Development and use of pharmacological probes of the CNS in man: evidence of cholinergic abnormality in primary affective illness.

The role of cholinergic mechanisms in the regulation of CNS functions was studied in normal humans. The purpose was to develop in vivo pharmacological techniques to assess central neurotransmitter activity in normals and apply them in primary affective illness and other neuropsychiatric conditions. Central cholinergic stimulation by cholinomimetics induced rapid eye movement (REM) sleep, dreaming, cortical arousal, and accelerated the REM cycle. Effects on memory included enhancement of serial learning, short-term consolidation of low-imagery words, and retrieval of clustered information. Analgesia and reduction of the P100 component of visual EEG evoked responses were also noted after physostigmine. Using the induction of REM sleep by arecoline as a "marker" of central cholinergic functioning, it was possible to (i) demonstrate the phenomenon of pharmacological denervation supersensitivity in normal humans after pretreatment with scopolamine, and (ii) demonstrate a significantly faster REM induction by arecoline in two groups of patients with primary affective illness (remitted and depressed) compared to normals. Rapid REM induction was found, not only in remitted patients who were drug-free for 2 weeks, but in patients who had never received somatic therapy. Pretreatment with scopolamine on three consecutive mornings also induced sleep changes at night in normals similar to several sleep abnormalities reported in primary affective illness. This was confirmed by a multivariate discriminate analysis program, which had previously been shown to separate depressed patients, insomniacs, and normals. On the basis of these data, it is proposed that cholinergic abnormalities may be present in primary affective illness during both the ill and the well states.