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At the beginning of the twentieth century, Western culture had few drugs that were useful to treat central nervous system (CNS) disorders, including mental illness. Ethyl alcohol, used alone or as a component of numerous patent medicines, had use, perhaps as a sedative. Other sedatives, such as chloral hydrate, were available as sleep-inducing agents. More potent sedatives such as nitrous oxide and diethyl ether were used as general anesthetics. Morphine had been isolated from crude opium and was used as an analgesic. Cocaine was used as a local anesthetic. Virtually all of these drugs had abuse potential. By the 1920s, drug abuse had become a significant problem, and this problem continues into the twenty-first century.
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This situation continued until the 1950s, at which time a revolution in psychopharmacology began, a revolution that continues into the twenty-first century. Thus, the field of psychopharmacology is really only about 50 years old! In the 1950s and 1960s, significant advances (Julien 2000) included:
(a) Development of the barbiturates as sedativehypnotic drugs. Recognition of their toxicity and abuse potential led to identification and development of the benzodiazepines as safer agents for the treatment of anxiety states and insomnia.
(b) Development of the phenothiazines for the treatment of schizophrenia. Recognition of the therapeutic limitations and toxicities of these drugs led to development of the atypical antipsychotics in the 1980s and 1990s.
(c) Development of several classes of antidepressant drugs effective in the treatment of major depression and dysthymia. These included the monoamine oxidase inhibitors and the tricyclic antidepressants. This was followed in the 1980s and 1990s by development of less toxic antidepressants such as the serotonin-specific reuptake inhibitors and ‘dual action’ antidepressants. As the twenty-first century begins, additional classes of safer and even less toxic antidepressants are being introduced. These include a specific norepinephrine reuptake inhibitor, COMT-inhibitors, a selective, reversible MAO-inhibitor, a neurokinin-1 receptor antagonist, and ‘natural’ products such as St. John’s wort and DHEA (an adrenal androgen).
(d) Identification of the therapeutic efficacy of lithium in the treatment of bipolar illness. In the 1990s, safer and less toxic alternatives were developed. These included at least 6 different antiepileptic drugs, atypical antipsychotic drugs, and ‘natural’ products such as omega-3 fatty acids.
(e) Identification of the usefulness of certain of the antidepressant drugs and atypical antipsychotics in the treatment of specific anxiety disorders (e.g., post- traumatic stress disorder (PTSD), phobias, panic disorder, and obsessive-compulsive disorder), and behavioral disorders with associated symptoms of agitation, aggression, and violence.
(f ) Development of psychostimulant agents effective in the treatment of childhood, adolescent, and adult attention-deficit hyperactivity disorder (ADHD), Alzheimer’s disease, narcolepsy, and other disorders of attention, thought, and memory.
(g) Development of drugs useful in the treatment of Parkinson’s disease. Here we include dopamine replacement agents, dopamine receptor agonists, and a variety of other drugs that have improved the lives of individuals suffering from this disorder.
(h) Development of new anesthetic agents, allowing for the provision of safe anesthesia in patients in any state of health, debility, or surgical requirement. Such agents include ketamine, etomidate, non-toxic inhalation agents, and ultrashort-acting narcotics and muscle relaxants.
Thus, major psychiatric illnesses and other brain disorders have become, for the first time in human history, amenable to pharmacologic treatment; and the search for more effective, more tolerable, and safer drugs continues. As of 2001 at least 102 new medications are in development for treating mental illness. This includes 23 drugs for dementias, 19 for substance abuse disorders, 18 for depression, 15 for schizophrenia, 16 for anxiety disorders, 5 for eating disorders, 4 for ADHD, and 2 for treating PTSD.
It is important to note, however, that psychopharmacology involves much more than the development and testing of new therapeutic agents. Psychopharmacology has also provided powerful tools to study and characterize neurochemical pathways in the brain, and how these pathways may be involved in the pathophysiology and treatment of psychiatric illness (Duman 1999). This work has focused largely on neurotransmitter systems, including the synthesis, release, and metabolism of neurotransmitters and also of the receptor subtypes that control both presynaptic release and postsynaptic actions of neurotransmitters. All of this is to enable science to better understand brain physiology as well as to expand our knowledge of therapeutic targets.
In recent years, the fields of molecular pharmacology and pharmacogenetics have contributed mightily to neuroscience. Many of the enzyme and receptor targets for psychotherapeutic drugs have been identified, sequenced, cloned, three-dimensional structures proposed, and shown to be part of larger families of receptors with multiple homologous members (Julien 2000, Tallman 1999). Both therapeutic actions and side effects of drugs can often be explained by the interactions with multiple different types of receptors. For example, some antidepressants bind to and block the presynaptic transporters for serotonin and norepinephrine as well as postsynaptic receptors for histamine and acetylcholine. Other classes of antidepressants are quite specific for blocking either a single presynaptic transporter or a specific postsynaptic receptor (Figure 1; from Amara and Sonders 1998). This allows one to tailor a specific drug for a specific patient.
