Neurotransmitters and Drug Abuse

Chapter 21 Neurotransmitters and Drug Abuse


This chapter recapitulates and expands information on the major neurotransmitters’ synthesis, metabolism, functional anatomic pathways, and mechanism of action. In addition, it reviews their altered activity in important neurologic disorders and treatments. With a few exceptions, the chapter restricts the discussion of neurotransmitters’ role to central nervous system (CNS) diseases and does not address psychopharmacology. This chapter reviews the following neurotransmitters:




Monoamines



Dopamine




Anatomy


Three “long dopamine tracts” hold the greatest clinical importance in neurology:



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FIGURE 21-1 Coronal view of the midbrain, which gives rise to several dopamine-producing tracts – including the nigrostriatal, mesolimbic, and mesocortical. The nigrostriatal tract begins in the substantia nigra (SN), the large curved black structures in the base of the midbrain (see Fig. 18-2). The red nuclei (RN), which receive cerebellar outflow tracts, sit above the substantia nigra. The upper portion of the midbrain, the tectum (Latin, roof; tego, to cover), contains the aqueduct of Sylvius (A), which is surrounded by the periaqueductal gray matter, and the superior colliculi (SC). The oculomotor nuclei (III), which give rise to the third cranial nerves, lie midline, just below the aqueduct.


In addition to these long tracts, several “short dopamine tracts” hold clinical significance. The tubero-infundibular tract connects the hypothalamic region with the pituitary gland. Dopamine in this tract suppresses prolactin secretion and thus inhibits galactorrhea. (Its absence or blockade of its activity promotes galactorrhea.) Another short tract exists within the retina.



Receptors


Although neuroscientists have identified numerous dopamine receptors, the most important ones are the D1, D2, and closely related receptors. The D1 receptor group includes both the D1 and D5 receptors. The D2 receptor group includes the D2, D3, and D4 receptors. These dopamine receptors are coupled to guanine nucleotide-binding protein (G proteins). Because they exert their effects through second messengers, such as cyclic AMP, neuroscientists consider them “slow” neurotransmitters.


The D1 and D2 receptors remain the most important in extrapyramidal system disorders (Table 21-1). Both types of these receptors are plentiful in the striatum, but D1 receptors are more abundant and more widely distributed.


TABLE 21-1 Pharmacology of D1 and D2 Receptors



































  D1 D2
Effect of stimulation on cyclic AMP production Increased Decreased
Greatest concentrations Striatum, limbic system, and cerebral cortex Striatum, substantia nigra
Effect of dopamine Weak agonist Strong agonist
Effects of dopamine agonists Vary with agonist Strong
Effect of phenothiazines Strong antagonist Strong antagonist
Effect of butyrophenones Weak antagonists Strong antagonists
Effect of clozapine Weak antagonist Weak antagonist

When antipsychotics block D2 receptors, the reduced dopamine activity induces parkinsonism, raises prolactin production (inducing galactorrhea), and places patients at risk for tardive dyskinesia. Some atypical antipsychotic agents, particularly risperidone and its active metabolite paliperidone (Invega), raise prolactin serum concentration and induce galactorrhea. Even nonpsychiatric medications that decrease dopamine activity, such as metoclopramide (Reglan), which blocks D2 receptors, and tetrabenazine (see Chapter 18), which depletes dopamine from its presynaptic storage vesicles, increase prolactin serum concentration and induce parkinsonism. In contrast, clozapine, which shows little D2 receptor affinity, does not lead to either of these problems.


Physicians should bear in mind that finding an elevated serum prolactin level does not always indicate use of a dopamine-blocking medication or the presence of a pituitary tumor (see Chapter 19). The most common cause of serum prolactin elevation is pregnancy.



Conditions due to Reduced Dopamine Activity





Parkinson Disease.


In Parkinson disease, the progressive degeneration of dopamine-synthesizing neurons in the substantia nigra leads to increasingly severe dopamine deficiency. Neurologists treating Parkinson disease patients attempt to enhance dopamine activity in three ways.



1. As a first-line treatment, they administer the dopamine precursor L-dopa. As long as enough nigrostriatal (presynaptic) neurons remain intact, DOPA decarboxylase converts L-dopa to sufficient quantities of dopamine to reverse the symptoms (see Fig. 18-3).


2. As the disease progresses, the presynaptic neurons degenerate beyond the stage where they can synthesize, store, and appropriately release dopamine. At this time, if not as a first-line treatment, neurologists add a dopamine receptor agonist to the medication regimen. As a substitute or supplement for L-dopa, dopamine agonists, such as pramipexole, ropinirole, and apomorphine, stimulate dopamine receptors. That stimulation replicates dopamine’s effect and alleviates symptoms.


