Causes and consequences of the loss of serotonergic presynapses elicited by the consumption of 3,4-methylenedioxymethamphetamine (MDMA, ?ecstasy?) and its congeners

Abstract

The massive and prolonged stimulation of serotonin (5-HT)-release and the increased dopaminergic activity are responsible for the acute psychomimetic and psychostimulatory effects of 3,4-methylenedioxy-methamphetamine (MDMA, "ecstasy") and its congeners. In vulnerable subjects, at high doses or repeated use, and under certain unfavorable conditions (crowding, high ambient temperature), severe, in some cases fatal, averse systemic reactions (hyperthermia, serotonin-syndrome) may occur during the first few hours. Animal experiments revealed the existence of similar differences in vulnerability and similar dose- and context-related influences on a similar sequence of acute responses. The severity of these acute systemic responses is closely related to the severity of the long-term damage to 5-HT axon terminals caused by the administration of substituted amphetamines. Attempts to identify the mechanisms involved in this selective degeneration of 5-HT presynapses brought to light a multitude of different factors and conditions which either attenuate or potentiate the loss of 5-HT terminals caused by MDMA and related amphetamine derivatives. These puzzling observations suggest that the degeneration of 5-HT presynapses represents only the final step in a sequence of events which compromise the ability of 5-HT terminals to maintain their functional and structural integrity. Substituted amphetamines selectively tax energy metabolism in 5-HT presynapses through their ability to exchange with 5-HT and to dissipate transmembrane ion gradients. The active carrier systems in the vesicular and presynaptic membrane operate at a permanently activated state. The resulting energy deficit can no longer adequately restored by the 5-HT presynapses when their availability of substrates for ATP production is additionally reduced by the hyperthermic and other energy consuming reactions which are elicited by the systemic administration of substituted amphetamines. The exhaustion of energy in 5-HT nerve terminals compromised all energy-requiring endogenous mechanisms involved in the regulation of transmembrane-ion exchange, internal Ca(++)-homeostasis, prevention of oxidative stress, detoxification, and repair. Above a critical threshold the failure of these self-protective mechanisms will lead to the degeneration of the 5-HT axon terminals. Based on the role of 5-HT as a global modulatory transmitter-system involved in the stabilization and integration of impulse flow between distributed multifocal neuronal networks, the partial loss of 5-HT presynapses must be expected to impair the ability of these networks to maintain the integrity of signal flow pattern, and increase the likelihood of switching to unstable information processing. Behavioral responding may therefore become more dominated by activities generated in individual networks, and hitherto "buffered" personality traits and predisposition may become manifested as defined psychiatric syndromes in certain predisposed subjects.

Serotonergic dysfunction: Brain imaging and behavioral correlates

“…An alternative hypothesis has been suggested, that impulsive aggressiveness is not a specific correlate of central serotonergic dysfunction and that a dysfunction of serotonergic neurotransmission is more credibly related to negative mood states such as anxiety or depression (Artigas, 1995;Knutson et al, 1998;Owens & Nemeroff, 1994;Young, Warsh, Kish, Shannak, & Hornykeiwicz, 1994). In accordance with this view, the pleasant psychopathological effects of "ecstasy" (methylenedioxymethamphetamine) have been associated with acute serotonin release (Huether, Zhou, & Ruther, 1997). Moreover, improvement of negative mood states during medication with selective serotonin reuptake inhibitors (SSRIs) has been attributed to an increase rather than a decrease in synaptic serotonin concentrations, an observation that is difficult to reconcile with the notion of serotonergic neurotransmission stimulating a punishment system (Artigas, 1995;Kreiss & Lucki, 1995;Limberger, Starke, & Singer, 1990;Muck-Seler, Jevric-Causevic, & Diksic, 1996).…”

Êxtase (MDMA): efeitos farmacológicos e tóxicos, mecanismo de ação e abordagem clínica

“…Huether et al 43 relataram que o MDMA estimula a liberação de DA em sinapses dopaminérgicas e que a ativação dos receptores 5-HT2A, por meio da liberação de 5-HT, parece facilitar a liberação de DA induzida pela anfetamina. Esses mesmos autores sugerem que a administração de antagonistas de 5-HT2A atenue os efeitos de análogos anfetamínicos (MDMA) sobre a liberação de DA.…”

Primeiro perfil do usuário de "êxtase" (MDMA) em São Paulo

“…(Rattray, 1991). Corrobora essa hipótese a afirmação de que a liberação de 5-HT promovida pela MDMA é sódio-dependente (Huether et al, 1997). Do citoplasma da célula nervosa a 5-HT é rapidamente liberada para o espaço extracelular através de transportadores serotonérgicos.…”

“…Do citoplasma da célula nervosa a 5-HT é rapidamente liberada para o espaço extracelular através de transportadores serotonérgicos. A liberação de 5-HT induzida pela MDMA pode ser bloqueada por inibidores de recaptação de serotonina, como por exemplo a fluoxetina (Huether et al, 1997;Rattray, 1991). Essa observação sugere duas hipóteses: a primeira é de que a MDMA é transportada passivamente para dentro da célula nervosa desencadeando a liberação de 5-HT vesicular para o citoplasma; nesse caso, a fluoxetina bloquearia os transportadores impedindo a liberação de 5-HT citoplasmática na fenda.…”

“…In vivo, há poucas evidências sugerindo que a MDMA cause, diretamente, liberação de DA na maioria das regiões cerebrais (Rattray, 1991). Pesquisa mais recente descreve que a MDMA estimula a liberação de DA em sinapses dopaminérgicas (Huether et al, 1997). Segundo seus autores, parece que a MDMA ultrapassa a membrana pré-sináptica através de um processo passivo, A interação com o receptor alfa-2 adrenérgico deve ser relevante para os efeitos cardiovasculares, ou seja, aumento do batimento cardíaco, hipertensão e arritmias.…”