Tuesday, July 28, 2015

Schizophrenia, Neuroleptic Drugs, and Extrapyradamidal Movement Disorders

Forest water cascades down a precipice with a deafening roar-a jest.

Author note: This paper was written in 1990 when I had a passion for biological psychology, in a manic burst of energy. T.M. was a fellow I worked with at the University of Utah. His end was very tragic, even though I was not there to see it. Apparently, he had a bad habit of eating scraps of food out of garbage cans. One fine day he died after vomiting blood at work. There were earlier reports, in the student newspaper, before his death, when T.M. after switching medications was seen racing around the building where he worked shouting death threats at people. The etiology of that malady would have been interesting study and might have contributed something to the literature, if anyone had cared enough to write a summation. Essentially, this whole paper was written precisely to understand what was happening to T.M., and to learn something about a topic that was of considerable interest to me at the time.

The history of neuroleptic drugs and schizophrenia has been a controversial and interesting one. For instance, it was once thought that dopamine was only a precursor to norepinephrine, and that dopamine did not exist independently as a neurotransmitter within the brain.  It was not until 1964 when Dahlstrom and Fuxe discovered a histological technique to distinguish dopamine from norepinephrine that dopaminergic pathways in the brain were considered seriously. Now with the biochemical isolation of dopamine beta hydroxylase, an enzyme that regulates the production norepinephrine from dopamine, and from electron microscopy, which has revealed both storage boutons and chemical synaptic membranes, has the existence of a separate and distinct dopamine active neuron been identified.

The pharmacological action of the neuroleptic drugs were once thought to block dopaminergic post-receptor sites, increasing the release and turnover of dopamine within both the mesolimbic/mesocortical and nigrostriatal pathways of the brain. However, recent research has determined that the biochemical action of these pathways may not be identical, in fact, many theorists have argued that the nigrostriatal and mesolimbic/mesocortical pathways work quite independently. The therapeutic properties of several neuroleptic drug derivatives may in fact depend upon specific actions of receptor sites. For example, thioxanthenes are D1 receptor type specific, some phenothiazines block D1 pre-receptors and D2 post-receptors, and butyrophenones are D2 specific post receptor blockaders. Therefore, variations in pharmacological action would be expected both in acute immediate reactions and over chronic durations, including rates of dopamine syntheses and turnover, and tolerance effects to the neuroleptic drug in question.

This paper will briefly review the neuroanatomy of the dopaminergic systems of the brain. Then this paper will attempt a limited discussion of some recent efforts to solve the puzzle of neuroleptic drug action in the fight against certain schizophrenic disorders, and the consequent acute and chronic extrapyramidal side effects of these drugs. This paper will then attempt a limited review of some theories of schizophrenia, including hemisphere disorders, acute positive symptom schizophrenia that is dependent upon excess dopamine in the brain, chronic negative symptom schizophrenia that may be due to organic dopaminergic neuronal damage, and how this condition resembles idiopathic Parkinson disease. Then there will be a brief presentation of two acute Parkinson movement disorders attributed directly to neuroleptic drug action, akinesia and akathisia. Then we will discuss tardive dyskinesia, a disorder known to directly result from chronic administration of neuroleptic drugs. Next, we will attempt to discuss some current theories of dopamine receptor subtypes, the adenylate cyclase, cAMP theory, the D2 post receptor supersensitivity theory, and the D3 autoreceptor theory. As will be seen these receptors work in quite independent fashion, they may have quite different roles to play in schizophrenic management with neuroleptic drug therapy and may contribute quite differently to extrapyramidal movement disorders. Then we will conclude with a case study of a person receiving neuroleptic drugs. Where does his behavior "fit" in this scheme?

Neuroanatomy: The Dopamine Pathways

The dopamine system has been divided into four major subdivisions: nigrostriatal, mesolimbic, mesocortical, and tuberoinfundibular. The tuberoinfundibular dopaminergic pathways of the brain originate within hypothalamus and extend to the pituitary gland and governs mainly endocrine functions; inhibition of growth hormone and release of prolactin. There has yet to be any definite proof that either schizophrenic symptomatology or extrapyramidal side effects are contingent upon the tuberoinfundibular region, however several receptors have been identified with in vitro experimental techniques, especially with the bovine parathyroid gland (cAMP dependent) and with prolactin release (non cAMP dependent.) More of this research will be discussed under the dopamine receptor segment of this paper.

The mesolimbic/mesocortical region, or neuron group designated through the histological techniques of Dahlstrom and Fuxe (1964), as A10 dopaminergic neurons, seem to mediate certain positive schizophrenic states, and neuroleptic drugs seem to act by post receptor blockade to reduce acute schizophrenic symptoms. The anatomy of the mesolimbic/mesocortical system has been described as follows. "The cells of origin for this pathway are found in the midbrain. They primarily surround the interpencular nucleus in the ventral tegmental area. Areas demonstrated to be innervated by these cells include the olfactory tubercles and accumbens nucleus, central nucleus of the amygdala, and lateral septal nucleus. Recent evidence also suggests that A10 cells may project to the lateral basal and posterior lateral nuclei of the amygdala as well as to the ventral lateral caudate nucleus. It is not known at this time if the A10 cells branch so that one cell innervates both the limbic and cortical areas or if there are separate cells for each system. In terms of responses to drugs, the A10 cells appear relatively homogeneous. In contrast to the diffuse innervation of the cerebral cortex by the norepinephrine (NE) system, the dopamine (DA) innervation was found to be localized to discrete areas of the cortex: the gyrus cinguli, entorhinal cortex, and prefrontal cortex." (Bunney and Aghajanian, 1978).

The nigrostriatal dopaminergic pathway originates within the zona compacta containing over 3000 dopamine endogenous cell bodies with collaterals ascending throughout the extrapyramidal motor system of the brain.  The extrapyramidal system is defined as "a functional, rather than anatomical, unit comprising the nuclei and fibers (excluding those of the pyramidal tract) involved in motor activities; they control and coordinate especially the postural, static, supporting, and locomotor mechanisms.  It includes the corpus striatum, subthalamic nucleus, substantia nigra, and red nucleus, along with their interconnections with the reticular formation, cerebellum and cerebrum; some authorities include the cerebellum and cerebrum and vestibular nuclei." (Dorland's Pocket Medical Dictionary, 1977).

