S.R. White

THE EFFECTS OF METHYLENEDIOXYMETHAMPHETAMINE (MDMA, “ECSTASY”) ON MONOAMINERGIC NEUROTRANSMISSION IN THE CENTRAL NERVOUS SYSTEM

Methylenedioxymethamphetamine (MDMA, Ecstasy) is a popular recreationally used drug among young people in Europe and North America. The recent surge in use of MDMA and increasing concerns about possible toxic effects of the drug have inspired a great deal of research into the mechanisms by which the drug may affect the central nervous system. This paper reviews studies on the neurochemical, behavioral and neurophysiological effects of MDMA, with emphasis on MDMA effects in regions of the brain that have been implicated in reward. Experiments in awake, behaving laboratory animals have demonstrated that single injections of MDMA increase extracellular levels of the neurotransmitters dopamine (DA) and serotonin (5HT) in the nucleus accumbens and in several other brain regions that are important for reward. Most of the behavioral and electrophysiological changes that have been reported to date for single doses of MDMA appear to be mediated by this MDMA-induced increase in extracellular DA and 5HT. As an example, MDMA-induced hyperthermia and locomotor hyperactivity in laboratory animals can be blocked by administering drugs that prevent MDMA-induced 5HT release and can be attenuated by administering 5HT receptor antagonists, whereas effects of MDMA on delayed reinforcement tasks appear to be mediated by MDMA-induced increases in extracellular DA. Similarly, the effects of MDMA on neuronal excitability in the nucleus accumbens and in several other brain regions can be prevented by administering drugs that block MDMA-induced 5HT release and can be attenuated by depleting brain DA levels or by administering either DA D1 receptor antagonists or 5HT receptor antagonists. In addition to the acute effects of MDMA, it is now well established that repeated or high-dose administration of MDMA is neurotoxic to a subpopulation of 5HT-containing axons that project to the forebrain in laboratory animals. Recent studies have shown that this neurotoxic effect of MDMA is associated with long-duration changes in both DA and 5HT neurotransmission in the nucleus accumbens. Whether these long-duration changes in neurotransmission might be related to reports of depression and other psychopathologies by some frequent users of MDMA remains to be determined. Methylene-dioxymethamphetamine has been found to increase extracellular levels of norepinephrine and to alter brain levels of several neuropeptides as well as altering levels of DA and 5HT. Much additional research is required to understand the multiple ways in which this complex drug may alter neurotransmission in the brain, both acutely and in the long term.

MDMA elicits behavioral and neurochemical sensitization in rats

Rats were treated with repeated injections of saline or one of two doses of (±)3,4-methylenedioxymethamphetamine (MDMA; 5 or 20 mg/kg, SC). Rats pretreated with either of the two repeated MDMA treatment regimens demonstrated an augmented increase in motor activity to an injection of MDMA made 12 days after the last repeated injection compared with either the first MDMA injection or MDMA given to animals pretreated with repeated saline. Furthermore, animals pretreated with the highest dose of repeated MDMA revealed a greater behavioral response to cocaine (15 mg/kg, IP). Microdialysis was conducted in the nucleus accumbens and the capacity of MDMA (5 mg/kg, SC) to elevate extracellular dopamine content was augmented in rats pretreated with repeated MDMA compared with the animals pretreated with repeated saline. These data reveal repeated MDMA administration produces behavioral sensitization and enhanced dopamine transmission in the nucleus accumbens of rats.

Serotonin depolarizes cat spinal motoneurons in situ and decreases motoneuron afterhyperpolarizing potentials

Mechanisms by which serotonin produces a long duration facilitation of spinal motoneuron excitability were investigated in decerebrate cats using intracellular recording combined with extracellular microiontophoresis. Serotonin was found to produce a slowly developing, small amplitude, long duration depolarization of the spinal motoneurons. This finding conflicts with early reports of serotonin-induced rapid hyperpolarization of cat spinal motoneurons, but exactly corresponds to more recent findings in rat facial motoneurons. The depolarization was accompanied by an increase in motoneuron excitability and an increase in membrane input resistance. In addition, serotonin reduced the motoneuron postspike afterhyperpolarizing potential in several motoneurons even through depolarization consistently occurred.

Methylenedioxymethamphetamine depresses glutamate-evoked neuronal firing and increases extracellular levels of dopamine and serotonin in the nucleus accumbens in vivo.

