Schizophrenia, Neuroleptic Drugs, and Extrapyramidal Movement Disorders

Terry D. Holfeltz

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 an 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 of 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 was 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 a 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 the hypothalamus and extend to the pituitary gland and govern mainly endocrine functions; inhibition of growth hormone and release of prolactin. There has yet to be any definitive proof that either schizophrenic symptomatology or extrapyramidal side effects are contingent upon the tuberoinfundibular region, however, several receptors have been identified within 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 the 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 interpeduncular 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 is 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 postsynaptic 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 Possibilities

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, a 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 are 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 become 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 are 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 neurotransmitters in left limbic structures such as the amygdala, which is thought to mediate startle responses and rage responses, it may be hypothesized that dysfunction in this structure would result in states of hyperarousal, 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 nonserial 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 postsynaptic 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 supersensitivity 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 super sensitive 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 the synthesis of both norepinephrine and dopamine. Also, blocking dopamine receptors with pimozide 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 hypermotility associated with 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 the 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 the 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 postsynaptic 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 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 neurotransmitters. Other causes of akinesia may be increased dopamine turnover without compensating an 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 sees motor improvements. (Personal observation; Case #T.M.,1990) Increases in motor responsiveness over time may reflect direct synaptic changes of the 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 the 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 the 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 the 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 were given, suggesting that the aversive stimuli were 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 a 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 the 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 setpoint changes to accommodate this increase of neurotransmitter. In conclusion, akathisia, a Parkinson like disorder may be a result of hyperarousal of the mesolimbic/mesocortical dopaminergic pathway. This may partially explain why hyperarousal 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 is 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 supersensitivity 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 supersensitivity to a state of hyposensitivity 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 Acetylcholine 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 antipsychotics 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 neostriatal, 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 an 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 the 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 receptors. (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 are thought to regulate normal activity in the neostriatum. The dopaminergic agonists presently used may achieve some of their therapeutic effects by directly stimulating dopamine receptors; however, some of their therapeutic effects may be a consequence of stimulating the dopamine receptor upon the cholinergic interneuron and thereby restoring the balance between the dopaminergic systems in the neostriatum. Prior to the advent of L-DOPA therapy for Parkinsonism, cholinergic antagonists were widely used." (Stoof, 1985)

Receptors

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 the 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.
Radioligand: 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-flupenthixol.

Dopamine D2 Receptors: Unassociated.
Radioligand: 3H-butyrophenones.
Dopamine: Agonist n molar potency.
Apomorphine: Agonist n molar potency.
DA Ergots: Agonist n molar potency.
Selective Antagonist: metoclopramide.
Radiolabeled Ligand: dihydroergocryptine.

Dopamine D3 Receptors: Unassociated.
Radioligand: 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 monophosphate system. The cAMP synthesis and storage in D1 receptors seem to be mediated by 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 the 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 radioligand binding. Neither consequence expected from neuroleptic drug lesions occurred. According to one author, D1 receptor sites are not involved with the 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 neostriatum 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 colorization. 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 the 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 antischizophrenic effect of these drugs." (Creese, 1976) This study also found in relation to the motor effects of neuroleptics, "potency's of neuroleptics in competing for [3H]-Haloperidol binding correlates extremely closely (r>0.9) with their potency's 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 antipsychotic 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 autoreceptors. Recent electrophysiological studies in animals indicate that in A10 neurons (the origin of the mesolimbic pathway) antipsychotic 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 stereoisomers have potent active antipsychotic effects that are isomer specific. For example, recent evidence has shown that for many phenothiazines and thioxanthenes, which inhibit the dopamine stimulated the formation of cAMP, that only the (+) isomer of butaclamol and the alpha isomer of flupenthixol have dopamine antagonist activity, and only these isomers have antipsychotic 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 Protest

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 protest, 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 the 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 any augmentation in binding on the lesioned side. (3) The occurrence of enhanced dopamine receptor binding in association with behavioral supersensitivity indicates that the increased number of receptor sites may, in part, account for the behavioral effect of the lesion. (Creese, 1978)

Protest procedures testing receptor activities within the extrapyramidal motor system with experimental drugs such as (3-(3-Hydroxyphenyl)-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 supersensitivity and created serious doubts concerning the excessive dopamine theory. This prompted neurologists to inquire into the

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, and 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 "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."  Pantani 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 ingrained in all great professional cyclists.  His mother scolded him for giving his bicycle washes in the bathtub.

When Marco Pantani turned professional he wanted to quit because he thought 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 family.

In the family of professional cycling, millions of euros are cycled in sponsorship money, and millions more can be earned by a professional rider in commercial endorsements contingent 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 family survives unimpeded.

But Marco Pantani was an impulsive man.  Marco Pantani 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 family 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 big money gamblers were out to fix the 1999 Giro d' Italia!  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 doping doctor who experimented on riders with recombinant EPO under the pretext of developing a test to detect recombinant EPO.  Nevertheless, Marco Pantani was convinced 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 the 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, "he knew the doping test was coming, so he could have taken preventive measures to avoid detection if he had done anything wrong."  Of course, Marco Pantani knew as the leader of the Giro d' Italia he would be subjected to mandatory dope tests.  The real question is if Marco Pantani knew a mandatory test was required, why did his hematocrit test above the legal limit?

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 was 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 he set the record up L'Alpe d'Huez, and won the Tour de France and Giro d' Italia in the same year.  (1998)

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 climbers.  If Lance Armstrong was full to the gills with dope, what about Marco?

Conclusion

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 me 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, Sir Bradley Wiggins, 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 family 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.

The stench, something is rotting, the air is saturated.  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 the family 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 demean 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!