3. As long as dopamine synthesis continues, neurologists prescribe medicines that slow L-dopa metabolism in the periphery but allow DOPA to continue forming dopamine centrally. Working in that way, two Parkinson disease medications – carbidopa and entacapone – inactivate enzymes that metabolize L-dopa and thereby enhance dopamine activity (see Fig. 18-11). Carbidopa inactivates DOPA decarboxylase. Entacapone inhibits COMT, which normally inactivates L-dopa by converting it to 3-O-methyldopa. Both enzyme inhibitors act almost entirely outside the CNS because they have little ability to penetrate the blood–brain barrier. Therefore, they do not interfere with basal ganglia dopamine synthesis. Giving these enzyme inhibitors along with L-dopa enables small doses of L-dopa to be effective. Moreover, the small doses of dopamine reduce its systemic side effects, such as nausea, vomiting, cardiac arrhythmias, and hypotension.


Commercial preparations combine enzyme inhibitors with L-dopa to prevent its metabolism outside the brain. For example, Sinemet combines carbidopa with L-dopa and Stalevo adds entacapone to carbidopa and L-dopa. As compared to L-dopa alone, L-dopa–carbidopa combinations, such as Sinemet (Latin, sine without, em vomiting), almost completely eliminate the side effects of nausea and vomiting.


Another therapeutic option entails protecting dopamine itself from metabolic enzymes, particularly MAO. Selegiline (deprenyl [Eldepryl]) inhibits MAO-B, one of the two major forms of MAO. Selegiline readily penetrates the blood–brain barrier and, by inhibiting MAO-B, preserves both naturally occurring and L-dopa-derived dopamine. Another advantage of selegiline is that its metabolism yields small amounts of amphetamine and methamphetamine that partially offset Parkinson disease-related fatigue and depression.


Although antidepressant MAO inhibitors inactivate both MAO-A and MAO-B or only MAO-A, selegiline inhibits only MAO-B. In its usual therapeutic dose (≤10 mg) for Parkinson disease treatment, selegiline preserves dopamine but does not place patients, even if they eat tyramine-containing foods, at risk of a hypertensive crisis. Nevertheless, neurologists cautiously use serotonin-enhancing medicines, such as triptans for headaches and selective serotonin reuptake inhibitors for Parkinson disease-induced depression, in patients taking selegiline.




Neuroleptic-Malignant Syndrome.


An acute absence of dopamine activity causes the parkinson-hyperpyrexia or central dopaminergic syndrome, which neurologists still call the neuroleptic-malignant syndrome (NMS) (see Chapter 6). Administering dopamine agonists may compensate for the absence of dopamine activity and alleviate some of the symptoms, but treatment is generally supportive. Patients usually require parenteral treatment, such an intramuscular injections of the dopamine agonist apomorphine, because the severe muscle rigidity prevents their swallowing pills and the urgency of the situation demands treatment with rapid onset of action.



Conditions due to Excessive Dopamine Activity


Of the several mechanisms that might lead to excessive dopamine activity, the most common is the administration of L-dopa. Cocaine and amphetamine also cause excessive dopamine activity by provoking dopamine release from its presynaptic storage sites and then blocking its reuptake. Some psychiatric medications, such as bupropion (Wellbutrin), also block dopamine reuptake. In a different mechanism, possibly underlying some cases of tardive dyskinesia, increased sensitivity of the postsynaptic receptors results in excessive dopaminergic activity.


Whatever the cause, excessive dopamine activity produces a range of side effects from psychosis to hyperkinetic movement disorders. For example, Parkinson disease patients who take excessive L-dopa may develop visual hallucinations, paranoia, and thought disorders that can reach psychotic proportions. Excessive dopamine activity also produces hyperkinetic movement disorders, such as chorea, tremor, tics, dystonia, and the oral-buccal-lingual variety of tardive dyskinesia.


As a less dramatic example of the effects of excessive dopamine, some Parkinson disease patients become overly involved with stimulating activities, such as sex and gambling. In these cases, neurologists diagnose the dopamine dysregulation syndrome or impulse control disorder (see Chapter 18). They usually ascribe the aberrant behavior to dopamine-induced novelty seeking and inattention.


On the other hand, with a small increase in dopamine activity, as occurs with bupropion treatment, individuals enjoy a sense of well-being. That sensation, however, represents a mere glimmer of a cocaine or amphetamine rush.


