Ron;
15 years ago, I did a lot of reading on theories of the causes of Schizophrenia and why standard antipsychotic medications are suspected to work. Crudely put, the broad thought was that too much dopamine leads to auditory and visual hallucinations and psychosis. These major antipsychotic medications inhibit or slow down the processing of dopamine. The drugs used to control schizophrenia may share similar problems with Parkinson’s Disease treatment i.e. trying to regulate dopamine and ending up with too much dopamine or not enough. Look at, for example how many PD meds cause symptoms related to psychosis/ depression or how many things go wrong when we get too much dopamine. Chlorpromazine came out in the 50’s so surely the BBB must have been examined in Chlorpromazine’s development and subsequent decades of use. The discussion below ties Schizophrenia and Parkinson’s Disease on a few points. It is also interesting to note that prolonged use of anti-psychotic medications causes tardive dyskenesia and other parkinsonian features. These medications inhibit dopamine. Your discussion on BBB and permeability may be enlightened by examining Schizophrenia and the ways antipsychotic drugs work.
I pulled the following from:
http://www.benbest.com/science/anatmind/anatmd10.html
Phenothiazine derivatives
Phenothiazine: One of a group of tranquilizing drugs with antipsychotic actions thought to act by blocking dopaminergic transmission (messages sent using the substance dopamine) within the brain.
Schizophrenia is thought to be due to an overstimulation of D2 receptors in the mesolimbic and mesocortical systems. Evidence for the "excess dopamine" theory of schizophrenia comes largely from the fact that D2 antagonist drugs alleviate the symptoms, whereas substances which increase D2 stimulation, such as amphetamines, can induce psychotic symptoms (which are reversible with D2 antagonists). About 10% of Parkinsonian patients given DOPA treatment will develop psychotic symptoms resembling schizophrenia.
The major classes of antipsychotic drugs are the phenothiazines (e.g., chlorpromazine), the butyrophenones (e.g., haloperidol) and the thioxanthenes (e.g., chlorprothixene). Butyrophenones are 100 times more potent against D2 receptors than against D1 receptors. The similarity in shape between a portion of the chlorpromazine molecule and dopamine indicates how chlorpromazine could bind to a dopamine receptor without triggering a response.
The mesolimbic & mesocortical dopaminergic systems are thought to play an important role in motivation, by attaching cognition of incentive significance to stimuli. In experiments on animals that are motivated to electrically self-stimulate themselves with electrodes implanted in their brains, dopamine is the mediating neurotransmitter for the locus ceruleus, lateral hypothalamus, ventral tegmental area and sulcal prefrontal cortex (but not the nucleus accumbens or substantia nigra).
Cocaine particularly increases dopaminergic activity in the mesolimbic areas of the brain by inhibiting dopamine re-uptake in the ventral tegmental area and the nucleus accumbens. Amphetamine seems more generalized in its action, not only by inhibiting re-uptake, but by releasing dopamine from most brain regions. Both cocaine & amphetamine produce feelings of psychological energy & arousal, associated with diminished appetite & need for sleep. Both cocaine & amphetamine can lead to visual & tactile hallucinations as well as paranoid thinking, although the psychotic effects of amphetamine may also be mediated by increased serotonin release. Chronic amphetamine users seem to lose a capacity for normal pleasure -- which has been correlated with neuron degeneration in the mesolimbic area.
Perception of time-intervals is believed to be mediated by spiny neurons located in the striatum of the basal ganglia. Timing begins with a burst of dopamine and ends with a recognized signal. Marijuana slows subjective time by lowering dopamine available, whereas cocaine and methamphetamine accelerates the sense of time by increasing dopamine availability. (Adrenaline and stress hormones can also "make seconds feel like hours".)
There is no answer required to what I’ve written here, but I believe it would be a service to your UK professor to consider Manic Depression, Schizophrenia, theories re: Dopamine, theories of the disease and tardive dyskenesia and parkinsonian damage from long term use of phenothiazines. She may find some of the leg work already done. Wish I knew more. When God creates a 48 hour day . ... Guy