Neurotransmitters in the mammalian circadian system.

This discussion of the roles of transmitters in the circadian system has focused mostly on the entrainment mechanism because it is not clear to what extent neurotransmission is important to the other major function of circadian systems, rhythm generation. Schwartz et al (1987) have presented evidence that the circadian pacemaker in the SCN continues to run, but cannot be entrained by light, when tetrodotoxin is used to block sodium-dependent action potentials. Although other forms of intercellular communication are not ruled out, these results suggest that classical synaptic neurotransmission is important for entrainment but not for rhythm generation. That the SCN contains a cholinergic marker like ChAT and is responsive to cholinergic agents but does not bind nicotine or ACh reflects a general problem in reconciling functional, physiological, and anatomical markers of neurotransmission. A mismatch between the anatomical distributions of transmitters and their receptor-binding sites is a common observation, the meaning of which remains enigmatic (Herkenham 1987). Also, the neurophysiological consequences of injections of drugs into parts of the brain involved in rhythm regulation remain largely unknown. Interpretations of the effects of these treatments on rhythms are predicated on assumptions that may not be valid; e.g. that a bolus injection of an excitatory substance has its primary effect by activating neurons. Still to be established is whether the effects of drugs when they are administered in behavioral pharmacology studies reflect their effects on cellular functions and on neuronal responses to photic cues when they are delivered at near-physiological levels to single neurons.