PS 3010 Behavioural Pharmacology Semester 2: 20042005 Lecture 6 a

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PS 3010 Behavioural Pharmacology Semester 2
2004-2005 Lecture 6 a bSchizophrenia, and
antipsychotic drugs

• Prof Michael H. Joseph
• School of Psychology

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Introduction

• The schizophrenias constitute one of the two
  major groups of psychotic disorders, the other
  being the affective disorders.
• Psychotic disorders are those which affect the
  whole psyche, or mind.
• So, their symptoms are more severe, or at least
  more all encompassing, than the other major group
  of psychiatric disorders, the neuroses.
• Schizophrenia is fairly common (1-2 lifetime
  risk) It has fascinated doctors, psychologists
  and philosophers because it appears to reflect a
  breakdown in the normal organisation of
  particular mental functions, including aspects of
  thinking, and perhaps consciousness.

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Symptoms of schizophrenia

• Can occur in any combination, and individual
  symptoms may appear and disappear during the
  illness. Nonetheless they are not arbitrary, and
  indeed show stereotyped formats, which makes them
  easy to recognise, if not always to describe.
• Can be divided into positive and negative
  symptoms.
• Positive symptoms refer to experiences and
  behaviours which are not present in normal
  individuals, and include
• Hallucinations, Delusions, Thought
  disorder. OHD

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Hallucinations, Delusions

• Hallucinations are false sensory experiences,
  and can occur in any modality, but by far the
  most common are auditory. A common report is
  that of hearing voices, often talking about the S
  subject. There may be one or more, and a
  particularly diagnostic indication is third
  person voice(s). This means talking about the
  subject in the 3rd person (hes crossing the
  road), NOT that there are at least 3 voices.
• Delusions are false beliefs. These can be on
  any subject, but are most commonly paranoid (the
  FBI is spying on me), or grandiose (I am
  superhuman, a god, Napoleon)

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Thought disorder

• TD is a loosening of associations, disorders in
  the flow of thought, and jumping of thought from
  one topic to another.
• This is inferred from disorders in the structure
  of the patients speech, or discourse.
• Note that this, like the other positive symptoms,
  is based on what the patient says, or tells us.
• This subjective element bedevils objective and
  unambiguous diagnosis of schizophrenia.
• Note also that this differs from the other two
  positive symptoms, in that they are well
  organised, while this is disorganised.

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Negative symptoms

• Refer to the absence of experiences and
  behaviours which are present in normal
  individuals.
• They include poverty of speech, muteness
  flattened affect psychomotor retardation.
• Quite a common pattern is that positive (type I)
  symptoms are predominant in the early stages, and
  that negative (type II) symptoms emerge over
  time.
• Certainly they can co-exist however, and usually
  overlap.
• Other symptoms include incongruous affect,
• and (non-specific) anxiety and
  depression.
• Concept of three types of syndrome
• positive, disorganised and negative

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Genetic aspects

• If you have schizophrenia, then it is more likely
  that you will have relatives who have been, or
  will be, diagnosed as schizophrenic.
• The risk factor decreases with increased genetic
  distance from a schizophrenic relative.
• Thus it is very likely that there is a genetic
  component. However the concordance in identical
  (MZ) twins is only some 50 thus it is not a
  simple gene disorder.
• Concordance studies in adopted children show that
  the risk is that attributable to the biological
  mother, and not the adoptive mother, thus the
  familial risk is not attributable to patterns of
  child rearing, etc.

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Early ideas about the biology of schizophrenia

• Schizophrenia was recognised and described in the
  latter part of the 19th C by Kraepelin and
  Bleuler.
• Although these psychiatrists believed that there
  probably was a biological origin, evidence was
  scanty.
• The rise in psychological theories related to
  psychoanalysis led others to assert that it was a
  purely psychological disorder.
• Before the genetic studies mentioned above, it
  was suggested that it might be the result of
  early childhood experience or other abnormalities
  of development related to environmental factors.
• An axiom of my clinical psychology training was
• there is no physical abnormality in the brain
  in S.