With the identification and cloning of different receptor subtypes, whole new generations of drugs specific for each subtype will allow for new advances in the treatment of mental disorders. For example, there are over 15 subtypes of serotonin receptors all of which are potential therapeutic targets. Tallman (1999) states that ‘taken together, over 1,000 GProtein Couples Receptors, over 100 ligand-gated and other ion channel subunits, over 20 reuptake proteins, almost 50 cytokine, 25 nuclear receptor, and several thousand other molecular targets have been cloned, expressed in mammalian, yeast, or insect cells, and are currently available to the pharmaceutical drug discoverer as potential therapeutic targets for agonist or antagonist discovery.’
Classically, a drug is often characterized by a fairly rapid-onset action in a specific model (i.e., it blocks a specific receptor). However, the therapeutic action may take days or weeks of therapy to become evident. This difference in time course has led to the hypothesis that the therapeutic action of many drugs is dependent on adaptations to the acute drug action (Duman 1999). For example, antidepressants acutely block a reuptake transporter, but the clinical relief of depression may take 6 weeks to become evident. Identification of the relevant adaptations, which can be thought of as a form of drug-induced neural plasticity, could occur at several cellular levels, including receptor and second-messenger coupling, modification of intracellular signaling pathways, alterations in nuclear transcription of receptor protein production, or ‘remodeling’ of intracellular architecture by regeneration, reconfiguration, or modification of intracellular ‘neurotropic factors’ (Duman 1999, Russo-Neustadt et al. 1999, Brown et al. 1999). Figure 2 (Duman et al. 1997) illustrates a model of such an interaction between acute drug effects and chronic ‘plastic’ neuroadaptations. The complexity of these adaptations is at least comparable to that of the complex neuronal circuitry in the brain and in the etiology of psychiatric illness. In addition, drug action interacts with genetic and environmental influences to modulate these neuroadaptive influences. For example, a ‘Brain-Derived Neurotropic Factor’ (BDRF) is poorly expressed in clinical depression and in stressful situations characterized by elevated levels of glucocorticoids (Duman 1999). The combination of exercise and an antidepressant (either a tricyclic-type or a monoamine oxidase inhibitor) exerts a positive and additive effect on BDRF messenger RNA expression in rat hippocampus over a period of 20 days (Russo-Neustadt et al. 1999). This is consistent with enhanced BDRF mRNA expression after antidepressant treatment and increased expression of the transcription factor cAMP response element binding protein (CREB) in rat hippocampus (Duman 1999, Nibuya et al. 1996, Tao et al. 1998). One implication of this is that it explains the additive effects of medication and behavioral therapies in the treatment of depression. It may also encourage the development of better behavioral treatments aimed at reducing depression and anxiety, and enhanced psychological capacity for dealing with chronic stress (Duman 1999).
Here, we have been discussing the interface between the molecular actions of drugs and their clinical utility in the treatment of disorders of the nervous system. This interface lies within the purview of neuropsychopharmacology; a unique, integrated area of science and medicine that is ideally positioned to ask fundamental questions about drugs, their actions on minute subunits of the nervous system, and how these drugs may be used for therapeutic benefit in human beings (Walker 1999). While molecular biology holds out the promise of giving a complete understanding to all aspects of biology, pharmacology is charged with understanding the actions of a drug at all levels of biology, from its effects on the genetic code or biomolecule to large populations of human persons. Indeed, it is equally important for the pharmacologist to determine the interaction of a drug with its ‘receptor,’ with the transduction mechanisms that result and lead to cellular action, to integration at the organ or system level, and to the effects on the whole person. Thus, pharmacology offers a complete picture in which a drug is ‘mapped’ all the way from its initial action at a bio-macromolecule through to effects on a human population with all of the social, economic, and geographic constraints of the latter (Walker 1999). In essence, pharmacologists will translate fundamental genetics and structural biology into drugs with therapeutic value (Burks 1999). To illustrate this characterization of a psychoactive drug, we consider tetrahydrocannabinol, the active ingredient in marijuana.
In 1964, delta-9-tetracydrocannabinol (THC) was isolated from marijuana and identified as its pharmacologically active ingredient. About 10 years later, it was hypothesized that THC and other cannabinoids act via a distinct set of receptors. In 1986, THC was found to inhibit the activity of the intracellular enzyme adenylate cyclase, and such inhibition required the presence of a newly identified G-protein complex. In 1990, that receptor was isolated, purified, the amino acid sequence determined, and the receptor cloned. The receptor was found to be a specific G-proteincoupled receptor that inhibits adenylate cyclase, binds cannabinoids, inhibits calcium ion flux and facilitates potassium channels (Childers and Breivogel 1998, Felder and Glass 1998). This ‘cannabinoid receptor’ is a chain of 473 amino acids with seven hydrophobic domains that extend through the cell membrane (Fig. 3). When THC binds, it activates G-proteins that act upon various effectors including the secondmessenger enzyme adenylate cyclase and both potassium and calcium ion channels (Fig. 4; from Childers and Breivogel 1998).