The nucleus accumbens has been implicated as an important site for the actions of many drugs that are used recreationally. This study examined the effects of methylenedioxymethamphetamine (MDMA), a euphoric and hallucinogenic drug, on glutamate-evoked neuronal firing and on extracellular levels of dopamine and serotonin in the nucleus accumbens of the rat. Microiontophoretic application of MDMA inhibited glutamate-evoked firing of most of the nucleus accumbens cells that were tested (83 of 86), as did microiontophoretic application of dopamine and serotonin. MDMA-induced inhibition of glutamate-evoked firing was partially blocked by the dopamine antagonist SCH39166 and was attenuated by combined pretreatment with inhibitors of both serotonin and catecholamine synthesis, p-chlorophenylalanine and alpha-methyl-p-tyrosine. MDMA applied directly into the nucleus accumbens and adjacent regions of the ventral striatum through a dialysis probe increased extracellular levels of both dopamine and serotonin. These results indicate that MDMA has inhibitory effects on glutamate-evoked neuronal firing in the nucleus accumbens and suggest that the inhibition is mediated by increased extracellular dopamine and serotonin. Furthermore, these results permit MDMA to be added to the extensive list of abused drugs that have been demonstrated to elevate extracellular levels of dopamine and serotonin in the nucleus accumbens.

Receptor subtypes mediating facilitation by serotonin of excitability of spinal motoneurons

Serotonin receptor ligands, with differential affinity for subtypes of serotonin (5-HT) receptors, were administered intravenously or iontophoretically to urethane-anesthetized rats and the effects of these compounds on glutamate-evoked firing of spinal motoneurons were tested. The excitability of spinal motoneurons was markedly enhanced after intravenous administration of the selective 5-HT1A ligand 8-hydroxy-2-(di-n-propylamino) tetralin (DPAT) in rats with acute spinal transections at C1. However, local application of DPAT, directly into the ventral horn by microiontophoresis, inhibited the glutamate-evoked firing of motoneurons in direct contrast to the facilitatory effects of iontophoretically applied 5-HT. The DPAT-induced inhibition may have been nonspecific, since it was not antagonized by methysergide. Other 5-HT agonists, with relatively selective affinity for 5-HT1B, 5-HT1C and 5-HT2 receptors, increased the excitability of spinal motoneurons when applied iontophoretically or intravenously. The excitatory effect of iontophoretically applied 5-HT was antagonized by the nonselective 5-HT antagonist, methysergide and by ketanserin and ritanserin, which have relatively selective affinity for 5-HT1C and 5-HT2 receptors. These results indicate that 5-HT1A receptors do not mediate facilitation of excitability of motoneurons produced by local application of 5-HT directly into the vicinity of the motoneurons. However, the marked increase in firing of motoneurons that was caused by intravenous administration of DPAT in spinal transected rats, suggests that 5-HT1A receptors in the spinal cord may participate in 5-HT-induced enhancement of somatomotor outflow, at sites presynaptic to the motoneurons. The iontophoretic results suggest that 5-HT1B, 5-HT1C and 5-HT2 receptors may all play a role in facilitation of the excitability of spinal motoneurons by locally applied 5-HT. Differentiation between these subtypes of receptor awaits the development of more completely selective agonists and antagonists.

Norepinephrine effects on spinal motoneurons

Intracellular recordings from cat spinal motoneurons in situ demonstrated that microiontophoretic application of NE with low-intensity ejection currents produces a slowly developing, small-amplitude depolarization of the cells, in contrast to early reports of NE-induced hyperpolarization. This depolarization was associated with an increase in excitability of the cells and a decrease in membrane conductance. These observations are consistent with the hypothesis that NE reduces potassium conductance in spinal motoneurons as has been proposed for facial motoneurons (VanderMaelen and Aghajanian, 1980) and thalamic neurons (McCormick and Prince, 1988). The time course of the facilitatory effects of NE on cat motoneuron excitability recorded intracellularly agreed very closely with the time course of NE-induced facilitation of glutamate-evoked excitability in rat spinal motoneurons recorded extracellularly. The similarity of the observations in rats and cats suggests that NE functions generally to enhance mammalian motoneuron responsiveness to excitatory input.

Chapter 11 Serotonin, norepinephrine and associated neuropeptides: effects on somatic motoneuron excitability

Publisher Summary In a laboratory electrophysiological techniques are used to address the question of how monoaminergic and peptidergic inputs may affect the excitability of the motoneurons in rats and cats in situ. This chapter reviews these in situ findings and compares them to in situ and in vitro studies from laboratories. Some new evidence about interactive effects of serotonin and neuropeptides on motoneurons is also presented. Monoaminergic and peptidergic effects on brainstem and spinal cord motoneurons are discussed within the framework of an emotional motor system that has a modulatory effect on motoneuronal excitability. The chapter also chapter considers postsynaptic effects of serotonin, colocalized neuropeptides and norepinephrine on motoneuron excitability. However, all of these substances have actions on interneurons that are presynaptic to the motoneurons. These indirect actions on interneurons may interact with postsynaptic effects on the motoneurons in simple or complex fashions. Similarly, norepinephrine appears to enhance spinal motoneuron excitability by both direct postsynaptic actions that lead to motoneuron depolarization and increased excitability, and by indirect actions on interneurons that prevent interneuronal-mediated inhibition of the motoneurons.

