Depletion of serotonin using p-chlorophenylalanine (PCPA) and reserpine protects against the neurotoxic effects of p-chloroamphetamine (PCA) in the brain

Berger, Urs V.; Grzanna, Reinhard; Molliver, Mark E.

doi:10.1016/0014-4886(89)90071-x

Cited by 31 publications

(12 citation statements)

References 20 publications

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“…**P Ͻ 0.05 compared with MDMA-injected wildtype (MDMA wt). nergic toxicity and the amount of intracellular 5HT levels (Berger et al, 1989). Intracellular analysis of MAO-B within 5HT neurons could also rule out whether in MAO-B knockout mice a regional compensatory effect is taking place.…”

Section: Discussionmentioning

confidence: 99%

Biochemical effects of the monoamine neurotoxins DSP-4 and MDMA in specific brain regions of MAO-B-deficient mice

Fornai

Giorgi

Gesi

et al. 2001

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Section: Discussionmentioning

confidence: 99%

Biochemical effects of the monoamine neurotoxins DSP-4 and MDMA in specific brain regions of MAO-B-deficient mice

Fornai

Giorgi

Gesi

et al. 2001

Synapse

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“…Each of the hitherto proposed hypothesis on the possible mechanisms which may lead to the loss of 5-HT nerve terminals explained some, but not all of these protective or preventive effects. The concept of energy exhaustion proposed here, however, predicts that the long-term damage to 5-HT nerve endings should be less pronounced under conditions a) When the vesicular 5-HT stores are depleted by prior administration of 5-HT releasers (see Berger et al, 1989Berger et al, , 1992a or when the uptake of released 5-HT is blocked (see Schmidt, 1987), so that less 5-HT is inefficiently transported and less ATP is consumed for the restoration and maintenance of ionic gradients; b) when the hyperthermic response is attenuated by drugs which antagonize the rise of body temperature caused by the activation of 5-HT-and DA-receptors involved in central thermoregulation (Schmidt et al, 1990b;Miller and O'Callaghan, 1994), so that more energy-rich substrates can be supplied to the brain; c) when the amphetamine-like psychostimulatory effects, and therefore the degree of general arousal and hyperactivity are reduced e.g. by pretreatments which prevent the activation of the dopaminergic system, e.g., by lesions of the DA-system (see Schmidt et al, 1985;Stone et al, 1988), by prior DA-depletion or by inhibition of DA-synthesis (see Axt et al, 1990;Brodkin et al, 1993), by administration of DAantagonists (see Schmidt et al, 1985;Hewitt and Green, 1994), by pharmacologic manipulations of other transmitter systems involved in the regulation of presynaptic DA-output, including administration of 5-HT2-receptor antagonists (see Schmidt et al, 1991;Gudelsky et al, 1994), of GABA-agonists and/or glutamate (NMDA) antagonists (see Finnegan et al, 1990;Colado et al, 1993;Colado and Green, 1994) or by drugs which cause a general reduction of global energy metabolism in the brain, such as sedativa and anesthetics (see Schmidt et al, 1990a); d) when the oxidative pressure in 5-HT nerve terminals is reduced, e.g., by prior administration of antioxidants and radical scavengers (see Hirata et al, 1995;Gudelsky, 1996); by treatments which reduce the uptake and possible formation of toxic metabolites in 5-HT presynapses (see Iyer et al, 1994;Sprague and Nichols, 1995) or presumably by any other treatment which improves global energy metabolism in the brain.…”

Section: Causes Of Long Term Damage To 5-ht Projectionsmentioning

confidence: 97%

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

Huether

Zhou

Rüther

1997

J. Neural Transmission

125

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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.

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“…When slices were preincubated for 2-4 hr with the 5-HT-depleting agent p-chloroamphetamine (pCA; 10 PM) (Berger et al, 1989;Champney and Matthews, 1991), cocaine (3 PM) failed to inhibit the GABA, IPSP. This is in contrast to the direct agonist effects of sumatriptan (0.3 and 1 .O PM), which inhibited the IPSP with similar potency to that observed in untreated slices (Fig.…”

Section: Normal Suu Msmentioning

confidence: 99%

Cocaine inhibits GABA release in the VTA through endogenous 5-HT

1994

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The ventral tegmental area (VTA) is thought to be involved in the addictive properties of many drugs, including cocaine. It has been hypothesized that cocaine exerts its actions in the VTA by blocking the reuptake of dopamine released from the dendrites of the A10 dopamine neurons, thus prolonging the actions of dopamine at D2 autoreceptors. However, cocaine also blocks the reuptake of the other monoamines, including serotonin (5-HT). Using intracellular recordings from midbrain dopamine neurons in a brain slice preparation, we have found that cocaine (0.1–10 microM) inhibited the GABAB IPSP in a dose- dependent manner. This effect was observed in the presence of the D2 dopamine receptor antagonists sulpiride (1 microM) and eticlopride (0.1 microM). 5-HT mimicked this effect, as did the selective 5-HT1D receptor agonist sumatriptan and the 5-HT-releasing agent fenfluramine. The actions of both 5-HT and cocaine were attenuated by the 5-HT1C/D antagonist metergoline. Pretreatment of slices with the 5-HT-depleting agent p-chloroamphetamine (pCA; 10 microM) abolished the inhibition of the GABAB IPSP by cocaine but failed to affect the actions of sumatriptan. We conclude that cocaine acts to modulate the GABA input to A10 dopamine neurons via inhibition of the 5-HT transporter, increasing the concentration of 5-HT at presynaptic 5-HT1D receptors. These actions of cocaine were apparent at lower concentrations than those required to act via inhibition of the dopamine transporter. This reduction of inhibitory synaptic input into the VTA would be expected to attenuate the GABA-mediated feedback inhibition from the nucleus accumbens, thus leading to increased activation of dopamine neurons.

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Depletion of serotonin using p-chlorophenylalanine (PCPA) and reserpine protects against the neurotoxic effects of p-chloroamphetamine (PCA) in the brain

Cited by 31 publications

References 20 publications

Biochemical effects of the monoamine neurotoxins DSP-4 and MDMA in specific brain regions of MAO-B-deficient mice

Biochemical effects of the monoamine neurotoxins DSP-4 and MDMA in specific brain regions of MAO-B-deficient mice

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

Cocaine inhibits GABA release in the VTA through endogenous 5-HT

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