Serotonin depletion

As was previously mentioned, a hangover-like syndrome is common the next day after use of MDMA. MDMA withdrawal, which is thought to be caused by serotonin depletion, can last for weeks and includes symptoms of depression, anxiety, restlessness, and insomnia (Allen et al. 1993 McGuite et al. 1994). No specific treatments are currently indicated fot this withdtawal syndrome, although the antidepressant bupropion may be helpful (Solhkhah... 

Li, A. Marek, G. Vosmer, G. and Seiden, L. MDMA-induced serotonin depletion potentiates the psychomotor stimulant effects of MDMA on rats performing on the differential-reinforcement-of-low-rate (DRL) schedule. Society for Neuroscience Abstracts 12 609, 1986. 

Harvey, J.A. McMaster, S.E. and Fuller, R.W. Comparison between the neurotoxie and serotonin-depleting effeets of various halogenated derivatives of amphetamine in the rat. J Pharmacol Exp Ther 202 581, 1977. 

Berger. U. Grzanna, R. and Molliver, M.E. The neurotoxic effects of p-chloroamphetamine (PCA) in the rat brain are blocked by serotonin depletion. Twenty-First Meeting of the Swiss Societies for Experimental Biology. Abstract. Experientia, in press. 

Fuller, R.W. Perry, K.W. and Molloy, B.B. Reversible and irreversible phases of serotonin depletion by 4-chloroamphetamine. Eur J Pharmacol 33 119-124, 1975a. 

The results of the studies reviewed here show that the neurotoxic effects of MDMA generalize to the primate. Further, they indicate that monkeys are considerably more sensitive than rats to the serotonin-depleting effects of MDMA, and that the dose-response curve of MDMA in the monkey is much steeper than in the rat. Perhaps as a consequence of this, the toxic effects of MDMA in the monkey involve serotonergic nerve fibers as well as cell bodies, whereas in the rat, only nerve fibers are affected. The present studies also show that the toxic dose of MDMA in the monkey... 

COMMENT The main point that 1 wanted to make is that it is very important to attempt to develop models where one is looking at least at some sort of in vivo integrated preparation. We look at serotonin depletion. We look at dopamine depletion. We have a variety of different mechanisms. Again we really do not know what, at this point in time, the serotonin depletion is doing. I think 1 know what it means if you deplete dopamine beyond a certain level. But even there, it is difficult to put an exact degree of impairment on the levels of dopamine depletion that we see in most of these models. 

Further investigation of the possibility that inhibitors of the serotonin uptake carrier protect against serotonin depletion by /r-chloroamphetamine, fenfluramine, MDMA, MDA, and methamphetamine because they prevent the accumulation of those drugs within serotonin nerve terminals is warranted, but at present compelling evidence for this mechanism does not exist. 

So I think you can debate that issue about 99 or 95 percent depletion. I think that if you probe those animals with the proper pharmacological agents and proper environmental situation, you will pick up deficits. I think the lack of knowledge about what the serotonin systems do is the basis of the problem here. We don t know what the behavioral consequences of the serotonin depletion are. 

But I think we have the tools in behavioral pharmacology to conduct tests in rats that will be sensitive to serotonin depletion. And I assume that those can be extrapolated to primates. 

Systemic injection of flesinoxan increases W and reduces SWS and REMS in the rat (Monti Jantos, 2003). Similar effects have been observed following the administration of 8-OH-DPAT to vehicle-treated and serotonin-depleted animals (Dugovic Wauquier, 1987 Monti Jantos, 1992 Monti et al, 1990, 1994). Pretreatment with (—)pindolol or p-MPPI reverses the effect of 8-OH-DPAT on W and SWS (Monti Jantos, 1992 Sorensen et al, 2001). All these findings indicate that the postsynaptic 5-HTia receptor has a role in the occurrence of arousal. 

Chu, T., Kumagai, Y., DiStefano, E.W., and Cho, A.K., Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion, Biochem. Pharmacol. 51(6), 789-796, 1996. 

Baumann, M.H., Ayestas, M.A., Dersch, C.M., and Rothman, R.B., l-(m-Chlorophenyl)piperazine (mCPP) dissociates in vivo serotonin release from long-term serotonin depletion in rat brain, Neuropsychopharmacology 24(5), 492-501, 2001. 

Robinson, T.E., Castaneda, E., and Whishaw, I.Q., Effects of cortical serotonin depletion induced by 3,4-methylenedioxymethamphetamine (MDMA) on behavior, before and after additional cholinergic blockade, Neuropsychopharmacology 8(1), 77-85, 1993. 

