Editorial
Extrapyramidal System: Neuropharmacology & Clinical Relevance
  The 'neuronal' outflow tract from the brain to skeletal muscles, outside of the Pyramidal tracts constitute 'extrapyramidal system'. The major components of the extrapyramidal system are: lentiform nucleus (caudate & putamen), the globus pallidus, substantia nigra and the subthalamic necleus. The major anatomical focus for the Psychiatrists is the pathways shuttling between midbrain and the basal ganglia. The introduction of the 'magic bullet', chlor promazine, to the Psychiatric armamentarium fueled interest and further progress in Psychopharmacology. Along with this, the side effects produced by the drug generated new scientific enthusiasm in the study of neuropharmacology of extrapyramidal system. The biochemical organisation of the basal ganglia is rather well studied, But the functional significance of basal ganglia os not much understood (Marsden, 1982). A capsule review of the anatomy and pharmacology of extrapyramidal system may fecilitate better awareness of some of the clinical situations faced by Psychiatrists.
Neuroanatomical and neurochemical aspects
Lantiform Nucleus
Substantia Nogra
Afferent Transmotter Released Efferent Transmotter Released
Striatonigral GABA, Dynorphin, Substance P Nigrostriatal Dopamine
Pallidonigral GABA To Tegmentum GABA
From Raphe Nucleus Serotonin To superior colliculus GABA
From tegmentum Ach To thalamus GABA
From motor/prefrontal cortex GABA, Glutamate Aspartate To midbrain & Pontine central gray Not known
From nucleus accumbance GABA TO amygdala Dopamine
From anterior hypothalamus Oxytocin? Vasoprassin To olfactory bulb Dopamine
From subthalamus Not known           
From amygdala Not known             
From lateral habenula Not known            
Globus Pallidus
Afferent Transmotter Released Efferent Transmotter Released
Striatopallidal Enkiphalins Substance P GABA, Dynorphin To subthalamic nucleus GABA
From nucleus accumbens GABA To caudate nucleus GABA
From subthalamic nucleus Not known To substantia nigra GABA
From Tegmentum Not known To entopeduncular nucleus GABA
              To raphe nucleus, reticular & Medial dorsal nuclei of thalamus Not known

Clinical Relevance
Parkinson's Syndrome
Substantia Nogra
Afferent Transmotter Released Efferent Transmotter Released
Striatonigral GABA, Dynorphin, Substance P Nigrostriatal Dopamine
Pallidonigral GABA To Tegmentum GABA
From Raphe Nucleus Serotonin To superior colliculus GABA
From tegmentum Ach To thalamus GABA
From motor/prefrontal cortex GABA, Glutamate Aspartate To midbrain & Pontine central gray Not known
From nucleus accumbance GABA TO amygdala Dopamine
From anterior hypothalamus Oxytocin? Vasoprassin To olfactory bulb Dopamine
From subthalamus Not known             
From amygdala Not known            
From lateral habenula Not known           
Globus Pallidus
Afferent Transmotter Released Efferent Transmotter Released
Striatopallidal Enkiphalins Substance P GABA, Dynorphin To subthalamic nucleus GABA
From nucleus accumbens GABA To caudate nucleus GABA
From subthalamic nucleus Not known To substantia nigra GABA
From Tegmentum Not known To entopeduncular nucleus GABA
             To raphe nucleus, reticular & Medial dorsal nuclei of thalamus Not known
Clinical Relevance
Parkinson's Syndrome
Afferent Transmotter Released Efferent Transmotter Released
Thalamostriatal Pathway Nor Known striatonigral Pathway GABA,SubstanceP, Dynorphin
Corticostriatal Pathway Glutamate Cholecystokinin StriatoPallidal Pathway GABA,Enkephalins, Dynorphin, Substance P
Nigrostriatal Pathway Dopamone Cholecystokinin Pathways to Subthalmic Nuecleus Not Known
Pathway from Locus ceruleus Norepinephrine Pathway to entopeduncular nucleus Not Known
Pathway from mammillarybody & reticular formation Histamin                  
Pathway from dorsal raphe Serotonin                 
Pallidal Striatal Pathway GABA                 
Amygdalostriatal Pathway Cholecystokinin? Somatostatin      
Substantia Nogra
Afferent Transmotter Released Efferent Transmotter Released
Striatonigral GABA, Dynorphin, Substance P Nigrostriatal Dopamine
Pallidonigral GABA To Tegmentum GABA
From Raphe Nucleus Serotonin To superior colliculus GABA
From tegmentum Ach To thalamus GABA
From motor/prefrontal cortex GABA, Glutamate Aspartate To midbrain & Pontine central gray Not known
From nucleus accumbance GABA TO amygdala Dopamine
From anterior hypothalamus Oxytocin? Vasoprassin To olfactory bulb Dopamine
From subthalamus Not known      
From amygdala Not known      
From lateral habenula Not known      
Globus Pallidus
Afferent Transmotter Released Efferent Transmotter Released
Striatopallidal Enkiphalins Substance P GABA, Dynorphin To subthalamic nucleus GABA
From nucleus accumbens GABA To caudate nucleus GABA
From subthalamic nucleus Not known To substantia nigra GABA
From Tegmentum Not known To entopeduncular nucleus GABA
        To raphe nucleus, reticular & Medial dorsal nuclei of thalamus Not known

