membrane transporter (reuptake site) Stimulates release of neurotransmitter from presynaptic nerve terminal Serotonin
MDMA
MAOA Monoamine oxidase type A
MDMA 3,4-Methylenedioxymethamphetamine Small amount of serotonin enters the neuron ~30% ~70% MitochondriaMitochondria
Serotonergic
nerve terminal
(the cell body originates in the raphe nuclei)
Excessive
serotonin
in the synaptic cleft (due to enhanced secretion
and reuptake inhibition) Most of the serotonin
is blocked from being reuptaken into the neuron and is available
for postsynaptic interaction
Excessive secretion of
dopamine and norepinephrine
from dopaminergic neurons of the mesolimbic ('reward') pathway and noradrenergic neurons originating in the locus ceruleus, respectively (by similar mechanisms?)
MAOA
5-HIAA 5-Hydroxyindole acetic acid
(metabolite of serotonin)
VMAT2 Vesicular monoamine transporter
type 2
Notes about the scheme
The illicit drug used most commonly by young people at parties and ‘raves’ is 3,4-
methylenedioxymethamphetamine
(MDMA) or ‘ecstasy’. The mechanism of action of MDMA is not completely understood, but it is believed to inhibit the reuptake of serotonin, to facilitate serotonin release, and to a lesser extent enhance dopamine and norepinephrine release from presynaptic nerve terminals. The serotonin boost can produce a sense of emotional closeness, elation, and sensory delight, and, along with the potential of MDMA to increase dopamine transmission in the
‘reward’ pathway, it might be associated with the addictive properties of the drug.
The acute adverse effects of MDMA may include increased heart rate and blood pressure, tremor, sweating, bruxism, and life-threatening hyperthermia that may be further complicated by rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. The cytochrome P450 enzyme CYP2D6 is the primary metabolizer of MDMA. Hence, potent CYP2D6 inhibitors (bupropion, cocaine,
fluoxetine, haloperidol, methadone, paroxetine, pimozide, quinidine, and ritonavir) potentially slow the metabolism of MDMA and may further stimulate its toxic
effects. The proserotonergic effects of MDMA can be augmented by the ingestion of other proserotonergic drugs. These drugs (e.g. various
amphetamines) may be ingested inadvertently
as contaminants of MDMA. Proserotonergic drugs such as amphetamines,
clomipramine, fluoxetine, lithium, St John’s wort, tramadol, and venlafaxine
prescribed for medical disorders may increase the likelihood and severity of the serotonergic effect of MDMA. A florid central serotonin syndrome involving autonomic, cognitive, neuromuscular symptoms may develop. Moderate symptoms manifest as sweating, shivering, hyperreflexia, and agitation; severe symptoms include myoclonus, diarrhea, and fever. The most serious cases of central serotonin syndrome can develop with the irreversible
monoamine oxidase inhibitors (MAOIs).
Cases of death have been reported from MDMA interactions with the irreversible MAOI
phenelzine and the reversible MAOI
moclobemide. Linezolid, a new antibacterial
with mild MAOI properties, may also interact dangerously with MDMA. The plasma
concentration of MDMA increases 9–15% when the drug is taken with alcohol. More
importantly, this combination leads to a longer- lasting feeling of euphoria and the false
impression that one’s performance of a task has improved when it has actually been impaired.
The most troublesome, potential outcome adverse effects of MDMA ingestion result from sympathetic overload, and include tachycardia, mydriasis, diaphoresis, tremor, hypertension, arrhythmias, parkinsonism, esophoria (a tendency for the eyes to turn inward), and urinary retention. The most dangerous effects of MDMA ingestion is hyperthermia and the associated serotonin syndrome, resulting in rigidity, myoclonus, autonomic instability, rhabdomyolysis, and acute renal failure. Psychiatric and neurological manifestations include confusion, delirium, paranoia, depression, irritability, and nystagmus.
Treatment includes primary supportive measures such as cardiorespiratory maintenance, cardiac monitoring, pulse oximetry, urinanalysis, chemical panel, toxicology screen, and seizure precautions. Hyperthermia should be treated by rapid cooling. Serotonin syndrome should be treated with primary supportive measures, and
cyproheptadine (an antihistaminergic and
5-HT2A blocker) or chlorpromazine should be
considered. Anxiety can be treated with
benzodiazepines. Severe hypertension may be
treated with labetalol (an a1- and b2-adrenergic
receptor antagonist), phentolamine (a potent a1-antagonist, or nitroprusside.
Rhabdomyolysis should be treated with alkaline intravenous fluids (D5W with sodium
bicarbonate). Gastrointestinal decontamination with activated charcoal and a cathartic may be useful in acute exposure if the drug was taken orally within the previous 60 minutes. Induction of emesis is not recommended.17–27
6.5 Abused substances – phencyclidine (PCP)
Supposed mechanism of dependence, withdrawal symptoms, and treatment options
Excess dopamine Activates the 'reward' pathway Central nervous system depression
(e.g. ‘negative’- like symptoms of schizophrenia) 'LSD-like' effects (?) (see text) Cations (mainly Ca2) Glutamate 'Net' effect of PCP on serotonergic system is unknown DA-PMT DA receptor NMDA rec. Decreased Ca2ⴙ in flux 5-HT1,2 5-HT-PMT ? ?
