Narcotic Drugs: Effects on the Serotonin Biosynthetic Systems of the Brain

Abstract

The effects of short- and long-term administration of morphine on the activity of two measurable forms of rat brain tryptophan hydroxylase were studied. Morphine administration produced an immediate decrease and a long-term increase in the nerve ending (particulate) enzyme activity but did not change the cell body (soluble) enzyme activity. Cocaine administration demonstrated a short-term decrease in measurable nerve ending enzyme activity that was due to the inhibition of the high affinity uptake (the Michaelis constant, K m is 10 -5 molar) of trytophan, the serotonin precursor. Cocaine did not affect the low affinity uptake (K m = 10 -3 molar) of tryptophan. Both the uptake of the precursor and the enzyme activity appeared to be drug-sensitive regulatory processes in the biosynthesis of serotonin.

Effects of Acute Cocaine Treatment on the Turnover of 5‐hydroxytryptamine in the Rat Brain

“…It is possible that cocaine stimulates 5-HT receptors directly and thus indirectly modifies release in vivo through a negative feedback system or that it directly inhibits 5-HT release. The effect of cocaine on 5-HT synthesis may also be partially mediated through a trans-synaptic feedback system (Anden, Corrodi & Fuxe, 1971), although tryptophan uptake appears to play a major role as shown by the in vitro studies (Knapp & Mandell, 1972). Our data are not sufficient to predict which, if any, of these mechanisms are involved.…”

“…Knapp & Mandell (1972) have shown that cocaine in vitro decreased 5-HT synthesis by inhibition of tryptophan uptake and not by direct inhibition of tryptophan hydroxylase. However, inhibition of synthesis, especially in the presence of the blockade of 5-HT uptake known to be an effect of cocaine (Ross & Renyi, 1969), would be expected to result in a precipitous fall in brain 5-HT levels.…”

“…Simon, Sultan, Chermat & Boissier (1972), in a behavioural study, have shown that, while cocaine has amphetamine-like activity, the cocaine-induced increased locomotor activity is neither blocked by inhibition of catecholamine synthesis with a-methyl-p-tyrosine (ct-MPT) nor by blockade of dopamine receptors with non-depressant doses of ,haloperidol. In addition, Knapp & Mandell (1972) 5 have recently shown that after acute cocaine administration particulate tryptophan hydroxylase activity is decreased and that this is attributable to blockade of the high affinity uptake of tryptophan. These findings suggest that the effects of cocaine on 5-hydroxytryptamine (5-HT) turnover be examined.…”

An Amphetamine Model of Manic Depressive Illness

“…Morphine inhibits tryptophan hydroxylase activity and also sup presses REM sleep. Again, both phenomena show a rebound increase following morphine withdrawal (37,59). As far as the amphetamines are concerned, one study, in guinea pigs, demonstrated a rebound increase in monoamine oxidase activity following methamphetamine withdrawal (75).…”

“…At the same time, there also occurs a re bound increase in the duration of REM sleep (59). The rise in tryptophan hydroxylase activity following morphine withdrawal may be cited as another example (37). Morphine inhibits tryptophan hydroxylase activity and also sup presses REM sleep.…”