It has been argued that the mesolimbic/mesocortical and nigrostriatal dopaminergic pathways work in an independent manner, with separate and distinct pharmacological action. For example, A10 neurons are thought not to contain receptors that are adenylate cyclase dependent. However, it has been thought that A9 neurons do contain cell bodies that are endogenous to the caudate nucleus that are cAMP dependent. It is also interesting to note that the site of action of certain neuroleptic drugs on A9 neurons is thought to block both presynaptic and postsynaptic receptor sites, while on A10 neurons the site of action of the same drugs is thought to be post synaptic only. In a related study it was found that thioridazine, chlorpromazine, and fluphenazine enanthate, in acute and chronic treatment significantly elevated homovanillic acid (HVA) levels in the striatum and limbic areas. However, the caudate nucleus, but not the limbic areas, showed a reduction in HVA following each of the three drugs when acute and chronic treatments were compared.(Bunney and Aghajanian, 1978). This is of extreme importance in explaining why neuroleptic drugs cause motor dystonia after prolonged use and may explain why mesolimbic/mesocortical receptors do not become tolerant to neuroleptic drugs over time.

Acute Schizophrenia and Hemisphere Dysfunction: Some Possibilties

There have been several theories to account for the etiology of schizophrenia.  One theory suggests that acute schizophrenia, composed of auditory and visual hallucinations, delusional states, flight of ideas, and hyperactive stereotyped behaviors, may be associated with an excess of dopamine in the mesolimbic/mesocortical dopaminergic pathways in the brain.

In relation to dopamine and hemisphere specificity, it has been hypothesized that dopamine content in the brain is left hemisphere specific and may govern effector responses, mostly motor in origin. This motor effector system is thought to work in conjunction with acetylcholine. Norepinephrine is thought to be right brain specific and probably mediates orientation responses. This orientation system is thought to work in conjunction with 5HT serotonin. (It is interesting to note that norepinephrine and dopamine are thought to be the excitatory neurotransmitters of arousal and exploratory behavior, while acetylcholine and 5HT serotonin are thought to act as inhibitory transmitters. Thus a homeostatic balance is maintained within the organism with this synergistic neurotransmitter system. Disruptions in the system reasonably can be assumed to cause irrational behavioral/cognitive states).

It is thought that novel stimuli impinging upon an organism is first processed by the right brain orienting system that works in a holistic fashion. The right brain is thought to process information like an analog computer, while the left brain is thought to process information like a serial computer. Therefore, it has been hypothesized that novel information is first analyzed in large chunks of information, which is right brain dominant, and this process is thought to continue until selective chunks of information becomes manageable enough to transfer to left brain information processing centers. After the left brain association cortex has serially processed the right brain inputs, the emphasis is thought to transfer to effector dopaminergic extrapyramidal (nigrostriatal) centers for proper motor responses. Synergistic imbalances of neurotransmitter substances dopamine and acetylcholine is thought to produce an overload of responsiveness to habituated stimuli resulting in stereotyped behavior. This type of behavioral stereotypy has been observed in rats who have been subjected to toxic doses of amphetamine, a catecholamine agonist. Note: acetylcholine is thought to have two different receptors, nicotinic and muscarinic. The extrapyramidal system is thought to contain endogenous cell bodies that are 90% muscarinic in origin.

In relation to brain hemispheres and emotions the evidence is still not conclusive. The right cortex is thought to mediate the afferent input of emotionality, including facial cues, auditory interpretation of other directed vocalizations, and other significant semantic contextual clues. Right frontal lobe damage is thought to interfere with emotionally specific cues resulting in agnosia, and blunted, flat or inappropriate affect. (Tucker, 1981)

One study has directly found excessive dopamine levels in the left amygdala of deceased schizophrenic patients, but dopamine levels within the right amygdala appear to be normal. (Tepper, 1985) In relation to the imbalance of neurotransmitter in left limbic structures such as the amygdala, which is thought to mediate startle responses and rage responses, it may be hypothesized that a dysfunction in this structure would result in states of hyper arousal, panic attacks, and inappropriate bursts of anger. It may also be suggested that in theory, a left hemisphere amygdala that is malfunctioning due to an overload of dopamine, would create severe startle responses and severe displays of euphoria, commonly seen with patients suffering from amphetamine toxicity. An overload of dopamine in the left amygdala may also create a condition resembling mania, a condition characterized by expansive ideas, global non serial reasoning, an over positive self image, over enthusiasm of the self, an inability to perceive bodily faults, and an under responsiveness to criticism. This may happen due to a left amygdala signal override of afferent information that cancels out the normal inhibitory right amygdala inputs, and/or other regulatory neurotransmitters resulting in a scrambled stimulus response network.

The Role of Amphetamine Psychosis and Catecholamine Excess

Several studies have determined that amphetamine is a direct catecholamine agonist. Amphetamine acts to release both dopamine and norepinephrine, blocks synaptic re-uptake, and exerts direct action at post synaptic receptors. Toxic levels of amphetamine produce symptoms that are indistinguishable from acute schizophrenia. These symptoms include well formed paranoid delusions, various forms of stereotyped compulsive behavior and either visual or auditory hallucinations. (Angrist and Gershon, 1980) Animal studies utilizing amphetamine have added strength to the excessive brain dopamine theory. One study has suggested that chronic use of amphetamines may produce long lasting or irreversible depletion of dopamine in the caudate nucleus. This change is associated with the development of exaggerated startle reactions, dyskinesias, and postural abnormalities, possibly resulting from secondary supersensitvity of dopamine receptors in the caudate nucleus. (Jaffe, 1980)

The implication is obvious. Post receptor affinity changes have occurred to compensate for a lack of caudal dopamine synthesis encountered in chronic amphetamine use, resulting in new post receptor set points that are supersensitive to dopamine release. If the natural depletion of dopamine has resulted in post receptor affinity changes as described above under chronic amphetamine abuse, then the cessation of amphetamine would increase the motor stereotypy

