EDITORIAL

Neuropharmacology in the Next Millennium: Promise for Breakthrough Discoveries

Pharmacology has provided powerful tools to study zyme), although most receptors and isozymes are ex- and characterize neurochemical pathways in the brain, pressed in more than one brain region making this very and how these pathways may be involved in the patho- difficult. This also poses problems for pharmacological physiology and treatment of psychiatric illness. This studies where drugs are often administered peripherally work has focused largely on neurotransmitter systems, and have access to the entire brain. On the other hand, including the synthesis, release, and metabolism of the therapeutic efficacy of a drug may be enhanced by monoamines and receptor subtypes that control pre- its ability to influence multiple receptor or enzyme sub- synaptic release of neurotransmitters and their postsyn- types. A good example of this is the atypical antipsy- aptic effects. In addition, pharmacological tools have chotic clozapine, which antagonizes multiple monamine been useful for developing models of certain neurobio- receptor subtypes. This combination of receptor actions logical disorders. However, little progress has been is thought to account for the superior efficacy of cloza- made over the past 40 years in the development of novel pine, as well as other putative atypical antipsychotics, therapeutic agents (an exception is the recent finding relative to more selective agents (e.g., selective dopa- that a neurokinin-1 receptor antagonist has antidepres- mine D4 receptor antagonists). However, the nonselec- sant efficacy), and the underlying etiology of psychiatric tivity of clozapine (or olanzapine, for example) most illnesses has remained largely unknown. This is un- likely also accounts for its side effects, including in- doubtedly a result, in part, of the complex nature of creased weight gain. Nevertheless, these agents provide disorders of the brain, combined with the fact that most an example of how drugs of the future may have a spec- of these disorders are syndromes and are thought to trum of neurochemical targets that together result in a have multiple underlying determinants. Another factor greater efficacy and reduced time lag. contributing to this problem is that the therapeutic ac- The second complication in understanding the action tion of most psychotropic agents is dependent on long- of psychotropic drugs is the requirement for chronic term treatment and the consequent molecular and cel- treatment. This has led to the hypothesis that the thera- lular adaptations that occur over time. Thus, future peutic action of these treatments is dependent on adap- progress in development of novel therapeutic agents tations to the acute drug actions (e.g., blockade of mono- and identification of the etiology of psychiatric illnesses amine reuptake or metabolism for antidepressants, or will be dependent upon basic and clinical research to antagonism of monoamine receptor subtypes for anti- characterize the complex neurobiology underlying these psychotic agents). Identification of the relevant adapta- disorders. tions, which can be thought of as a form of drug- Complex disorders, such as depression and schizo- induced neural plasticity, could occur at several cellular phrenia, involve multiple brain regions and interactions levels, including regulation of neurotransmitter recep- among these regions as well as other areas. This makes tor coupling and intracellular signaling pathways that it extremely difficult to pinpoint the primary patho- control virtually every aspect of neuronal function. The physiological determinants of these disorders. This also complexity of possible adaptations of these pathways is poses difficult problems for identifying drug targets at least comparable to that of the complex neural cir- and developing efficacious therapeutic agents. On the cuitry involved in drug action and etiology of psychiat- one hand, the target should be a specific receptor sub- ric illnesses. However, this is a very exciting area of re- type (or subtype of some other signaling protein or en- search because, like the synaptic plasticity that underlies

NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 2 © 1998 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(98)00105-5

98 Editorial NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 2

learning and memory, characterization of drug-induced ations. Moreover, new strategies have been developed plasticity will provide vital information on how differ- for inducible and region specific expression or knock- ent brain systems adapt to sustained stimulation or in- out of genes. This avoids complications that are en- hibition. This information, in turn, will provide novel countered in traditional knock-out and transgenic strat- targets for the development of therapeutic agents. More- egies, including the developmental adaptations which over, this information will be critical for understand- occur and the indirect actions that the altered gene may ing the etiology of complex psychiatric illnesses that are have via its effects on other tissues or brain regions. influenced by different environmental factors which Neurotropic-viral expression systems have also proven could have a major impact on neural adaptive mecha- to be extremely useful for inducing localized expression nisms. For example, it is likely that adaptive plasticity of a gene product. Although these strategies are not of a neuronal system is critical to the development of routine, they are rapidly spreading and becoming more normal responses to environmental inputs, including readily available. For example, it is now possible to or- physical as well as psychosocial challenges. A break- der genetically engineered mice from one of several an- down in the ability to mount the appropriate adaptive imal vendors that act as clearing houses for research responses could contribute to the etiology of certain dis- laboratories. Similarly, it is only a matter of time before orders. This breakdown could occur for a variety of rea- viral expression systems are available commercially. In sons, including environmental and genetic factors. In combination with the continued development of drugs either case, further characterization of the mechanisms with different receptor subtype or isozyme profiles, it underlying neural plasticity to drugs, as well as environ- will be possible to selectively increase or decrease the mental stimuli, will be essential to a better understand- function of a membrane or cytoplasmic protein and ing of the molecular and cellular basis of drug action and thereby determine its cellular and behavioral actions. disease etiology. The application of these approaches offers tremendous Characterization of the neurobiological mechanisms optimism for major breakthrough discoveries in neurobi- that underlie neural plasticity, as well as the the neural ology. With these advances, in combination with genetic circuitry that conveys this information, is no small task. analysis of psychiatric disorders and continued progress In addition, identification of the pre- and postsynaptic in brain imaging, the next millennium will witness a new receptor subtypes and isozymes that acutely control era of psychiatry as it becomes a fullfledged partner to neural plasticity and that may be relevant substrates for molecular medicine. This multidisciplinary approach to the development of therapeutic intervention represents understanding the neurobiology and pharmacology of a significant challenge. However, significant technical psychiatric disorders is also particularly appropriate and and conceptual advances have been made at all levels well suited for the goals of Neuropsychopharmacology. of neurobiology that will enable the success of these goals to be achieved during the next millennium. Ad- Ronald S. Duman, Ph.D. vances in molecular gene engineering now make it pos- Associate Professor of Psychiatry and Pharmacology sible to knock-out and then rescue a gene and to study Yale University School of Medicine the cellular and behavioral phenotype of the gene alter- New Haven, Connecticut