Neuropsychopharmacology

History

Drugs such as thorazine and lithium which showed some clinical specificity for mental illnesses such as depression and schizophrenia. Until that time, treatments that actually targeted these complex illnesses were practically non-existent. The prominent methods which could directly affect brain circuitry and neurotransmitter levels were the pre-frontal lobotomy, and electroconvulsive therapy, the latter of which was conducted without muscle relaxants which often caused the patient great physical injury.

The field now known as neuropsychopharmacology has resulted from the growth and extension of many previously isolated fields which have met at the core of psychiatric medicine, and engages a broad range of professionals from psychiatrists to researchers in genetics and chemistry. The use of the term has gained popularity since 1990 with the founding of several journals and institutions such as the Hungarian College of Neuropsychopharmacology^[1]. This rapidly maturing field shows some degree of flux, as research hypotheses are often restructured based on new information.

Overview

An implicit premise in neuropsychopharmacology with regards to the psychological aspects is that all states of mind, including both normal and drug-induced altered states, and diseases involving mental or cognitive dysfunction, have a SPECT). These imaging techniques are extremely sensitive and can image tiny molecular concentrations on the order of 10^-10 M such as found with extrastriatal D₁ receptor for dopamine.

One of the ultimate goals is to devise and develop prescriptions of treatment for a variety of neuro-pathological conditions and psychiatric disorders. More profoundly, though, the knowledge gained may provide insight into the very nature of human thought, mental abilities like learning and memory, and perhaps consciousness itself. A direct product of neuropsychopharmacological research is the knowledge base required to develop adverse effects.

The groundwork is currently being paved for the next generation of signal transduction, any of which may still be a target for specific therapy. At present, novel pharmacological approaches to diseases or conditions are reported at a rate of almost one per week^[3].

Neurotransmission

So far as we know, everything we perceive, feel, think, know and do are a result of neurons firing and resetting. When a cell in the brain fires, small chemical and electrical swings called the EEG device.

By the last decade of the 20th century, the essential knowledge of all the central features of neurotransmission had been gained ^[4]. These features are:

• The synthesis and storage of neurotransmitter substances,
• The transport of synaptic vesicles and subsequent release into the synapse,
• Receptor activation and cascade function,
• Transport mechanisms (reuptake) and/or enzyme degradation

The more recent advances involve understanding at the serotonin receptor for example.) It is often found that receptor subtypes have differentiated function, which in principle opens up the possibility of refined intentional control over brain function.

It has previously been known that ultimate control over the membrane voltage or potential of a nerve cell, and thus the firing of the cell, resides with the trans-membrane metabotropic type, G-proteins will cause metabolism inside the cell that may eventually change other ion channels. Researchers are better understanding precisely how these changes occur based on the protein structure shapes and chemical properties.

The scope of this activity has been stretched even further to the very blueprint of life since the clarification of the mechanism underlying metabotropic processes, also actually modulates gene expression. This is most prominently achieved through modification of the transcription initiation process by a variety of transcription factors produced from receptor activity.

Aside from the important pharmacological possibilities of gene expression pathways, the correspondence of a gene with its protein allows the important analytical tool of gene knockout. Living specimens can be created using homolog recombination in which a specific gene cannot be expressed. The organism will then be deficient in the associated protein which may be a specific receptor. This method avoids chemical blockade which can produce confusing or ambiguous secondary effects so that the effects of a lack of receptor can be studied in a purer sense.

Drugs

The inception of many classes of drugs is in principle straightforward: any chemical that can enhance or diminish the action of a target protein could be investigated further for such use. The trick is to find such a chemical that is receptor-specific (cf. "benzodiazepines).

New endogenous chemicals are continually identified. Specific receptors have been found for the drugs modafinil which was already being used only a year prior.

The next step, which major CRF₁ blockers, and 5HT_2c blockers^[8]. Another is the proposal of new routes of exploration for anti-psychotics such as glycine reuptake inhibitors^[9]. Although the capabilities exist for receptor-specific drugs, a shortcoming of drug therapy is the lack of ability to provide anatomical specificity. By altering receptor function in one part of the brain, abnormal activity can be induced in other parts of the brain due to the same type of receptor changes. A common example is the effect of D₂ altering drugs (neuroleptics) which can help schizophrenia, but cause a variety of dyskinesias by their action on motor cortex.