Brody, J. F., Jr. (1970) Behavioral effects of serotonin depletion and of p-chlorophenylalanine (a serotonin depletor) in rats. Psychopharmacologia, 14 14-33. 

Kohler, C., and Lorens, S. A. (1978) Open field activity and avoidance behavior following serotonin depletion A comparison of the effects of parachlorophenylalanine and electrolytic midbrain raphe lesions. Pharmacol. Biochem. Behav., 8 223-233. 

Lorens, S. A. (1978) Some behavioral effects of serotonin depletion depend on method A comparison of 5,7-DHT, p-chlorophenylalanine, p-chloroamphetamine and electrolytic raphe lesions. Ann. NY Acad. Sci., 305 532-555. 

Joseph, J. A., and Appel, J. B. (1977) Behavioral sensitivity to LSD Dependency upon the pattern serotonin depletion. Pharmacol. Biochem. Behav., 6 499-504. 

Vergnes, M., Depaulis, A., and Boehrer, A. (1986) Parachlorophenyl-alanine-induced serotonin depletion increases offensive but not defensive aggression in male rats. Physiol Behav 36 653. 

These data and findings from serotonin depletion studies show that, in patients treated successfully, NA and serotonin systems are involved in maintenance of drug-induced remission. However, the absence of an increased severity in depressive symptoms in drug-free patients with depression suggests that alterations in serotonin and catecholamine release may not be causally involved in the pathophysiology of mood disorders. 

Source. Adapted from Delgado PL, Price LH, Miller HL, et al Rapid Serotonin Depletion as a Provocative Challenge Test for Patients With Major Depression Relevance to Antidepressant Action and the Neurobiology of Depression. Psychopharmacology Bulletin 27 321-330, 1991. Used with permission. 

Beiko J, Candusso L, Cain DP The effect of nonspatial water maze pretraining in rats subjected to serotonin depletion and muscarinic receptor antagonism a detailed behavioural assessment of spatial performance. Behav Brain Res 88 201-211, 1997... 

Bennett-Clarke CA, Leslie MJ, Lane RD, Rhoades RW. Effect of serotonin depletion on vibrissa-related patterns of thalamic afferents in the rat s somatosensory cortex. J Neurosci 1994 14 7594-7607. 

Rhoades RW, Chiaia NL, Lane RD, Bennett-Clarke CA. Effect of activity blockade on changes in vibrissae-related patterns in the rat s primary somatosensory cortex induced by serotonin depletion. J Comp Neurol 1998 402 276-283. 

ClPhe is a competitive inhibitor of both phenylalanine and tryptophan hydroxylases, and produces selective irreversible inhibition in vivo of both enzymes159. As a tryptophan hydroxylase inhibitor, 4-ClPhe has been used extensively in a wide range of psychopharmacology experiments based on in vivo serotonin depletion. The ability of 4-ClPhe to produce increased levels of Phe in vivo has made it useful in the development of models for phenylketonuria160. 

Possibly the best evidence suggesting involvement of norepinephrine and serotonin in major depressive disorder devolved from depletion studies (Delgado et al., 1990). In these stndies, patients who have responded to treatment for depression are given procedures, which deplete brain levels of serotonin or norepinephrine. Serotonin levels are decreased by nse of a low monoamine diet, followed by a drink which inclndes all the amino acids except the serotonin precnrsor tryptophan. Norepinephrine levels are depleted by administration of alpha-methylparatyrosine. In patients who had responded to treatment with a serotonergic antidepressant, depletion of serotonin cansed a prompt and dramatic, but brief reoccurrence of the symptoms of major depression. In patients who had responded to treatment with a noradrenergic antidepressant, depletion of norepinephrine caused a relapse into depression. The converse was not true in other words, serotonin depletion did not canse relapse in patients who responded to noradrenergic antidepressants, and vice versa. 

Baumann MH, Ayestas MA, Rothman RB. 1998. Functional consequences of central serotonin depletion produced by repeated fenfluramine administration in rats. J.Neurosci. 18 9069-77... 

Farfel, G.M. Vosmer, G.L. and Seiden, L.S. The A-methyl-D-aspartate antagonist MK-801 protects against serotonin depletions induced by methamphetamine, 3,4-methylenedioxymethamphetamine and / -chloroamphetamine. Brain Res 595 121-127, 1992. 

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