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Biochemical models of schizophrenia

• The earliest biological models of S came from
  observations of the actions of hallucinogenic
  drugs.
• Drugs such as LSD and mescaline are
  hallucinogenic - result in perceptual
  disturbances and hallucinations.
• Hallucinogens are analogues of either
  catecholamine or indoleamine transmitters, and
  act on the same receptors.
• Since e.g. mescaline was a methylated analogue of
  noradrenaline, it was suggested that
  schizophrenia might result from abnormal
  methylation of such natural products, to produce
  similar substances, either in the brain, or that
  reached the brain after synthesis in the body.

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Biochemical models of schizophrenia (cont.)

• Other methylated analogues of CAs and IAs were
  synthesised, or extracted from natural sources
  such as toads and toadstools (witches take note),
  and found to have hallucinogenic properties also.
• This led to a search for such compounds in the
  blood or urine of S patients and a number of
  promising candidates were turned up. One of the
  best was the pink spot (observed on paper
  chromatography).
• Unfortunately these proved to be related either
  to medication, or to abnormalities of diet, or
  proved to be present in many other disorders in
  which hallucinations were not present.
• It did lead to a paper with the memorable title
  Pink spots and red herrings, and it did teach
  us a lot about how to do clinical research, and
  just how difficult it was to identify suitable
  control subjects.

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Drugs for schizophrenia

• A major breakthrough came from the introduction
  (1950s) of drugs effective against the symptoms
  of S.
• The first of these was chlorpromazine (CPZ),
  synthesised as an antihistamine. Given to
  surgical patients to reduce shock, it was quickly
  found to exert a profound calming effect.
• Tried on psychotic patients, and relieved many
  positive, and to some extent negative, symptoms
  of S.
• Use spread rapidly across the world, and
  revolutionised the treatment of patients, and the
  atmosphere of psychiatric hospitals.

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Drugs for schizophrenia II

• On its own, CPZ provided little clue as to how it
  worked, as you would expect from its trade name,
  LARGACTIL, which comes from its having a
• LARGe number of ACTIons.
• However, the emergence of Parkinsonian side
  effects pointed the finger at the involvement of
  the neurotransmitter dopamine.
• CPZ was shown to increase DA metabolism in rats,
  and Carlson, taking a hint from the
  neurochemistry of Parkinsons disease,
  ingeniously suggested that this increase in DA
  transmission was in fact a compen-sation for
  reduced DA transmission, following receptor
  blockade (work which led on to the award,
  recently, of a Nobel prize).

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Drugs for schizophrenia III

• CPZ is a phenothiazine the discovery of other
  classes of drugs which were effective against
  schizophrenia - butyrophenones (eg HAL),
  thioxanthines (eg FLU) quickly enabled this
  result to be triangulated what did they have in
  common?
• The ability to measure binding to DA receptors in
  vitro, allowed a comparison of potency in binding
  to calf brain DA receptors and clinically
  effective dose.
• An extremely strong correlation was demonstrated
  (see well loved graph).
• These drugs are collectively known as
  neuroleptics, or brain grabbers.

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DA antagonists improve S, but do agonists
worsen it ?

• Amphetamine, whose main action is to increase DA
  transmission, both exacerbates S in sufferers,
  and precipitates psychotic symptoms in abusers.
• In fact amphetamine abusers can present with a
  perfect mimic of paranoid schizophrenia, which
  can fool even an experienced psychiatrist, until
  the history of drug abuse emerges.
• Furthermore, both of these effects of amphetamine
  respond to neuroleptic treatment

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Dopamine Theory of Schizophrenia

• These two types of observations, then, form the
  basis of the DA theory of S.
• A particularly nice confirmation of the role of
  DA blockade in neuroleptic action was provided by
  the trial of the isomers of Flupenthixol (FLU) -
  supports the crucial role of DA blockade in the
  action of neuroleptics.
• FLU is a neuroleptic drug, usually used as a
  Racaemic (equal) mixture of two isomers.
• Only one isomer (a) is able to block the DA
  receptor effectively.