Modern studies are revealing details of mechanisms of damage to the nervous system such as SERT, long-lasting reduction of serotonergic axons and terminals is found from short-term use, and regrowth may be of compromised function.

Neural circuits

It is a not-so-recent discovery that many functions of the brain are localized to associated areas like motor and speech ability. Functional associations of brain anatomy are now being complemented with clinical, behavioral, and genetic correlates of receptor action, completing the knowledge of neural signalling (see also: Human Cognome Project). The signal paths of neurons are hyper-organized beyond the cellular scale into often complex neural circuit pathways. Knowledge of these pathways is perhaps the easiest to interpret, being most recognizable from a systems analysis point of view, as may been seen in the following abstracts.

Progress has been made on central mechanisms of glutamate in the frontal cortex, while simultaneously in the locus coeruleus sensory information is promoted and spontaneous activity decreases. One hypothesis suggests that in the frontal cortex, 5HT_2A promotes late asynchronous excitatory post-synaptic potentials, a process antagonized by serotonin itself through 5HT₁ which may explain why SSRI's and other serotonin-affecting drugs do not normally cause a patient to hallucinate.

 

Circadian rhythm, or sleep/wake cycling, is centered in the suprachiasmatic nucleus (SCN) within the hypothalamus, and is marked by adenosine builds up from the metabolism of ATP throughout the day, it binds to adenosine receptors, inhibiting the basal nucleus. The PAH is then activated, generating slow-wave sleep activity. Caffeine is known to block adenosine receptors, thereby inhibiting sleep among other things.

Research

Research in neuropsychopharmacology comes from a wide range of activities in neuroscience and clinical research. This has motivated organizations such as the American College of Neuropsychopharmacology (ACNP), the European College of Neuropsychopharmacology (ECNP), and the Collegium Internationale Neuro-psychopharmacologicum (CINP) to be established as a measure of focus. The ECNP publishes "European Neuropsychopharmacology", and as part of the Nature Publishing Group, the ACNP publishes the journal Neuropsychopharmacology, and the CINP publishes the journal International Journal of Neuropsychopharmacology with Cambridge University Press. In 2002 the most recent comprehensive collected work of the ACNP, "Neuropsychopharmacology: The Fifth Generation of Progress" was compiled. It is one measure of the current state of knowledge, and might be said to represent a landmark in the century-long goal to establish the basic neuro-biological principles which govern the actions of the brain.

Many other journals exist which contain relevant information such as "Neuroscience". Some of them are listed at Brown University Library.

See also

• Psychoactive drug

v • d • e Medication > Psychopharmacology)

References

("4th Gen." and "5th Gen." refer to ACNP, see links)

1. ^  "The history of HCNP:Exchanging information and catalysing progress", ECNP Newsletter, N7 (2004)
2. ^ Fujita, M. and Innis, R. B., "In vivo Molecular Imaging: Ligand Development And Research Applications", (5th Gen. Prog.)
3. ^ Tallman, J. F., "Neuropsychopharmacology at the New Millennium: New Industry Directions", Neuropsychopharmacology 20 (1999)
4. ^ Bloom, F. E., "Introduction to Preclinical Neuropsychopharmacology", (4th Gen. Prog.)
5. ^ Watson, S. J. and Cullinan, W. E., "Cytology and Circuitry", (4th Gen. Prog.)
6. ^ Physicians' Desk Reference, 1990, 2005
7. ^ Erowid, "The Neuropharmacology of γ-hydroxybutyrate (GHB)" (2004)
8. ^ Tallman, J. F., Cassella, J., Kehne, J., "Mechanism Of Action Of Anxiolytics", (5th Gen. Prog.)
9. ^ Depoortère, R., et al, "Neurochemical, Electrophysiological and Pharmacological Profiles of the Selective Inhibitor of the Glycine Transporter-1 SSR504734, a Potential New Type of Antipsychotic", Neuropsychopharmacology 30, pp1963-1985, (2005)
10. ^ Abraham, H. D., Mccann, U. D., Ricaurte, G. A., "Psychedelic Drugs", (5th Gen. Prog.)
11. ^ Colwell, C. S., "Circadian Rhythms", (4th Gen. Prog.)
12. ^ Lewy, A. J., "Circadian Phase Sleep And Mood Disorders", (5th Gen. Prog.)