  Membrane receptors for neuromodulators (NM) are highly regulated in their
distribution and efficacy - a phenomenon which influences the individual cell's
response to central signals of NM release. Even though NM receptor regulation
is implicated in the pharmacological action of many drugs, and is also known to
be influenced by various environmental factors, its functional consequences and
modes of action are not well understood. In this paper we summarize relevant
experimental evidence on NM receptor regulation (specifically dopamine D1 and
D2 receptors) in order to explore its significance for neural and synaptic
plasticity. We identify the relevant components of NM receptor regulation
(receptor phosphorylation, receptor trafficking and sensitization of
second-messenger pathways) gained from studies on cultured cells. Key
principles in the regulation and control of short-term plasticity
(sensitization) are identified, and a model is presented which employs direct
and indirect feedback regulation of receptor efficacy. We also discuss
long-term plasticity which involves shifts in receptor sensitivity and loss of
responsivity to NM signals. Finally, we discuss the implications of NM receptor
regulation for models of brain plasticity and memorization. We emphasize that a
realistic model of brain plasticity will have to go beyond Hebbian models of
long-term potentiation and depression. Plasticity in the distribution and
efficacy of NM receptors may provide another important source of functional
plasticity with implications for learning and memory.