Dopaminergic neurons from the ventral tegmental area
Serotonergic neurons from the raphe nuclei
(e.g. PCP stimulates and inhibits serotonergic transmission
at the same time)
Stimulates Inhibits Dopamine Serotonin PCP 5-HT Serotonin DA Dopamine
LSD Lysergic acid diethylamide
NMDA rec. N-Methyl-D-aspartate receptor
PCP Phencyclidine
PMT Plasma membrane transporter 5-HT1,2 Serotonergic receptor subtypes Treatment
options
Drugs that alleviate psychosis and possibly 'reward' (all antagonize the postsynaptic
dopaminergic receptor)
Antipsychotic drugs
Drugs that decrease some of the excitatory effects of PCP
Benzodiazepines
Phencyclidine (PCP) is a synthetic drug that is
often abused; in the USA, it is probably second to marijuana in frequency of use among drugs of abuse. The substance was originally developed as a general anesthetic. However, the medical use of PCP is presently contraindicated due to its potential severe adverse side-effects – mainly delirium (in about 33% of abusers), agitation, hallucinations, and rhabdomyolysis (in about 2%). It alters sensory perception and may produce peculiar experiences and even psychotic behavior. Clinical studies have consistently shown that a single exposure to PCP may produce behavioral disruption in healthy individuals that mimic schizophrenic symptoms.
PCP seems to be unique among
psychostimulants because of its ability to cause not only ‘positive’ psychotic symptoms such as delusions and hallucinations but also ‘negative’ or deficit state symptoms of schizophrenia. Hence, PCP stands as the current best model of schizophrenia in humans and animals, which may lead to new medications that could be helpful to people who do not respond to the
antipsychotic drugs (APDs) that are currently
available.
Notes about the scheme
Scientists have recently begun to focus on the potential of PCP as a probe for a new model for understanding and treating schizophrenia. Although amphetamines may also produce symptoms that closely mimic those of schizophrenia, PCP-induced symptoms in humans (especially its capacity to induce ‘positive’- and ‘negative’-like symptoms) appear to offer a more complete model of schizophrenia than that offered by amphetamine-induced symptoms. The ability of PCP to produce schizophrenia-like symptoms in healthy people is related to its ability to block the N-methyl-D-
aspartate (NMDA) receptor (see Section 4.2), which is one of the various receptors in the brain though which the neurotransmitter glutamate exerts its effect. PCP intoxication may be viewed as occurring in three stages. Mild intoxication, the first and most common stage, is manifested
primarily by psychiatric signs and symptoms. Acute exposure to PCP may cause intense psychosis; visual hallucinations; delusions and euphoric or flattened affect; impaired cognition; and increased frontal blood flow. Repeated exposure to PCP may cause intense psychosis; auditory hallucinations; delusions with religious content; thought disorder; anxious, labile, or paranoid affect; persistent impaired cognition; overt impulsiveness; social incompetence; poor social judgment; poor attention span and concentration; poor interpersonal relationships; and decreased frontal blood flow. Thus,
long-term, but not acute, PCP exposure models the behavioral and metabolic dysfunction of schizophrenia. In the second stage, patients can often become stuporous and comatose, but they still have intact deep pain responses. In the third stage, patients tend not to respond to deep pain stimuli, and death can follow.
No antidote has been found beneficial, to date, for PCP intoxication. Treatment is symptomatic, and includes careful
monitoring of the patient’s level of consciousness and their cardiovascular and respiratory
functioning. Activated charcoal is indicated if the patient reaches the hospital soon enough.
Treatment of PCP intoxication includes
APDs and benzodiazepines; for more severe
intoxication, treatment in an intensive care unit is mandatory. However, the use of APDs should be limited to severe psychotic/agitated patients, since these agents can lower the seizure
threshold and induce convulsions, or they may cause averse side-effects that can aggravate patients’ problems (e.g. akathisia and
dystonia). If APDs are employed, it is preferred to use high-potency drugs (e.g. haloperidol), since these have a relatively reduced capacity to induce seizures compared with the low-potency
phenothiazines (e.g. chlorpromazine, levomepromazine, and thioridazine) or
some of the relative newly introduced
second-generation APDs (SGAs: clozapine, olanzapine, and quetiapine).
Benzodiazepines are usually used to treat
autonomic instability, muscle spasms, and PCP- induced seizures, and may also aid in controlling some of the aggressive/agitated behavior.28–30
6.6 Abused substances – alcohol
Supposed mechanism of dependence, withdrawal symptoms and treatment option