In a related study it was found that hyperactivity and stereotypies occurring after administration of amphetamines to rats were blocked by pretreatment with alpha-methyl-tyrosine, which inhibits synthesis of both norepinephrine and dopamine. Also, blocking dopamine receptors with primozide or haloperidol before administering amphetamine prevented the appearance of stereotypy and hyperactivity, suggesting that dopamine may be the significant neurotransmitter in these behaviors. Thus, the dopamine induced psychomimetic effects of amphetamines prompted further investigations into the possibility that excessive dopamine neurotransmission is responsible for schizophrenic symptoms. (Garver, 1975)

It has been known for several years that neuroleptic drugs such as the phenothiazines and butyrophenones are effective in counteracting amphetamine psychosis, and in reducing symptoms of acute positive symptom schizophrenic states. Neuroleptics have been found to directly block dopamine post receptor sites, increasing dopamine turnover, at least acutely, as measured by increases in 3H-Dopamine, and central nervous system (CNS) metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), and to block norepinephrine receptors reducing the synthesis and turnover of this transmitter. Norepinephrine over synthesis has been known for years to be a direct cause of manic states in man. So a possible hypothesis to explain the neurotransmitter interaction of reduced schizophrenic/manic states and hyper motility associated these disorders may be reduced norepinephrine synthesis and increased dopaminergic neuron hyperpolarization working in combination.

Chronic Schizophrenia and Idiopathic Parkinsonism: DA Neuron Lesions?

Chronic negative symptom schizophrenic disorders seen in catatonic disorders, with rigid muscular posturing, and flat affect, do not respond well to neuroleptic treatment. It has been hypothesized that chronic schizophrenia may be due directly to striatal/caudal/cerebral/endogenous organic brain damage, or to conditions resulting in neuronal atrophy. This may result in dopaminergic under activity. This may also explain why the dopamine precursor L-DOPA is effective with some chronic negative symptom schizophrenic patients.

L-DOPA is a well known dopamine agonist and for years has been effective in improving symptoms of idiopathic Parkinson disease. As is known, idiopathic Parkinson disorders are the direct result of degeneration of neostriatal dopaminergic pathways in the caudate nucleus. Since Parkinson disease is composed of muscular rigidity and lack of spontaneity in movement, it has been hypothesized that L-DOPA may increase dopamine synthesis and turnover in the caudate to compensate for intrinsic destruction of dopaminergic neurons, and reduce post receptor site activity. These pharmacodynamics may account for the improvement of chronic schizophrenic patients as well.

Parkinson Side Effects: Akinesia and Akathisia

An immediate extrapyramidal side effect observed with neuroleptic drug administration beside muscle tonus, is the Parkinson like disorders akinesia and akathisia. Akinesia is characterized by rigid posturing, fixed gaze, lack of normal arm movements from side to side when walking, shallow voice, and flat affect. Akinesia disorders have been artificially generated in animals using reserpine. The main action of reserpine is to prevent the storage of dopamine in neuronal granules by blocking dopamine reuptake for packaging. Neuroleptic drugs by blocking post synaptic dopamine neurons may produce the same effect: producing a shortage of synaptic dopamine making contact with post receptor sites. This may occur even though the action of neuroleptic drugs is to initially increase dopamine turnover.

Reserpine is not thought to have action on post receptor sites and consequently does not cause a chemical denervation of these receptors. However, it has been thought to cause post neuronal damage with long term administration, due to an unnatural depletion of neurotransmitter. Other causes of akinesia may be increased dopamine turnover without compensating a increase in positive post receptor sensitivity, or an increase in receptor numbers, at least initially. This effect is no doubt time and dose dependent. This hypothesis has limited behavioral support. Some patients who exhibit akinesia do so for only limited amounts of time, usually under acute neuroleptic treatment. Chronic neuroleptic treatment studied for long amounts of time generally see motor improvements. (Personal observation; Case #T.M.,1990) Increases in motor responsiveness over time may reflect direct synaptic changes of neurotransmitter, or dopaminergic neuronal changes, or receptor affinity changes.

One note of caution concerning patients with akinesia disorders. Under acute treatments when the Parkinson type disorder is observed, many psychiatrists confuse the neuroleptic drug side effects with chronic schizophrenic motor disorders. The problem may be connected with the indifference to environmental stimuli studied in patients with chronic schizophrenic disorders. A study has been initiated to test environmental perception by rats undergoing neuroleptic treatments. The test consists of classical conditioning of rats to avoid shock (the conditioned avoidance response or CAR). Rats conditioned to avoid shock onset with a visual cue, such as a diminution of light, were later tested under clinical doses of neuroleptic drugs. Even though rats under normal untreated conditions escaped shock onset, rats on neuroleptic drugs no longer did so. This suggests that although rats perceived the conditioned stimuli, they no longer perceived it as important. This indifference to conditioned stimuli was reversed by dopamine agonist drugs.

In a related study, rats could avoid being shocked by climbing a pole in a certain amount of time, after onset of a signaling stimulus. The stimulus would continue throughout the period of the shock (such as diminished light) and restored to normal (standard laboratory lighting) after cessation of the shock period. Therefore, the rat could discriminate between cues requiring avoidance versus non avoidance behavior, could perceive onset of danger, could determine how long to continue avoidance behavior and when to determine when to discontinue this behavioral response. Under chronic neuroleptic treatment the rats continued to step down onto the electrical apparatus even after the signaling stimuli was given, suggesting that the aversive stimuli was not perceived correctly. This was thought to be a direct result of the drug efficacy and not due to the sedative effect of the drugs. The normal response pattern of avoidance was resumed with dopamine agonist drugs. The step down test has been used for years as a measure for testing the efficacy of neuroleptic experimental drugs.

This indifference to environmental cues may also result from lack of motivation. Rats with striatal lesions will swim if thrown into a tank cold water even after they have maintained rigid posturing for hours. This has also been discovered in patients with idiopathic Parkinson's disorders. People with this condition will leap up and run out of the room when someone shouts "fire!" although they have been immobile for hours. So, in conclusion, reduction in behavior suggesting side effects of certain schizophrenic disorders should be gauged extremely cautiously to ascertain whether the behavior is due to the disease state or the treatment regimen.

