extrapyramidal system of the brain is an extensive, complex network that moderates and adjusts motor... 

Drugs that affect autonomic functions or the extrapyramidal system... 

Rinvik E, Grofova I, et al (1979) A study of the afferent connections of the subthalamic nucleus in the monkey and cat, using the HRP technique. In Poirier LJ, Sourkes TL and Bedard PJ (Eds), The Extrapyramidal System and Its Disorders. New York Plenum Press, pp 53-70. 

Nigrostriatal Substantia nigra (A9 area) Caudate nucleus Putamen Extrapyramidal system, movement Movement disorders... 

The action of the phenothiazines on the extrapyramidal system is now well recognized and a source of concern and at times alarm when individuals develop bizarre extrapyramidal motor effects. Fortunately, these effects soon wear off with cessation of the drug. 

---