COMPENSATORY PROCESSES MAINTAINING FUNCTION AFTER GENE DELETION OF DA RECEPTOR SUBTYPES INDICATE NOVEL DRUG TARGETS

schizophrenia and bipolar disorder would emerge, ideally, from increased

understanding of their pathobiology, but an alternative strategy is through

novel sites which operate in association with known therapeutic targets or

impact on other neuronal processes of putative relevance to these

conditions.  In mice with targeted gene deletion [‘knockout’] of the D₂

dopamine receptor, responsivity to challenge with a selective D₂-like

agonist is eliminated, as expected, in the manner of an animal given a large

dose of a D₂-like antagonist antipsychotic such as haloperidol; yet,

in the absence of D₂-like agonist challenge, the ethogram of their

spontaneous behaviour is little altered.  This suggests the operation of

compensatory non-dopaminergic processes consequent to the developmental absence

of D₂ receptors which are able to regulate topographical function

under tonic, naturalistic conditions.  Thus, resolution and direct

manipulation of such processes might indicate a novel, non-dopaminergic

therapeutic target.  In R6/1 mice transgenic for the Huntington

gene, progressive emergence of neurologic phenotype was prevented or materially

diminished by continuous administration of essential fatty acids from

conception, without alteration in underlying pathology.  This illustrates

that the functional consequences of a neuroprogressive process can be

ameliorated by an early and sustained intervention.  The concept may be