Akathisia is a Parkinson like disorder characterized by the subjective feeling of restlessness. People suffering from this disorder are unable to sit in one place for any period of time, jog in place, resort to obsessive compulsive hand wringing among other hyper activities. Given doses dopamine agonist the symptoms increase in frequency and intensity. The direct cause of akathisia is unknown but it may be the result of increased striatal turnover of dopamine bombarding post receptor sites that have not made set point changes to accommodate this increase of neurotransmitter. In conclusion, akathisia, a Parkinson like disorder may be result of hyper arousal of the mesolimbic/mesocortical dopaminergic pathway. This may partially explain why hyper arousal in this disorder is beyond conscious control.

Chronic Tardive Dyskinesia

Chronic Tardive dyskinesia is the only extrapyramidal system disorder known to be directly attributed to chronic neuroleptic treatment regimens. Long term schizophrenic patients in countries that do not use neuroleptic drug regimens, lack patients with Tardive symptoms. (See an excellent review by Baldessarini and Tarsy, 1978) Tardive dyskinesia is characterized by orofacial, buccal, lingual dystonia, fly catching, grimacing, and in extreme cases body dystonia, leaning tower of Pisa disorder, and many others. The cause of Tardive disorders are unknown but according to one study, "there are rare reports of neuropathologic changes following prolonged neuroleptic treatment of patients without persistent extrapyramidal syndromes, noting scattered areas of neuronal degeneration and gliosis without convincing localization, and some suggestions that patients with drug induced Parkinsonism or Tardive dyskinesia have post mortem changes in the basal ganglia and midbrain." The same study concluded that prolonged exposure of animals to a neuroleptic agent leads to a prolonged (weeks) requirement for increased doses of the same agent (tolerance) or a dissimilar neuroleptic agent (cross tolerance) to block the behavioral effects of apomorphine; a dopamine agonist. (Baldessarini and Tarsy, 1978) This suggests that neuroleptic drugs do long term or irreversible damage to neostriatal dopaminergic pathways. This also suggests that long term chronic neuroleptic drug administration creates both super sensitive dopaminergic post receptors or the absolute number of these receptors within the neostriatum. A study designed to treat this idea was done with long term schizophrenic patients under neuroleptic drug treatment. The hypothesis originally tested the idea of receptor super sensitivity by suggesting that apomorphine, a dopamine agonist drug would intensify Tardive dystonia. The conclusion of this experiment was correct. However, the suggestion was advanced that perhaps with long term administration of apomorphine receptor sensitivity would change from a state of super sensitivity to a state of hypo sensitivity due to the effects of increased dopamine activity. Ironically enough the experiment produced the desired effect, reduced Tardive symptoms to a state of remission for several years! (Baldessari and Tarsy, 1978) Due to the limited follow up of the patients of this study the results should be taken with a grain of salt, however, the prospect looks promising.

Extrapyramidal Effects: Dopamine and Acetytlcholine Imbalance?

It has long been determined that anticholinergic drugs are effective in reducing extrapyramidal movement disorders induced by neuroleptic drugs. According to one study the interactions of dopamine and acetylcholine neurons are as follows. Acute blockade of dopamine neurotransmission by antipsychotic agents increases the turnover and release of acetylcholine by within the striatum. Dopamine agonists exert the opposite effects. (Tepper, 1985) This contention has many psychiatrists convinced that the efficacy of neuroleptic drugs and the extrapyramidal sedative side effects are interdependent and act pharmacologically at the same site. However, this contention has been recently questioned.  It appears that not all neuroleptic drugs work in the same fashion. Piperazine phenothiazines have a high incidence of acute extrapyramidal side effects, and are probably the first choice of physicians who deal with violent patients, the sedative effects are obvious. However, neuroleptic drugs do exist that do not produce extreme sedation or high levels of extrapyramidal side effects. Clozapine and thioridazine (Mellaril) are two effective anti psychotics that do not produce extrapyramidal side effects. There have been several theories to account for this phenomenon. Some authors suggest that these drugs work on selective A10 dopaminergic pathways, mesolimbic/mesocortical, but not neostriatial, A9 neurons. According to one author, "Clozapine has a strong action on dopamine turnover in the limbic system and a relatively weak one in the striatum. Coincidentally, clozapine has antipsychotic efficacy but very few extrapyramidal side effects." (Bradley, 1986) It also appears that clozapine has an ability to block dopamine receptors in the nucleus accubens, but not in the caudate nucleus. This might provide an explanation other than it's anticholinergic activity for clozapine's unusual combination of antipsychotic efficacy and lack of extrapyramidal side effects. (Bunney and Aghajanian, 1978) Of course, the best theory, is that clozapine does a partial blockade of dopamine receptors. Thus catatonic patients show marked improvement with increased awareness and behavioral energy.

However, some authors suggest that a more probable explanation is the interaction of clozapine and thioridazine on dopamine/acetylcholine interactions in the brain. Most studies agree that neuroleptic drugs increase the release and turnover of disinhibited choline. This is one reason why some psychiatrists attempt to control unwanted motor effects of neuroleptic drugs with anticholinergics. The action of clozapine and thioridazine is thought to work without the increase in choline release by having a selective affinity for muscarine recptors. (Creese and Snyder, 1978)

In addition it has been found in relation to the interaction of dopamine and acetylcholine in motor disturbances, "it was found that drugs that blocked the action of norepinephrine and dopamine interfered with avoidance responding, but interestingly, these effects were also blocked by atropine and scopolamine, (an acetylcholine, muscarinic receptor antagonist) indicating that cholinergic neurons are part of an important link in the chain of neurons that maintains avoidance behavior." (Bartholini and Lloyd, 1980)

To summarize the dopamine/acetylcholine problem one author suggests that "Parkinson disease is a neostriatal dopamine deficiency syndrome. The loss of neostriatal dopamine disrupts the balance between the neostriatal dopaminergic and cholinergic systems that is thought to regulate normal activity in the neostriatum. The dopaminergic agonists presently used may achieve some of their therapeutic effect by directly stimulating dopamine receptors; however some of their therapeutic effect may be a consequence of stimulating the dopamine receptor upon the cholinergic interneuron and thereby restoring balance between the dopaminergic systems in the neostriatum. Prior to the advent of L-DOPA therapy for Parkinsonism, cholinergic antagnoists were widely used." (Stoof, 1985)


The roles of dopaminergic receptor subtypes have been controversial and confusing. Up to eight receptor subtypes have been proposed. However, three receptors have been theorized to have some part in reduction of schizophrenia and extrapyramidal side effects due to neuroleptic receptor blockade. A summary of receptor subtypes is given below, from (Kebabian,1983)

Dopamine D1 Receptors: Adenylate cyclase. Radio ligand: 3H-thioxanthenes. Dopamine: Agonist m molar potency. Apomorphine: Partial agonist or antagonist. DA Ergots: Potent antagonists n molar potency. Selective Antagonist: Unknown. Radiolabeled Ligand: cis-fupenthiol.