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the Flupenthixol trial

• Hence the two isomers (a, ß)were given separately
  to two groups of patients, and a third group
  received a placebo, for 4 weeks.
• In the first two weeks, improvements were similar
  in all three groups, but in the following two
  weeks, they were significantly greater in the a
  group. The other two groups were similar, i.e.
  the ß isomer had no advantage over placebo.
• However, the antipsychotic effect was delayed
  compared to the blockade of receptors.
• Hence DA blockade is critical for a clinical
  effect, but it is not enough in itself something
  else has to happpen.

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Which brain area is critical

• Where do DA blockers act in the brain in S ?
• Probably not the striatum on the grounds that
• EPS do not correlate with therapeutic efficacy
• Parkinsons disease and schizophrenia co-exist in
  at least a few patients.
• Some drugs which are highly selective for the
  mesolimbic system are effective antipsychotics,
  e.g. sulpiride.
• Given repeatedly, neuroleptics produce
  depolarisation block in the mesolimbic system,
  preferentially over the nigro-striatal system.

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DA and schizophrenia

• Need to distinguish between the DA theory, which
  is essentially an account of DAergic drug actions
  on symptoms, and the issue of whether
• DA systems are overactive in S, and perhaps
  especially so in the mesolimbic system.
• recall distinction for ACh / DA in PD
• What sort of evidence might address this question
  ?
• DA and metabolites PM brain, CSF, plasma or
  urine
• DA receptors PM brain. Increased D-2 receptors
  were found, but not confined to mesolimbic
  system. Problem of drug therapy (giving DA
  blockers does increase numbers of DA receptors
  supersensitivity). Evidence from a few patients
  who had been drug free at time of death suggested
  that only part of the effect was drug induced.

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DA and schizophrenia II

• More recently it has been possible to image
  receptors in vivo, using PET or SPECT scanning to
  image the binding of labelled DA antagonists
  (although difficult to resolve dorsal and ventral
  striatum striatum and accumbens).
• These studies have produced mixed results,
  depending on the exact ligand (antagonist) used.
• Another interesting application of this approach
  is to study the displacement of a labelled drug
  from receptors by DA released by amphetamine.

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DA and schizophrenia III

• In studies in which amphetamine has been given to
  induce DA release, greater DA release was
  observed in schizophrenic patients than in
  controls, after checking that plasma AMP levels
  were not different. More studies are needed.
• Overall, it has been very difficult to accumulate
  unambiguous evidence for increased DA function in
  S. Also the fact that nearly all S patients are
  on treatment (quite rightly) with DA blockers,
  which have marked effects on all aspects of DA
  transmission means that the question is very
  difficult to address take them off problem of
  rebound effects.

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DA and schizophrenia IV

• However, we noted above that the lack of evidence
  that DA systems are overactive in the disease
  state, does not go against the DA hypothesis, in
  its restricted form
• Do we have any evidence that there are physical
  abnormalities in the brain, and especially in the
  DA innervated areas ?
• As we have heard, it was an early tenet that
  there were no physical alterations in the brain
  in S.
• However the advent of CAT scanning at CRC/NPH,
  and the start up of the Division of Psychiatry
  there (which also conducted the flupenthixol
  trial) led to new studies in the early 1970s.

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Brain pathology and schizophrenia

• Evidence for physical changes in brain was found.
  CAT scanning revealed significant increases in
  ventricular areas in older subjects, but not so
  great that a diagnosis could be made !
• These have been confirmed in younger subjects
  using fMRI indeed they appear to be present from
  the early years.
• A particularly interesting study (Weinberger)
  used twins discordant for S (unusual). This
  showed a consistent increase in ventricular area
  in the twin who had S, when compared with the
  discordant co-twin.
• Again the difference is not large enough for
  diagnosis, but it is virtually always in the same
  direction illustrates advantages of a paired
  control.