In addition to their effects on movements, dopamine and its agonists, acting through the tubero-infundibular tract, inhibit prolactin release from the pituitary gland. Neurologists and endocrinologists prescribe bromocriptine and cabergoline, both dopamine agonists, to shrink pituitary adenomas and suppress their prolactin secretion. In the opposite situation, dopamine receptor blockade of the tubero-infundibular tract by typical neuroleptics and risperidone – but not clozapine or quetiapine – may enhance prolactin release and thereby raise its serum concentration. Patients taking these medicines often report decreased sexual drive and even galactorrhea.


Probably stemming from CNS rather than peripheral nervous system (PNS) dysfunction, habitual cocaine users often experience a paresthesia of ants crawling on or under their skin. Neurologists call this sensation a formication (Latin, formica, ant), but cocaine users call it “coke bugs.”



Norepinephrine and Epinephrine







Serotonin






Conditions due to Alterations in Serotonin Activity


Serotonin plays a major role in the daily sleep–wake cycle. The activity of serotonin-producing cells reaches its highest level during arousal, drops to quiescent levels during slow-wave sleep, and disappears during rapid eye movement (REM) sleep (see Chapter 17).


Depression is the disorder most closely associated with low serotonin activity. In the extreme, low postmortem CSF concentrations of HIAA, the serotonin metabolite, characterize suicides by violent means. This finding, one of the most consistent in biologic psychiatry, reflects low CNS serotonin activity. Similarly, individuals with poorly controlled violent tendencies, even those without a history of depression, have low concentrations of CSF HIAA.


Serotonin levels are also decreased in individuals with Parkinson or Alzheimer disease. Among Parkinson disease patients, the decrease is more pronounced in those with comorbid depression.


Sumatriptan and other triptans, a mainstay of migraine therapy, are selective 5-HT1D receptor agonists. Once stimulated, these serotonin receptors inhibit the release of pain-producing vasoactive and inflammatory substances from trigeminal nerve endings.


A series of powerful antiemetics, including dolasetron (Anzemet) and ondansetron (Zofran), are 5-HT3 antagonists. By affecting the medulla’s area postrema, one of the few areas of the brain unprotected by the blood–brain barrier, they reduce chemotherapy-induced nausea and vomiting. Similarly, second-generation antipsychotics typically act as antagonists of 5-HT2A as well as D2 receptors.


Although increased serotonin activity is often therapeutic, excessive activity poses a danger. For example, combinations of medicines that simultaneously block serotonin reuptake and inhibit its metabolism lead to serotonin accumulation. These combinations may cause toxic levels and the serotonin syndrome (see Chapters 6 and 18).


In another situation characterized by excessive serotonin activity, LSD (D-lysergic acid diethylamide) induces hallucinations and euphoria by stimulating 5-HT2 receptors. Similarly, “ecstasy” (methylenedioxymethamphetamine [MDMA]), although it also stimulates dopaminergic activity, greatly enhances serotonin activity by triggering a presynaptic outpouring. Ecstasy’s effects surpass LSD’s in stimulating serotonin activity.



Acetylcholine






Conditions due to Reduced ACh Activity at the Neuromuscular Junction


In the PNS, decreased neuromuscular ACh activity – from either impaired presynaptic ACh release or blockade of postsynaptic ACh receptors – leads to muscle paralysis. Conditions that interfere with ACh activity have different etiologies and induce distinct patterns of weakness. For example, in Lambert–Eaton syndrome, the paraneoplastic disorder, antibodies impair the release of ACh from presynaptic neurons and cause weakness of limbs (see Chapters 6 and 19). Botulinum toxin also impairs ACh release from the presynaptic neuron; when ingested as a food poison (botulism), it primarily causes potentially fatal weakness of ocular, facial, limb, and respiratory muscles. When injected into affected muscles for treatment of focal dystonia, medicinal botulinum toxin inhibits forceful muscle contractions because it slows or prevents ACh release from the presynaptic neuron at the neuromuscular junction (see Chapter 18).


At the postsynaptic neuron of the neuromuscular junction, curare, other poisons, and antibodies, such as those associated with myasthenia gravis, each block ACh receptors. The pattern of weakness in myasthenia gravis is distinctive: Patients have asymmetric paresis of the extraocular and facial muscles, but not the pupils. To overcome the ACh receptor blockade in myasthenia gravis, neurologists administer anticholinesterase (the common contraction of antiacetylcholinesterase) medications, such as edrophonium (Tensilon), pyridostigmine, and physostigmine, to inhibit cholinesterase and thereby reduce the breakdown of ACh in the synaptic cleft (see Chapter 6 and Fig. 7-6). The reliability of edrophonium in temporarily reversing myasthenia-induced paralysis has led to the “Tensilon test” (see Fig. 6-4).