Dopamine D2 Receptors: Unassociated. Radio ligand: 3H-butyrophenones. Dopamine: Agnoist n molar potency. Apomorphine: Agonist n molar potency. DA Ergots: Agonist n molar potency. Selective Antagonist: metroclopramide, sulpride. Radiolabeled Ligand: dihydroergotryptine.

Dopamine D3 Receptors: Unassociated. Radio ligand: 3H-Dopamine.

Note: The classification of D3 receptors was not included in Kebebian's classification beyond the information provided.

D1 receptors are indigenous to the striatum, have cell bodies within the striatum with collaterals ending within the substantia nigra. This receptor system was originally found in the bovine parathyroid gland. It has been found that dopamine causes a twenty to thirty fold increase in the content of cAMP in dispersed bovine parathyroid cells. (Brown and Dawson-Hughes, 1983) Increased synthesis of thyroxine has been discovered when these parathyroid cells were subjected to doses of dopamine agonist drugs. Neuroleptics countered this effect.

Originally dopaminergic receptors were thought to work by a dopamine sensitive adenylate cyclase, which in turn regulates a second messenger 3'5' cyclic adenosine mono phosphate system. The cAMP synthesis and storage in D1 receptors seem to be mediated by an excitatory guanosine triphosphate (GTP) link, which works on the adenylate cyclase to produce neurotransmitter by a process that is still unknown. (Kebabian, 1983) D1 receptors were once thought to be causal in schizophrenic disorders, but this assertion has been seriously questioned.

According to one study, "only the DA-stimulated adenylate cyclase is effectively inhibited in a competitive manner by the addition of low concentrations of neuroleptic drugs." (Clement-Cormier, 1974) The implication was, of course, that selective dopamine antagonist drugs would reduce dopamine synthesis and turnover by blocking the production of cAMP. However, it was discovered that destruction of endogenous D1 receptors in the striatum with 6oxyhydrodopamine (6OHDA), a dopaminergic neurotoxin, did not significantly lower striatal dopamine levels identified with [3H]-antagonist binding assays. In addition to this discovery, there was an autopsy done to determine whether chronic schizophrenic brains subjected to chronic neuroleptic drugs showed damage and regeneration of D1 neurons, or increased radio ligand binding. Neither consequence expected from neuroleptic drug lesions occurred. According to one author, D1 receptor sites are not involved with dopaminergic transmission in the brain. The in vivo accumulation of cAMP induced by apomorphine in the striatum was not blocked by sulpiride and haloperidol whereas the behavioral effects were blocked by both drugs. When labeled neuroleptics were injected into rats, the radioactive [3H]-antagonist binding was never found on D1 receptor sites." (Laduron, 1983) In conclusion, it may be asserted that in both the neosrtiatum and the substantia nigra the dopamine sensitive adenylate cyclase receptor is in search of a function.

Recent experiments have determined that a dopamine receptor may exist that is not cAMP specific. This was discovered in animal studies measuring melatonin secretion. Melatonin is a chemical that has an active process in animal skin coloration. It was found that dopamine inhibits the production of melatonin. But when using dopamine antagonist drugs to increase melatonin synthesis it was found that the increase was not cAMP dependent, suggesting that some other receptor than D1 is responsible for this process. This receptor has been designated D2. D2 receptors seem to work in the exact opposite fashion as D1 receptors, meaning that guanosine triphosphate (GTP) works to inhibit adenylate cyclase, which in turn inhibits cAMP synthesis. (Kebabian, 1983) D2 receptors have been found to be responsible for several other functions that are not D1 receptor dependent including inhibition of the chemoreceptor trigger zone. Dopamine agonist drugs such as apomorphine and bromocriptine cause vomiting, while neuroleptics have antiemetic effects.

In studies using kainic acid microinjections within the striatum, which selectively destroys endogenous D1 cell bodies but spares the dopaminergic nerve terminals, a substantial loss of striatal dopamine sensitive adenylyl cyclase activity was observed, but the procedure did not diminish the content of dopamine as measured with [3H]-antagonist binding assays. (Lee and Seeman, 1980.) Tritiated compounds such as [3H]-Haloperidol and [3H]-Spiroperidol compete with D2 receptor antagonists at post receptor sites. It has been suggested that "the clinical potency in schizophrenia of different types of neuroleptics correlates very closely with their D2 receptor antagonistic activity and their affinity for D2 receptors as measured by [3H]-antagonist binding." (Bradley, 1986) An additional study found that "the impressive correlation between the clinical, anti schizophrenic actions of neuroleptics and their blockade of D2 receptors labeled with [3H]-Haloperidol or [3H]-Spiroperidol is more striking than has been observed for any other biochemical effects of these drugs. It therefore seems likely that this action is intimately associated with the anti schizophrenic effect of these drugs." (Creese, 1976) This study also found in relation to motor effects of neuroleptics, "potencies of neuroleptics in competing for [3H]-Haloperidol binding correlate extremely closely (r>0.9) with their potencies in blocking apomorphine or amphetamine induced stereotyped behavior." (Creese, 1976)