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Brain pathology and schizophrenia II

• With these small differences, it is difficult on
  cross sectional scans to see which brain areas
  are affected.
• This information has come more from post mortem
  neuropathological studies, which have
  consistently shown abnormalities in the temporal
  lobe (planum temporale) and in the hippocampus,
  amygdala and associated limbic cortices.
• However, pathology is not seen in the n.Accumbens
  DA system.
• The detailed pathological studies seem to
  implicate glutamatergic neurones.

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Evidence supporting altered glutamate function in
schizophrenia 

• Psychotomimetic effects of phencyclidine (PCP) -
  blocks channel of NMDA glutamate receptors
• Neurochemical evidence for changes in GLU
  markers
• PM studies indicating reduced numbers of some
  subtypes or subunits of glutamate receptors in
  hippocampus. 
• Alteration in glutamate binding sites in orbital
  frontal cortex. Increased re-uptake sites
• PM studies indicating disorganisation of
  hippocampal pyramidal cells possible failure of
  migration during development.

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Glutamate, DA and schizophrenia

• Hence it is suggested that glutamate projections
  are disorganised, or under-active.
• How can this be linked with the pharmacological
  evidence that altering DA function in the
  accumbens has important effects on symptoms ?
• In fact the hippocampus, the amygdala and the
  frontal (limbic) cortex all send GLU projections
  to the accumbens, where they are inhibited by DA
  inputs from the mid-brain VTA.

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Glutamate, DA and schizophrenia

• Thus the effectiveness of blocking dopamine can
  then be understood as restoring the balance
  between reduced, or disorganised, GLU activity
  and normal DA.
• Dopamine is not overactive in an absolute sense,
  but in a relative sense - in relation to
  glutamate, presumably in the accumbens.
• analogous to ACh/DA in the striatum in PD

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Glutamate, DA and symptoms of S.

• Thus we postulate a defect in an interacting
  GLU/DA system. But note that all of the evidence
  has come from pharmacology, neuropathology and
  imaging studies, rather than neuropsychology.
• How do these changes, in GLU or DA function, or
  indeed both, in these areas, link to the SYMPTOMS
  of schizophrenia.
• The way things break down tells us about their
  normal function.  

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Glutamate, DA and symptoms

• And the normal function of these areas is
  described as memory, or spatial orientation, or
  locomotor activity, or motivation, or emotion.
• Although schizophrenics do have disturbances in
  all of these functions, none of them seems
  central to the presenting symptoms of S., or to
  the experience of S., as far as we can judge it.
• This is also relevant to the construction of
  Models for schizophrenia. To find effective
  drugs, we have in the past used animal models
  such as
• Catalepsy.
• Reversing locomotor-stimulating effects of
  amphetmine
• Impairing the conditioned avoidance response
  (CAR).

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DA and symptoms - psychology

• These are actually tests of the blocking of DA
  receptors, and given that DA receptor blockers
  are effective antipsychotics, the tests will have
  predictive validity.
• However, they will only enable us to identify
  further drugs of the same type. These will
  usually share the limitations, as well as the
  effectiveness, of established drugs.
• Thus it would be better to have behavioural tests
  which would have some relation to the symptoms of
  S. In order to do this we have to turn to
  psychologists to analyse the behavioural
  pathology underlying the symptoms.

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Symptoms and psychology

• There are many theories about pathologies which
  might underlie hallucinations (interpretations of
  inner sensory processes), or delusions (beliefs
  which have got past the censor).
• Thought disorders, in particular, seem to reflect
  a disturbance in the patterning of thought, in
  its normal flow. And many psychologists have
  pointed to disturbances in attention and
  filtering in S that might underlie this.
• Patients report that they are flooded with
  information, that they cant select the relevant
  stuff and concentrate on it, that they cant
  successfully exclude irrelevant material.

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Symptoms and attention

• One paradigm that Psychologists use to assess
  this is latent inhibition (LI).
• Stimuli which are repeated without consequence
  become harder to learn about in the future. This
  reflects the gating out of such stimuli, which
  are less likely to be useful, so that we can
  concentrate on new and changing stimuli.
• If there is a breakdown in this process, so that
  our attention is continually drawn to familiar
  and irrelevant stimuli, or irrelevant meanings,
  this will disrupt our train of thought, and also
  may result in inappropriate attributions of
  salience
• (I know the FBI is watching me because I keep
  seeing red cars in the street).

