Glutamatergic mechanisms mediating stimulant and antipsychotic drug effects

This paper presents an hypothesis regarding the functions of striatal dopaminergic and glutamatergic neurotransmission. It is suggested that the principal functional role of dopaminergic neurotransmission is to regulate the efficacy of cortico-striatal and cortico-accumbens neurotransmission. Increased activity at dopamine-mediated synapses is suggested to interact with neurotransmission at adjacent cortically derived glutamate-mediated synapses, facilitating communication from the cerebral cortex, and thereby causing behavioral stimulation. Decreased activity at dopaminergic synapses, as produced by neuroleptic drugs, causes changes in the activation of cortically derived synapses in the corpus striatum and nucleus accumbens which result in behavioral sedation and decreased activity. This hypothesis suggests that activity at dopaminergic synapses produces behavioral effects only insofar as these changes modulate cortico-striatal (or cortico-accumbens) activity, and further, that the manifestations of activity in cortico-striatal systems are modulated by activity at dopaminergic synapses. It is further suggested that when neuroleptics are administered chronically, adjustments in the efficacy of cortico-striatal neurotransmission are responsible for the antipsychotic effect of neuroleptic drugs.