In reference to neuroleptic drugs a persistent question has been raised, if the immediate effect of the drugs is a post receptor dopaminergic blockade, why is there a delay in the observed behavioral responses? One hypothesis maintains that immediate D2 receptor antagonism is not directly responsible for the anti psychotic effects of these drugs. Neuroleptic drugs may be mediated by secondary processes that are time dependent. Two such possibilities have been considered. (1) Slow induction of depolarization block of dopamine neurons by neuroleptics. (2) Homeostatic receptor changes involving dopamine auto receptors. Recent electrophysiological studies in animals indicate that in A10 neurons (the origin of the mesolimbic pathway) anti psychotic drugs produce a slowly developing depolarization block, which has a greater effect in reducing dopaminergic transmission than the initial dopamine receptor antagonism. (Ashton, 1987)

There has been a monumental effort recently to discover new neuroleptic compounds that are effective as selective receptor blockers that have good anti schizophrenic efficacy but that do not create extrapyramidal side effects. For example, it has recently been found that certain stereo isomers have potent active anti psychotic effects that are isomer specific. For example, recent evidence has shown that for many phenothiazines and thioxanthenes, which inhibit the dopamine stimulated formation of cAMP, that only the (+) isomer of butaclamol and the alpha isomer of flupenthixol have dopamine antagonist activity, and only these isomers have anti psychotic effects. (Iversen, 1981) Isolating specific isomers in the battle against schizophrenia has produced some exciting new research efforts including computer modeling of hypothetical compounds that may mimic the action of known dopamine agonists and antagonists. The hope of this research is to discover new and better dopamine specific drugs and to reduce as far as possible extrapyramidal motor syndromes.

The Rototest

Actual experimentation has been devised to test hypotheses related to dopamine depletion, receptor changes, and resultant motor behaviors in animals. The procedure, known as the rototest, has been devised to test motor actions of rats subjected to dopaminergic agonists or antagonists after specified extrapyramidal system lesions. Hypothesis: if post receptor Super sensitivity occurs after destruction of endogenous D2 cell bodies lesioned with neurotoxins such as 6OHDA or kainic acid, will the animal turn contralateral to the lesioned side, ipsilateral to the lesioned side, or neither? The expected result would be that the lesion should cause a depletion of dopamine on the lesioned side resulting in turning that is dependent upon the non lesioned side. Therefore, the animal should turn ipsilateral to the lesion. (Hemisphere specific.) However, in an attempt to maintain some sort of homeostatic balance, the post receptors on the lesioned side should produce either numerical increases in receptors or affinity changes to compensate for a lack of dopamine content, then over time, the animal should turn ipsilateral to the non lesioned side. This suggests that the turning is a direct result of receptor changes even with a reduced quantitative amount of endogenous dopamine within the lesioned extrapyramidal hemisphere. The results of an experiment conducted to test a similar hypothesis resulted in the following conclusions. (1) Behaviorally super sensitive rats show a 20-120% increase in [3H]-Haloperidol on the lesioned side compared to their own contralateral unlesioned side. (2) Rats that do not turn display essentially no augmentation in binding on the lesioned side. (3) The occurrence of enhanced dopamine receptor binding in association with behavioral super sensitivity indicates that the increased number of receptor sites may, in part, account for the behavioral effect of the lesion. (Creese, 1978)

Rototest procedures testing receptor activities within the extrapyramidal motor system with experimental drugs such as (3-(3-Hydroxy-phenyl)-N-n-propyldiperidine, (3-PPP), a drug that is not D2 receptor specific, or cAMP dependent, produced turning that could not justify current models of receptor super sensitivity and created serious doubts concerning the excessive dopamine theory. This prompted neurologists to inquire into the possibility of some other receptor functioning in a way that mediates the release and synaptic turnover of dopamine in the extrapyramidal motor system. This receptor has been designated D3 or the "auto receptor."

Auto Receptors Save the Excessive Dopamine Theory?

The solution to this problem stemmed from further research, which resulted in yet a third dopamine receptor designated the "auto receptor." Auto receptors seem to regulate impulse flow of neurotransmitter. Tyrosine hydroxylase seems to be inhibited by end product regulation. Neurotransmitter depletion in the synaptic cleft either by post receptor utilization or by extra synaptic degradation triggers the pre synaptic production of tyrosine hydroxylase. Autoreceptors seem to have extremely high threshold levels for dopamine, far greater than post receptor thresholds. One study has found that dopamine receptors in the substantia nigra may have auto receptors that are six to ten times more sensitive to dopamine than post receptors in the caudate nucleus. The same study also found that the dopamine agonist apomorphine decreased the rate of firing of dopamine neurons. Phenothiazine drugs seemed to counter this effect. (Kehr, 1972)

Excess neurotransmitter in the synaptic cleft results in auto receptor inhibition of endogenous pre synaptic transmitter production. The same effect has been hypothesized for interneurons, which are soma dendritic dopamine specific. These soma dendritic auto receptors seem to inhibit the production of both tyrosine hydroxylase, and to add negative values to the algebraic summation of the axon hillock.

One study has concluded that stimulation of the pre synaptic auto receptor inhibits tyrosine hydroxylase activity and dopamine synthesis within the dopaminergic nerve terminals in the neostriatum. And (1) blockade of dopaminergic receptors by administration of neuroleptics has been demonstrated to induce an allosteric activation of tyrosine hydroxylase which is accompanied by an increase in the turnover of dopamine and an accumulation of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). (2) Dopamine agonists produced a decrease of brain DOPAC and HVA concentrations, which can be antagonized by neuroleptic drugs. (3) Cessation of impulse flow in dopamine neurons can be achieved by administration of gammabutyrolactone (GBL). In the presence of a DOPA decarboxylase inhibitor this induces an accumulation of DOPA, an effect which can be antagonized by pretreatment with neuroleptic drugs. (Stoof, 1983)

The role of auto receptors in chronic neuroleptic bombardment may be summarized as follows. First, it has been hypothesized that auto receptors may actually become hypo sensitive to dopamine release and turnover, therefore failing to limit pre synaptic neurotransmitter release and turnover. If this condition is further augmented with post synaptic receptor super sensitive sites, the results may well be imagined, severe dystonia, and severe Tardive dyskinesia. It has also been discovered that chronic neuroleptic treatments produce a 28% increase in [3H]-Dopamine binding in the rat brain. (Lee and Seeman, 1980) If, hypothetically, this increase adds to further auto receptor rate limiting capacity of neurotransmitter, this may further augment post receptor affinity changes or dopaminergic neuronal damage, or both, all leading to enhanced undesirable motor changes.