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Latent inhibition (LI) in animals

• LI can be demonstrated, and indeed studied, in
  animals as well as man, and we can investigate
  the effects of DA, 5-HT and GLU manipulations on
  it.
• It is established that LI is disrupted in animals
  by amphetamine, and by other ways of increasing
  DA activity, provided that this is
  impulse-dependent.
• Established that this disruption is reversed by
  DA blocking drugs such as haloperidol
  (neuroleptic), and also by atypical antipychotics
• Such drugs, on their own, can enhance LI.

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Latent inhibition (LI) in humans

• These drug effects in animals can broadly be
  replicated in volunteer human subjects.
• Acutely ill schizophrenics, but not chronic
  patients, show disrupted LI in most (but not all)
  studies.
• Schizotypy also appears to be linked to reduced
  LI in most studies.
• Enhanced LI may provide a model which detects
  multiple classes of antipsychotics, not just
  neuro-leptics, and also has some face and
  construct validity for some of the symptoms of
  schizophrenia.

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Neuroleptics vs. atypical antipsychotics I

• All classes of classical neuroleptics (typical
  antipsychotics) block DA receptors, as shown.
• This means that they all have extrapyramidal
  (Parkinsonian) side effects (EPS) due to the
  block of DA receptors in the striatum
  (nigro-striatal DA system).
• These can be helped by anticholinergic medication
  (restores DAACh balance)
• In addition, and even more seriously, they can
  lead to tardive dyskinesia (TD).

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Neuroleptics vs. atypical antipsychotics II

• What are TDs ? - Choreic movements developing
  over time. Believed to relate to increases in DA
  receptors, since they respond acutely to an
  increase in neuroleptic dose.
• However this is a short-term solution, and TDs
  often limit therapeutic use.
• Psychiatrists have therefore sought antipsychotic
  drugs with less EPS.
• This then is the definition of an atypical
  antipsychotic one with reduced EPS liability.

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The prototypical atypical

• Clozapine was introduced clinically and found to
  be highly effective, but was withdrawn because of
  substantial risk of blood dyscrasias.
• However some psychiatrists thought it was so
  effective that they pressed for its continued
  use.
• It was reintroduced for use under strictly
  controlled conditions, with blood monitoring,
  in patients resistant to typical neuroleptics.
• Now established that it is effective, and
  especially so against negative symptoms
  resistant to neuroleptics.

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How does clozapine work

• Clozapine is also a 5HT-3 antagonist, and a D-3
  and D-4 antagonist.
• Recent flurry of interest in the D-4 receptor
  when Phil Seeman claimed that there was a very
  specific increase in D-4 receptors at PM in brain
  from Ss.
• He claimed that the discrepant results reported
  for D-2 receptors related to whether or not the
  ligands used bound to D-4 receptors also.
• However his results were obtained by differences,
  since he lacked good phamacological tools for D-3
  and D-4 receptors specifically.

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How does clozapine work II

• More recent studies have confirmed increases in
  D-4 receptors in NAC, and D-3 receptors in
  neostriatum and NAC.
• However, a drug which selectively blocked D-4
  receptors was not an effective antipsychotic.
• Hence actions on D-4 receptors may not account
  for therapeutic effect of atypical
  antipsychotics.
• Just as in the early days with chlopromazine, we
  need a wide range of compounds with and without
  clinical effectiveness to identify the critical
  components in atypical antipsychotic action.