Clinical Relevance
Parkinson's Syndrome
* Idopathic Parkinson's Disease is due to degeneration of cell bodies in the zona compact of the substantia nigra leading to degeneration of the dopaminergic nigrostriatal terminals. There is disproportionate actions of dopamine and acetyl choline, with a relative cholinergic preponderance (Borison & Diamond, 1987).
* Drug induced Parkinsonism is the result of postsynpatic dopamine receptor blockade leading to chemical denervaton.
* The mainstay of drug therapy in Parkinson's disease is by replenishing the depleted striatal dopamin transmission. This is done by the use of L-dopa/ L-dopa-Carbidopa combination. The other drugs employed are bromocriptine (direct dopamine agonist), Amantadine (Indirect dopamine agonist) and MAO Type B Inhibitor, deprenyl(Decreases dopamine catabolism).
* The best prodopaminergic agent for the treatment of drug induced Parkinsonism is amantadine, which does not adversely affect memory function and wich has least cardiovascular or autonomic side effects. Also, it lowers prolactine.
* anticholinergic agents are used to treat early features of Parkinsonism. These agents are reported to decrease cognition. Also, their use is limited due to cardiovascular and autonomic side effects. Some of these drugs have recreational abuse potential.
Dystonias
* There is poor clinical localization of the  brain structures involved in the underlying pathophysiology of dystonia. It is possible that multiple brain systems including extrapyramidal system are involved.
* Hypodopaminergic state may be the key factor in the genesis of drug induced dystonias. So a prodopaminergic drug may be prophylactically better than an anticholinergic drug.
* Some of the dystoias (Dystonia musculorum deformans and Meige's syndrome) respond well to anticholinergic agents.
* Acute drug induced dystonias respond better to anticholinergic drugs.
* Patients at greater risk for developing neuroleptic induced acute dystonia are males, the young and those taking high potency nueroleptics(Gelenberg, 1987).
Huntington's Chorea
* Huntington's Chorea is a functional hypo GABA-ergic, hypocholinergic, hyperdopaminergic state resulting from the degeneration of striatonigral GABA releasing fibers and cholinergic striatal interneurons.
* Dopamine blockade using haloperidol may provide a palliative treatment.
Tardive Dyskinesia
* A relative hypoGABA-ergic state may be the underlying mechanism, although hyperdopaminergic/hypocholinergic imbalance has been proposed.
* Benzodiazepines, drugs stimulating GABA receptors (THIP, muscimol) Propranalol and clonidine may be tried.
* Clozapine is least likely to produce tardive dyskinesia.
Akathisia
* Subjective feeling of restlessness, an extrapyramidal side effect of neuroleptic therapy may be due to interplay of  multiple brain systems.
* Anticholinergics, prodopaminergic drugs, benzodiazepines and clonidine have been successfully tried in Akathisia.
* The most promising results are with propranalol either alone or in combination with benzodiazepines.
Tourette's Disorder
* Possibility of a hyperdopaminergic - hypocholinergic tone in this disorder may be the basis for the use of haloperidol.
* Clonidine is probably the best agent of first choice in treating this disorder. (Norepinephrine system may have a role).
  The future research may unravel new insights into the pathophysiology of movement disorders and may decolop specific treatment with medications having least side effect potential.

DR.E. MOHANDAS,MD

Elite Mission Hospital, Thrissur.

References
1 Borison RL; Diamond BI (1987)- Neuropharmacology of the extrapyramidal system. J Clin Psychiatry 48 (9,Suppl): 7-12.
2 Gelenberg AJ (1987) Treating extrapyramidal reactions: some current issues. J Clin Psychiatry 48 (9,Suppl): 24-27
3 Marsden CD (1992) Neurotransmitters and CNS disease Basal Ganglia disease. The Lancet Nov.20,1141-1147.

DR.E. MOHANDAS,MD