Conditions due to Reduced ACh Activity in the CNS


In Alzheimer disease, the cerebral cortex has markedly reduced cerebral ACh concentrations, ChAT activity, and muscarinic receptors (see Chapter 7). In addition, some nicotinic receptors are depleted.


To counteract the ACh deficiency in Alzheimer disease, neurologists have attempted several strategies to enhance its synthesis or slow its metabolism. In hopes of driving ACh synthesis, they have administered precursors, such as choline and lecithin (phosphatidylcholine). Although analogous to providing a dopamine precursor (L-dopa) in Parkinson disease treatment, this strategy failed in reversing the symptoms of Alzheimer disease. A complementary strategy has been to slow ACh metabolism by administering long-acting cholinesterase inhibitors that cross the blood–brain barrier. Several such cholinesterase inhibitors, such as donepezil, may slow the progression of dementia in Alzheimer disease and several other illnesses (see Chapter 7).


Reduced ACh concentrations also characterize trisomy 21, which shares many clinical and physiologic features of Alzheimer disease. Also, the cortex in Parkinson disease and progressive supranuclear palsy (PSP) has reduced ACh concentrations.


Many studies have indicated that an absolute ACh deficiency or, compared to dopamine activity, a relative ACh deficiency causes delirium. Reduced ACh activity leading to cognitive impairment or delirium may occasionally have an iatrogenic basis. For example, scopolamine and other drugs that block muscarinic ACh receptors interfere with memory, learning, attention, and level of consciousness – even when given to normal individuals. In fact, scopolamine, which readily crosses the blood–brain barrier, induces a transient amnesia that has been a laboratory model for Alzheimer disease dementia.



Anticholinergic Syndrome


Chlorpromazine, other typical antipsychotic agents, and tricyclic antidepressants may block muscarinic ACh receptors and cause physical anticholinergic side effects, including drowsiness, dry mouth, urinary hesitancy, constipation, and accommodation paresis (see Chapter 12). Anticholinergic activity may also rise in individuals taking nonpsychiatric medicines, such as atropine, scopolamine, benztropine, and trihexyphenidyl. With enough anticholinergic activity, individuals develop the anticholinergic syndrome: dilated pupils, elevated pulse and blood pressure, dry skin and hyperthermia, and delirium that may progress to coma. In this situation physicians may administer physostigmine, an anticholinesterase that crosses the blood–brain barrier, to restore ACh activity.


In a related but interesting correlation, antipsychotic agents with the greatest muscarinic anticholinergic side effects, namely clozapine and olanzapine, have among the least tendency to produce parkinsonism and other extrapyramidal side effects. Conversely, antipsychotic agents with the least anticholinergic side effects have the greatest tendency to produce those extrapyramidal side effects.



Conditions due to Excessive ACh Activity


ACh intoxication takes the form of a massive, predominantly muscarinic parasympathetic discharge. Its primary features consist of bradycardia, hypotension, miosis, and a characteristic outpouring of bodily fluids in the form of excess lacrimation, salivation, bronchial secretions, and diarrhea. Depending on the poison, dose, and route of entry, victims may show signs of CNS involvement, which may include delirium, slurred speech, and seizures. Sometimes they may also show signs of PNS involvement, such as generalized flaccid paresis and fasciculations.


Medications, homicide, suicide, or accidents at home or work may lead to ACh poisoning. In most cases, inactivation of cholinesterase leads to a toxic accumulation of unmetabolized ACh in the brain, autonomic ganglia, and neuromuscular junction. For example, patients with dementia who accidentally take too many donepezil pills or apply rivastigmine patches without removing the old ones may eliminate their cholinesterase and allow an excess of unmetabolized ACh to accumulate. Similarly, eating certain mushrooms will also cause ACh toxicity. Individuals may suffer from exposure to common organophosphorus insecticides, such as parathion and Malathion, or they may swallow a Latin American rat poison, tres pasitos, which looks like grains of rice. Ingestion of these poisons may be the result of suicide or homicide attempts as well as occupational exposure. Similarly, many poison gases, such as the terrorist gas sarin, raise ACh concentrations to toxic levels.


Supporting vital functions, especially respiration, is essential. The specific treatment of ACh poisoning from organophosphate ingestion, which is probably the most common scenario, consists of the administration of atropine, which is a competitive inhibitor of ACh at muscarinic receptors, to reverse the parasympathetic overactivity, and pralidoxime to reactivate cholinesterase activity. Health care workers should remain aware that the poison often saturates the clothing of victims.