The identification of a naturally occurring ‘ligand’ that might function as a ‘natural THC’ remained to be demonstrated. In 1992 the arachidonic acid derivative anandamide was identified. This substance not only bound to the cannabinoid receptor, but produced cannabinoid-like behavioral, hypothermic, and analgesic effects that parallel those caused by THC. Indeed, anandamide exhibits the essential criteria required for its classification as the endogenous ligand at cannabinoid receptors.
In 1999, it was demonstrated that anandamide functions as a ‘partial agonist’ at hippocampal glutamate-releasing neurons to ‘reduce, but not totally block, excitatory transmission’ (Shen and Thayer 1999). This may explain not only an antiepileptic action of THC, but THC’s ‘neuroprotective antioxidant’ action as well (Hampson et al. 1998).
A cannabinoid antagonist has been synthesized; and mice lacking the cannabinoid receptor were bred and a lack of response to cannabinoid drugs demonstrated (Ledent et al. 1999). These same anandamide antagonists have been used to study dependence on THC; and, in 1999, a ‘marijuana abstinence syndrome’ was described (Haney et al. 1999a, 1999b).
Anandamide is synthesized within neurons by a condensation reaction between arachidonic acid and ethanolamine, under the regulation of calcium ions and cyclic adenosine monophosphate enzyme. It is broken down by a process of hydrolysis after carrier- mediated neuronal and astrocyte reuptake by an amidase for rapid hydrolysis (Piomelli et al. 1999). Anandamide, THC, and other anandamide-receptor agonists inhibit the presynaptic release of the excitatory neurotransmitter glutamate in the hippocampus (Shen et al. 1996). Thus, the hippocampus, cerebral cortex, cerebellum, and basal ganglia are major loci of action of THC because these structures are involved in cognition, learning, memory, mood, and other higher intellectual functions, as well as motor functions, all of which are affected by THC.
In the early 1990s, the unique pattern of localization of cannabinoid receptors in the brain was delineated (Herkenham 1992), with large numbers of receptors found in the basal ganglia, cerebellum, and cerebral cortex. The latter receptors for THC mediate the psychoactive effects of the drug. Cannabinoid receptors are also dense in the hippocampus; accounting for THC-induced disruption of memory, memory storage, and coding of sensory input. Brain stem structures do not bind cannabinoids; they do not depress respiration; and they are relatively nonlethal. Perhaps we can now rename the cannabinoid receptor as the anandamide receptor, recognizing the endogenous neurotransmitter for the receptor just as we define other transmitter-activated receptors.
How does this knowledge of THC pharmacology translate into clinical useful information? One of the major effects of marijuana in humans is disruption of memory, presumably due to the reduction in hippocampal activity. Such memory impairments can be attenuated by cannabinoid antagonists, implying that THC and anandamide-induced memory disruption is mediated by cannabinoid receptors and not by any indirect sedative mechanism (Mallet and Beninger 1998). THC impairs cognitive functions, perception, reaction time, learning, and memory. These impairments have obvious implications for psychomotor functioning, for example in the operation of a motor vehicle (Kurtzthaler et al. 1999).
THC and anandamide are both analgesic (at both spinal and brain stem levels). Cannabinoids produced analgesia, potentiating the analgesic action of morphine, increasing morphine’s potency; this action is blocked by cannabinoid antagonists, indicating again that THC is again acting through a cannabinoid receptor mechanism (Smith et al. 1998). In primates, THC decreases aggression, decreases the ability to perform complex behavioral tasks, seems to induce hallucinations, and appears to cause temporal distortions. THC causes monkeys to increase the frequency of their social interactions. Finally, THC can disrupt appetite regulation, inducing overeating in rats exposed to anandamide; providing evidence for the involvement of a central cannabinoid system in the normal control of eating.
Currently, there is one approved and several possible therapeutic uses for THC and its various derivatives. Dronabinol (Marinol), which is synthetic THC formulated in sesame oil, has been available for many years for use as an appetite stimulant in patients with AIDS and for use in the treatment of nausea and vomiting associated with chemotherapy in cancer patients. Other potential uses of dronabinol are to reduce the muscle spasms and pain in multiple sclerosis and reduce the intraocular pressure in glaucoma. Antidepressant and analgesic effects are also claimed, with analgesic actions best described in animal studies (discussed above).
The recent passage of initiatives legalizing the use of marijuana for medicinal uses has reopened this issue of therapeutics. Does marijuana have true therapeutic efficacy, equal to or greater than those of existing agents? The answer is muddied both by smoking as a route of administration and by the use of a crude product containing THC, which is only a weak agonist at cannabinoid receptors. Both of these facts limit the therapeutic use of smoked plant material as a therapeutic choice. The advent of highly potent synthetic analogues (pure anandamide agonists) and specific antagonists may make possible the development of compounds that lack the undesirable side effects of marijuana plant material (Adams and Martin 1996).
A 1999 report (Institute of Medicine 1999) concluded that cannabinoids have potential applicability for some human symptoms. However, the cannabinoids should be delivered by a mechanism other than inhaling smoke; the future may be non-smoked, inhaled molecules, whether they be natural THC from marijuana or totally synthetic compound. This entire area of research, drug development, and social discussion involves the input and opinion from both research and clinical pharmacologists.
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