This paper has attempted in part to review in a very basic manner some exciting research that has been conducted in association with neuroleptic drug administration both in an acute and a chronic fashion and the extrapyramidal motor consequences of these drugs. The assertion that sedative effects of neuroleptics are invaluable as a contingency factor in the control of acute positive symptom schizophrenia has been determined to be a short sighted assumption. If this view was accepted we would run a major risk of mistaking the natural course of the disease process for the extrapyramidal syndromes. And because so much confusion reigns concerning what to include as a characteristic of schizophrenia, including multiple scales, multiple subtypes of disorders, ad nauseam, why complicate matters?

Also, stereotyped pharmacological thinking distorts further research efforts designed solely to find drugs that are efficacious in the fight against schizophrenic states without producing unwanted side effects. We have discussed in some depth drugs which have a natural affinity for muscarinic acetylcholine receptors in the brain, especially clozapine and thioridazine. Although clozapine has only been used in limited experimental conditions due to the high bone marrow toxicity of the drug, why not continue to explore similar side chains to discover if possible wide range therapeutic benefits?

Impossibly rigid thinking could distort new research results as artifacts of the experimental design, or of unknown intermediate variables, or as simply anything other than causality. For example, we could discard as preposterous such assertions such as "rats treated with lithim ion (LI++) one week before and during haloperidol administration failed to develop the behavioral sensitivity response to apomorphine as measured by locomotor and stereotypic behavior." (Feldman and Quenzer, 1984) We could scoff, as professionals, and say, "this merely applies to animal studies, but in my personal behavioral observations, I have proved otherwise. Furthermore, most of these behavioral responses to drug combinations are merely species specific and therefore cannot be generalized to include homo sapiens."

In summary, new research techniques would be dismissed by old fashioned pharmacological reasoning and outdated techniques.

It has been emphasized many times that neuroleptic drug management strategies should be avoided at any possible time due to the unfortunate extrapyramidal side effects of these drugs. The long term consequences of chronic Tardive dyskinesia is in fact caused by neuroleptic drugs, and no cases of Tardive dyskinesia has ever been reported in countries without with out neuroleptic treatments of schizophrenic patients. Tardive dyskinesia once developed can only be reduced by larger doses of the drugs and the relief patients experience is only short lived in duration. Other methods have been suggested, for example, drug holidays, or refraining from muscular depot injections of the drug to reduce the incidence of extrapyramidal syndromes. However, we must re-emphasize that these suggestions are not always effective in reducing extrapyramidal effects because often these effects occur spontaneously, even after a single dose, and this propensity to develop side effects maybe nothing more than a genetic disposition or critical environmental stressors. So, to conclude, in an effort to reduce the complexity of the primary disorder, schizophrenia, plus to reduce the unwanted extrapyramidal side effects and the consequent discomfort of the patient, neuroleptics should be avoided unless no other alternative is available.


I would like to make a few comments concerning case #T.M., a young adult male, aged twenty one, who was diagnosed as schizophrenic and who was subjected against his will to perphenazine, a piperazine side chain phenothiazine. I would like to state that this individual at the onset of the drug developed motor symptoms that directly mimicked akinesia, i.e., rigid posturing, fixed gaze, lack of normal arm movements from side to side when walking, small voice, and pronounced lack of affect. It has been demonstrated in the clinical literature that perphenazine has a high incidence of extrapyramidal side effects, and a high sedative component. It has also been suggested that young male patients receiving neuroleptic drugs have a higher probability for extrapyramidal side effects, due in part to a higher endogenous content of natural dopamine in their brains. Female patients of the same age do not seem to be as prone to develop extrapyramidal syndromes, the biological differences for this distinction is still a mystery.

T.M.'s akinesia behavior persisted for several months but has now evolved into a person that might be indistinguishable from a "normal" person of his age group, except perhaps in the early morning hours, where his immobility persists to some degree. The early morning suppression in his behavior may be due to the natural sedative effect of the drug, since the patient has explained several times that he takes the drug at bedtime.

Sedative effect or not, the pronounced behavior change seen in this individual is worth some conjecture. What are we seeing, tolerance to the drug or some long lasting changes in dopamine receptor systems in his brain? Perphanazine has been blamed in the past for increasing the probability of Tardive dyskinesia after prolonged administration due to it's propensity to create acute extrapyramidal syndromes. The reason for T.M.'s increase in locomotion is unknown, but I can only hope that the drug is not creating extensive dopaminergic neuronal damage.

Unfortunately, in my limited review of the literature no one has systematically studied an individual subjected to neuroleptic drugs from onset to conclusion, on a day to day basis. Therefore, we must rely upon conjectures of professionals that may not be accurate, or appropriate, in determining what danger signs to be aware of as precursors to chronic dystonic states. Therefore, a real danger exists in patients like T.M. who are evaluated in an indifferent way by physicians who are too busy with other mental health problems. May we hope that in this case the problem does not become tragic. T.H. November 29, 1990.


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Friday, July 17, 2015

Marco Pantani: The Accidental Death of a Cyclist: Film Review

Marco Pantani was one of the greatest pure climbers cycling has ever known, and one of the most emotionally fragile.  Marco Pantani could sprint up mountain passes like an angel, with repeated attacks that would drop great Tour de France champions, Miguel Indurain, Lance Armstrong, Jan Ullrich, like hot stones.  Marco Pantani was the last rider to win the Giro d' Italia, Tour de France double in 1998, a feat that "Lance Armstrong never attempted."

The film is a biographical masterpiece.  Marco Pantani loved his bicycle as a youth, he assembled and disassembled his bicycle repeatedly in order to make it "lighter and faster."  He would be heard late at night adjusting his cleats, "backward and forward two centimeters at a time" attempting to find the perfect adjustment, a habit that is ingrained in all great professional cyclists.  His mother scolded him for giving his bicycle washes in the bath tub.