Neuropeptides



Gamma-Aminobutyric Acid – An Inhibitory Amino Acid Neurotransmitter






Conditions due to Alterations in GABA Activity


GABA deficiency is characterized by a lack of inhibition, which leads to excessive activity. For example, in Huntington disease, depleted GABA reduces inhibition in the basal ganglia, presumably leading to excessive involuntary movement, typically chorea. Tetanus and strychnine poisoning each illustrate the effects of decreased GABA activity (see later).


In the stiff-person syndrome, formerly known as the stiff-man syndrome, anti-GAD antibodies reduce GABA synthesis. The reduced GABA activity in this disorder leads to muscle stiffness and gait impairment that physicians might mistake for catatonia or an acute dystonic reaction to antipsychotic agents; however, the symptoms are not so acute or severe that neurologists might diagnose tetanus or strychnine poisoning. Neurologists usually diagnose the stiff-person syndrome by finding anti-GAD antibodies in the serum and CSF. In many cases, the stiff-person syndrome is associated with an underlying neoplasm, such as breast cancer, or various autoimmune diseases. Whatever the cause, immunomodulation and diazepam usually alleviate the stiffness.


Diets deficient in pyridoxine, the cofactor for GAD, impair GABA synthesis and cause seizures. Likewise, overdose of isoniazid (INH), which interferes with pyridoxine, occasionally leads to seizures. In both cases, the seizures respond to intravenous pyridoxine.


Several AEDs are effective, in part, because they increase GABA activity. For example, valproate (Depakote) increases brain GABA concentration. Tiagabine (Gabitril) inhibits GABA reuptake. Topiramate (Topamax) enhances GABAA receptor activity. Vigabatrin (Sabril) increases GABA concentrations by reducing its metabolic enzyme, GABA-transaminase.


In a different situation, flumazenil, a benzodiazepine antagonist, blocks the actions of GABA at its receptor and reverses benzodiazepine-induced stupor and hepatic encephalopathy. In the case of hepatic encephalopathy, flumazenil presumably displaces false, benzodiazepine-like neurotransmitters from GABA receptors (see Chapter 7).




Glutamate – An Excitatory Amino Acid Neurotransmitter





Conditions due to Alterations in NMDA Activity


Excessive NMDA activity floods the neuron with potentially lethal concentrations of calcium and sodium in several disorders. Through this process, excitotoxicity, glutamate–NMDA interactions lead to neuron death through apoptosis. Excitotoxicity may be intimately involved in the pathophysiology of epilepsy, stroke, neurodegenerative diseases (such as Parkinson and Huntington diseases), head trauma, and, conceivably, schizophrenia. In certain paraneoplastic syndromes, particularly one triggered by ovarian teratomas in young women, antibodies directed toward NMDA receptors create an autoimmune limbic encephalitis (see Chapter 19).


Consequently, one approach to stemming the progression of neurodegenerative diseases has been to use medicines that block glutamate–NMDA interactions. Despite this rationale, such medicines provide only a modicum of neuroprotection. For example, riluzole (Rilutek), which decreases glutamate activity, only transiently interrupts the progression of amyotrophic lateral sclerosis. Similarly, memantine (Namenda), an NMDA receptor antagonist, blocks its deleterious excitatory neurotransmission and slows the progression of Alzheimer disease for approximately only 6 months. Also, the AEDs, gabapentin and lamotrigine, are glutamate antagonists.


Despite the benefit of blocking glutamate in various diseases, deficient NMDA activity can also be harmful. For example, PCP and ketamine may block the NMDA calcium channel and cause psychosis.



Other Neuropeptides


Endorphins, enkephalins, and substance P, which are situated in the spinal cord and brain, provide endogenous analgesia in response to painful stimuli (see Chapter 14). Substance P and, to a lesser degree, other neuropeptides are depleted in Alzheimer disease. The other neuropeptides that are reduced include somatostatin, cholecystokinin, and vasoactive intestinal peptide.


A pair of neuropeptides, hypocretin-1 and -2, also known as orexin A and B, are excitatory neurotransmitters that play a crucial – but an ill-defined – role in locomotion, metabolism, appetite, and the sleep–wake cycle (see Chapter 17). Synthesized in the hypothalamus, where they are cleaved from a large precursor protein, these neuropeptides increase during wakefulness and REM sleep, and decrease during non-REM sleep. Unlike normal individuals, narcolepsy patients have little or no hypocretin in their CSF and their hypothalamus is devoid of hypocretin-producing cells.



Jun 4, 2016 | Posted by in NEUROLOGY | Comments Off on Neurotransmitters and Drug Abuse

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