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Freedman DX, Boggan WO. 
“Brain Serotonin Metabolism After Tolerance Dosage of LSD”. 
Advances in Biochemical Psychopharmacology. 1974;10:151-157.
Some 15 years ago we studied tolerance to LSD (Freedman, Aghajanian, Ornitz, and Rosner, 1958) because of intrinsic interest and as a "lever" to aid in defining the role of neurohumors and mechanisms of LSD action. Operationally, tolerance is a -decrement of effect contingent upon prior dosage schedule; the mechanisms are obscure. With appropriate behavioral measures in rat, we observe a diminished response intensity or duration, or both, after daily doses of LSD; increased dosage restores the initial response. A less distinct "short-term" tolerance occurs with LSD at hourly intervals (Freedman and Aghajanian, 1959). Tolerance is not "absolute"; there is an interaction of dosage, behavioral task, and drug effect (freedman, Appel, Hartman, and Knitters. Molliver, 1964a). In the rat, sympathomimetic effects (mydliasis, piloerection, pyrexia), EEG alerting, and hind-limb ataxia (lasting 45 to 60 min after moderate doses) show tolerance; centrally mediated parasympathomimetic effects (salivation and bradycardia­lasting 90 min or more) do not (Freedman et al., 1958). Tolerance is not evident with noxious reinforcement such as escape behavior (Appel, 1968; Hamilton, 1960). In man, subjective and sympathomimetic effects of 200mcg or less of LSD are absent by the third or fourth daily dose and return after 3 or 4 days of abstinence. In the rat, a behavioral effect gradually diminishes and is clear-cut after foul to seven daily doses; full
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