Cotransmitter-mediated locus coeruleus action on motoneurons.

This article reviews evidence for a direct noradrenergic projection from the dorsolateral pontine tegmentum (DLPT) to spinal motoneurons. The existence of this direct pathway was first inferred by the observation that antidromically evoked responses occur in single cells in the locus coeruleus (LC), a region within the DLPT, following electrical stimulation of the ventral horn of the lumbar spinal cord of the cat. We subsequently confirmed that there is a direct noradrenergic pathway from the LC and adjacent regions of the DLPT to the lumbar ventral horn using anatomical studies that combined retrograde tracing with immunohistochemical identification of neurotransmitters. These anatomical studies further revealed that many of the noradrenergic neurons in the LC and adjacent regions of the DLPT of the cat that send projections to the spinal cord ventral horn also contain colocalized glutamate (Glu) or enkephalin (ENK). Recent studies from our laboratory suggest that Glu and ENK may function as cotransmitters with norepinephrine (NE) in the descending pathway from the DLPT. Electrical stimulation of the LC evokes a depolarizing response in spinal motoneurons that is only partially blocked by alpha 1 adrenergic antagonists. In addition, NE mimicks only the slowly developing and not the fast component of LC-evoked depolarization. Furthermore, the depolarization evoked by LC stimulation is accompanied by a decrease in membrane resistance, whereas that evoked by NE is accompanied by an increased resistance. That Glu may be a second neurotransmitter involved in LC excitation of motoneurons is supported by our observation that the excitatory response evoked in spinal cord ventral roots by electrical stimulation of the LC is attenuated by a non-N-methyl-D-aspartate glutamatergic antagonist. ENK may participate as a cotransmitter with NE to mediate LC effects on lumbar monosynaptic reflex (MSR) amplitude. Electrical stimulation of the LC has a biphasic effect on MSR amplitude, facilitation followed by inhibition. Adrenergic antagonists block only the facilitator effect of LC stimulation on MSR amplitude, whereas the ENK antagonist naloxone reverses the inhibition. The chemical heterogeneity of the cat DLPT system and the differential responses of motoneurons to the individual cotransmitters help to explain the diversity of postsynaptic potentials that occur following LC stimuli.

Inhibitory effects of dopamine and methylenedioxymethamphetamine (MDMA) on glutamate-evoked firing of nucleus accumbens and caudate/putamen cells are enchanced following cocaine self-administration

Rats were allowed to self-administer cocaine during a 3-h session for 15 days. One to 11 days after the last cocaine exposure, rats were anesthetized with urethane and effects of microiontophoretically-applied dopamine on glutamate-evoked firing of neurons in the nucleus accumbens and in the caudate/putamen were tested. Dopamine produced a dose-dependent inhibition of glutamate-evoked firing in both the nucleus accumbens and the caudate/putamen of rats that had been repeatedly exposed to self-administered cocaine and in control rats. However, the DA-induced inhibition was significantly greater in the group that had self-administered cocaine. The cocaine self-administration group was significantly sensitized to the inhibitory effects of dopamine in both early (1-3 day) and later (9-11 days) periods of cocaine abstinence. Following cessation of repeated cocaine self-administration sessions, nucleus accumbens cells were also sensitized to the inhibitory effects of methylenedioxymethamphetamine (MDMA), a drug that increases extracellular levels of DA and serotonin in the nucleus accumbens. This sensitization to DA- and MDMA-induced inhibition in the nucleus accumbens and in the striatum indicates that long-term neuroadaptations occur in these regions of the nervous system following repeated exposure to self-administered cocaine.

Thyrotropin‐Releasing Hormone (TRH) Effects on Spinal Cord Neuronal Excitability

TRH is found in terminals in the dorsal, lateral, and ventral horns of the spinal cord and apparently has at least a weak facilitatory effect on excitability of neurons in all these locations. These findings suggest that TRH may facilitate transmission in somatosensory pathways, enhance sympathetic outflow from the spinal cord, and facilitate somatic motoneuron excitability, at least transiently. All studies that have examined TRH effects on spinal neuronal excitability have used exogenously administered TRH. Virtually nothing is known about how spinal neuronal functioning might be affected by TRH released from terminals after activation of TRH-containing cell bodies. The acquisition of this knowledge awaits the development of specific TRH antagonists. Preliminary experiments suggest that TRH may have prolonged facilitatory effects on the excitability of developing or damaged spinal cord neurons. Further studies are necessary to determine how TRH interacts with other neuroactive peptides and monoamines to affect excitability of neurons in the developing, damaged, and normal adult spinal cord.