Extrapyramidal nigrostriatal pathway

The nigrostriatal pathway participates in the production of smooth physical motion. It is not the brain area that works to initiate movement, which is in the cerebral cortex (pyramidal tract) it is the region that helps one to have fluid motion (extrapyramidal tract). Although many neurotransmitters are found in this latter system, two neurotransmitters—dopamine and acetylcholine—are predominantly involved in this pathway. The brain normally maintains a relatively stable ratio of dopamine and acetylcholine in the pathway. However, when something happens to upset this ratio, problems arise. 

As you might anticipate, dopamine receptor-blocking antipsychotics lower the functional dopamine/acetylcholine ratio in the nigrostriatal pathway. As a resnlt, the antipsychotics have the same effect in this pathway as idiopathic PD. This is how antipsychotics produce their so-called extrapyramidal side effects (EPS). EPS can take the form of parkinsonism (e.g., rigidity, tremor) or acnte dystonic reactions. 

Dopaminergic neuromodulatory system. The neurons that synthesize dopamine (structural formula in box) are found in the midbrain, from which they project to the limbic system (the mesolimbic pathway), the cerebral cortex (the mesocortical pathway), as well as to the extrapyramidal motor system (the nigrostriatal pathway). 

When D2 receptors are blocked in the nigrostriatal DA pathway, it produces disorders of movement that can appear very much like those in Parkinson s disease this is why these movements are sometimes called drug-induced parkinsonism (Fig. 11 —4). Since the nigrostriatal pathway is part of the extrapyramidal nervous system, these motor side effects associated with blocking of D2 receptors in this part of the brain are sometimes also called extrapyramidal symptoms, or EPS. 

Extrapyramidal effects Parkinsonian symptoms, akathisia (motor restlessness), and tardive dyskinesia (inappropriate postures of the neck, trunk, and limbs) occur with chronic treatment. Blocking of dopamine receptors in the nigrostriatal pathway probably causes these unwanted parkinsonian symptoms. Clozapine and risperidone exhibit a low incidence of these symptoms. 

Fig. 19.3 Sagittal brain section illustrating dopaminergic pathways. I. Mesolimbic pathway (overactive in psychotic illness according to the dopamine hypothesis of schizophrenia).VTA= ventrotegmental area. 2. Nigrostriatal pathway (involved in motor control, underactive in Parkinson s Disease and associated with extrapyramidal motor symptoms). 3. Tuberoinfundibular pathway (inhibits prolactin release from the hypothalamus).

Extrapyramidal symptoms. All classical antipsychotics are capable of producing these effects because they act by blocking dopamine receptors in the nigrostriatal pathway. The result is that some 75% of patients experience extrapyramidal symptoms which may appear shortly after starting the drug or increasing its dose (acute effects), or some time after a particular dose level has been established (tardive effects, see p. 387). 

Atypical antpipsychotics provoke fewer extra-pyramidal effects (less blockade of dopamine D -receptors in the nigrostriatal pathway). Nevertheless, extrapyramidal effects are seen, notably with high dose of risperidone (8-12 mg per day) and olanzapine (> 20 mg/day). 

The distribution of dopamine in the brain is very non-uniform. There is some in the limbic system, and a large proportion is found in the corpus striatum - a part of the extrapyramidal motor system which is concerned with the coordination of movement. Dopamine-containing nerves are found in three main pathways in the brain. The nigrostriatal pathway contains about 75% Of the dopamine in the brain, and the cell bodies lie in the substantia nigra and the nerves terminate in the corpus striatum. The second important pathway is the mesolimbic pathway, the cell bodies of which lie in the mid-brain and project to parts of the limbic system, particularly the nucleus accumbens. The third, the tubero-infundibular system, consists of short neurons that run from the arcuate nucleus of the hypothalamus to the median eminence and the pituitary gland, the secretions of which they regulate. 

In a few cases, marked extrapyramidal side-effects (akathisia, dystonia, and parkinsonism) have been reported with flupbenazine, perphenazine, sulpiride, and thiothixene when fluoxetine is added to the regimen. The mechanism is speculated to be the result of fluoxetine-induced further suppression of dopaminergic activity in the nigrostriatal pathways (serotonergic stimulation leads to decreased dopamine release), in addition to increases in their plasma concentration. Fluoxetine has been shown to increase haloperidol serum levels by about 20%, presumably via inhibition of cytochrome P450 enzymes. Fluoxetine can increase the risk of seizure induction when added to clozapine due to an increase in clozapine serum levels, or by additive effects. Concomitant treatment with fluoxetine and risperidone is associated with a mean 4-fold increase in the plasma concentration of risperidone. ... 

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.

FIGURE 10-12. The nigrostriatal dopamine pathway is part of the extrapyramidal nervous system and plays a key role in regulating movements. When dopamine is deficient, it can cause parkinsonism with tremor, rigidity, and akinesia/bradykinesia. When DA is in excess, it can cause hyperkinetic movements such as tics and dyskinesias. 

The four major dopamine pathways in the brain have been described. The me-solimbic dopamine system, which may mediate the positive symptoms of psychosis the mesocortical system, which may mediate the negative symptoms and cognitive symptoms of psychosis the nigrostriatal system, which mediates extrapyramidal... 

The interaction between dopamine and serotonin in the nigrostriatal dopamine pathway may explain why serotonin dopamine antagonists have propensity for reducing extrapyramidal reactions. True or False. 

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