When Marco Pantani turned professional he wanted to quit, because he thought that professional cycling was equivalent to "the mafia."  A very insightful precept.  In the mafia as a made guy you play by the rules, and maintain omerta, or silence about the organization.   In the organization of professional cycling millions of euros are cycled in sponsorship money, and millions more can be earned by a professional rider in commercial endorsements depending upon  performance.  Everybody plays by the same rules, everyone knows if you are successful you will be handsomely rewarded, but if you are caught cheating you will be thrown to the wolves to fend for yourself.  The big money players walk free, a dead soldier can be replaced instantly without a qualm, but the organization survives unimpeded.

But Marco Pantani was an impulsive man.  He was warned to share the wealth during the 1999 Giro d' Italia, to refrain from attacking the group, to allow other teams to win stages.  But Marco Pantani was a driven man who wanted to be immortal, like Fausto Coppi.   Marco Pantani wanted to humiliate his opponents, to dominate races with huge time gaps.  According to the film the organization sought a way to remove Marco Pantani from contention because he refused to share the wealth with other big money players.  There were also suggestions that big money gamblers were out to fix the 1999 Giro d' Italia, and what better way to guarantee a big payoff than to manufacture a positive dope test that would disqualify the odds on favorite? 

Suppositions, conspiracy theories.  There have been reports circulated that Marco Pantani's hematocrit measured above the fifty percent threshold for several stages before he was thrown out of the 1999 Giro d' Italia for "health reasons."  There is also the connection between Marco Pantani and Francesco Conconi, the Italian doctor who experimented on riders with recombinant EPO under the pretext of developing a test to detect recombinant EPO.  Nevertheless, Marco Pantani was convinced that he had been framed in a diabolical plot contrived by a group of greedy men who had been "corrupted."

Was Marco Pantani correct in his supposition?  Cycling, at that time, was rife with corruption. Drugs were being abused flagrantly.  The highest circle of the UCI could be manipulated with bribes.  The teams ran doping programs without sanction.  Dark days had descended upon cycling.  Marco Pantani denied any wrongdoing, he explained that "he knew the doping test was coming and that he could have taken preventive measures to avoid detection if he had done anything wrong."  The old defensive mechanism, deny, deny, deny.

It is incredibly sad to see a man lose his dignity.  Marco Pantani was bludgeoned everywhere he went.  Even on simple training rides he was sneered at by people who were convinced he was champion by means of dope.  The press were relentless in their accusations, the former hero of Italy had now become a goat.

But even downtrodden men recover and Marco Pantani had a will of iron.  Marco Pantani was hit head on by an automobile that somehow entered the course during a race.  His leg was broken with a compound fracture that required a metal splint to repair.  He had to undergo an extensive period of physical rehabilitation.  He was never expected to walk again let alone ride a bicycle.  Nevertheless, Marco Pantani did ride again, he rode so well that he set a record up L' Alpe d' Huez, and won the Tour de France and Giro d' Italia in the same year.

During the 2000 Tour de France Marco Pantani almost did the impossible.  He nearly caused Lance Armstrong to lose the race by setting an incredible tempo that made Lance Armstrong miss a feed, and bonk!  Unfortunately, Marco Pantani became a victim of his own stratagem, he experienced stomach cramps and had to withdraw from the race.

Marco Pantani was finished as a top world class rider, he was a broken man who was destined to find solace in cocaine.  His cocaine dependence would increase until he was found dead alone and abandoned in his hotel room.

Italy was shocked.  The people who had rejected Marco Pantani in life, mourned with loud lamentations his death.  His casket was carried on the shoulders of his admirers.  Eighty thousand people attended his funeral.

I wrote a comment to the Guardian newspaper online that was published.  I said the death of Marco Pantani, "broke my heart."  I watched the Mont Ventoux stage of the 2000 Tour de France dozens of times, marveling, entranced, in awe of those supreme athletes.  If Lance Armstrong was full to the gills with dope, what about Marco?


Nothing disgusts me more than to watch smug Greg LeMond comment like he is an exalted angel without blemish who is qualified to pontificate on the sins of others, while there may be many undiscovered skeletons in his own closet!  Sir Bradley Wiggins, most average in his tour performances before he became King and knighted, reminds one of the pre-cancer Lance Armstrong and the post-cancer survivor, money did not improve his performance, or the fact that he moved to a more prestigious team.  Yet his exaltedness wishes to comment for our elucidation, looking down his pointed beak in disapproval upon the unwashed who would dare to question the source of such inexplicable improvements.  We rabble who dare to presume are considered conspirators who would dare to spit in the soup of cycling expectations by scenting a pretender in our mists, much like David Walsh, holding his nose while manning the barricades.  The tone of the film was spoiled by the presence of such exalted beings, Greg LeMond and Sir Bradley Wiggins!

The Tour de France is not won on mineral water alone!  In my opinion, there has never been, nor will there ever be, a dope free Tour de France champion.  Cycling groupthink has evolved in an Orwellian sense to a higher plain of manipulative rhetoric.  Cycling wants so desperately to move on from the steroid era that it is fabricating reality by manufacturing new truths.  Ignorance is Strength.  Doping in cycling must continue unabated, the stakes are too high, but the organization wants the problem to vanish under the guise of distorted propaganda.  Sir Bradley Wiggins serves as an icon of this distorted propaganda, with his fabricated virtue, and his holy Team Sky, who are above reproach with their fabricated philosophy of "ride clean."  Yes, we have been spoon fed these assurances before, and we note with disdain that Team Sky has employed doctors who have spotty backgrounds.

Stench, something is rotting, the air is saturated.  "Right Guard will not help you here."  Marco Pantani was a pure climber, a great rider with a tortured soul.  A man who was spat upon by cycling.  A man who was singled out as an example and cruelly punished for playing the game by their rules.  Eighty percent of the pack was using performance enhancing drugs during the steroid era according to Tyler Hamilton; most of whom were never punished.

But cycling has always maintained a double standard.  Marco Pantani and Floyd Landis were forced out, in disgrace, mocked, vilified, while Alberto Contador was welcomed back with open arms all forgiven.

"Never again" is their mantra.  Never treat another rider in such a hypocritical fashion is my mantra.  Treat people with respect is my mantra.  We all make mistakes and deserve to be forgiven.  We do not need to drive riders to such desperate extremes that they need to take their own lives alone and forsaken.  Shame on us!  Equity for all, man the barricades!