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Further developments

• Pharmacologically, CLOZAPINE is a weak D-2
  antagonist, although it does have a very wide
  range of actions (dirty vs rich pharmacology).
• Believed that efficacy might reside in 5HT-2
  antagonism, with or without the weak D-2 antagm.
• This has sparked off a number of leads in drug
  companies, looking for the Clozapine without the
  blood problems.
• a) me too drugs 5HT-2 block greater than D-2
  (Lilly - Olanzepine)
• b) 5HT-2 block similar to D-2 block (Janssen
  - Risperidone)
• c) 5HT-2 block alone (Marion-Hoechst-Roussell)

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Atypicals other drug classes I

• Very selective D-2 antagonist.
• Sulpiride (Remoxipride, Raclopride)
• preferential action on meso-limbic DA not clear
  why
• D-1 antagonists.
• Not clear why these should work, and they don't.
• But at least avoid side effects - no D-2 block.
• D-2 partial agonists
• Aim to stimulate auto-receptors preferentially.
• Don't seem to work clinically

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Atypicals other drug classes II

• 5HT-3 antagonists
• Thought to inhibit enhanced DA activity by an
  action in NAC or VTA.
• Should avoid excessive reduction of DA function,
  but might depend upon whether DA activity is
  actually increased in schizophrenia.
• Clinical results not clear.
• Allosteric glutamate agonists.
• Rationale that they should have opposite effect
  to PCP.
• Should avoid neurotoxic risk from direct GLU
  agonist.
• Again clinical results poor, so far

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Sidelight, or perhaps tail-light

• Many psychotropic drugs have a complex spectrum
  of actions on different receptors or
  transmitters. Making them more selective has
  been an important goal of the pharmaceutical
  industry.
• This has sometimes reduced side effects, but has
  rarely increased clinical effectiveness.
• The bottom line is perhaps that psychiatric
  disorders are not one transmitter/one brain area
  disorders.
• Maybe, with hind-sight, Parkinsons disease was a
  bit of a red herring, as well as a shining beacon.

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References

• From core texts
• Carlson NR. Physiology and Behaviour, 7th
  edition 2001, Allyn and Bacon, Chapter 17,
  pp528-543
• Rosenzwieg et al, Biological psychology, 3rd
  edition, 2001, Sinauer, Chapter 16, pp436-447
• Feldman, Meyer and Quenzer, Principles of
  Neuropsychopharmacology, Chapter 18, pp 783-818.
• Probably as detailed as you need.
• Further specific references, for interest 
• Strange, P.G. (1992) Brain biochemistry and
  brain disorders, chapter 13, Schizophrenia,
  Oxford Univ. Press
• Weinberger, D R. (1987) Implications of normal
  brain development for the pathogenesis of
  schizophrenia. Arch Gen Psychiatry, 44, 660-669
  (July). (cont./)

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References

• Wolf, SS, Hyde, TM and Weinberger, DR. (1993)
  Neurobiology of schizophrenia, Current Opinion in
  Neurology and Neurosurgery, 6,86-92
• Kerwin, RW, and Murray, RM. (1992) A
  developmental perspective on schizophrenia.
  Schizophrenia Research, 7 1-12
• Feldon J, and Weiner I (1991) From an animal
  model of an attentional deficit towards new
  insights into the pathophysiology of
  schizophrenia. Journal of Psychiatric Research,
  26 345-366.
• Gray JA, Feldon J, Rawlins JNP, Hemsley DR,
  Dawling S, Smith AD (1991) The neuropsychology
  of schizophrenia. Behavioral and Brain Sciences
  14 1-20
• Reynolds G.P. (1992) Developments in the drug
  treatment of schizophrenia. Trends in
  pharmacological sciences, 13, 116-121 (March)
  (cont/)

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References and websites

• Andreasen, NC (1997) Linking mind and brain in
  the study of mental illness. Science, 275,
  1586-1593.
• Kapur, S (2003) Psychosis as a state of aberant
  salience a framework linking. Am J. Psychiat
  160, 13-23.
• Useful web sites http//salmon.psy.plym.ac.uk/
• Material from first and second year courses
  available. Looks exciting. By all means try it
  out, but I cant guarantee it for accuracy yet.
• And another http//www.dana.org/brainweb/
• A more general site, with material relating to
  all brain disorders. Run by a research-awareness-
  raising charity, which is also active in Europe
  as EDAB.