J. Frank Nash

Methamphetamine neurotoxicity and striatal glutamate release: comparison to 3,4-methylenedioxymethamphetamine.

The effect of repeated administration of either methamphetamine (MA), 3,4-methylenedioxymethamphetamine (MDMA) or vehicle on the extracellular concentrations of glutamate (GLU), aspartate, taurine, dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), was studied in awake, freely moving rats using in vivo microdialysis. MA (7.5 mg/kg, i.p.) administered every 2 h for a total of 3 injections, increased the extracellular concentration of GLU in the anteromedial striatum. By contrast, neither vehicle nor MDMA (9.2 and 13.8 mg/kg) increased GLU efflux following repeated administration. Both MA and MDMA increased the extracellular concentration of DA in the striatum. However, the cumulative increase in DA was significantly greater in the MDMA treated animals as compared to the MA group. The concentrations of DA, serotonin (5-HT) and their metabolites were determined in the striatum 7 days following the repeated administration of MA, MDMA and vehicle. MA, but not MDMA or vehicle, decreased the concentration of DA in the striatum. Conversely, MDMA (13.8 mg/kg) decreased the concentration of 5-HT, whereas MA, MDMA (9.2 mg/kg) and vehicle had no effect on striatal 5-HT content. These data are suggestive that the long-term (7 day) DA neurotoxicity produced by the repeated administration of MA is mediated, in part, by a delayed increase in extracellular concentrations of GLU. In contrast, repeated administration of MDMA, at a dose which produced a long-term (7 day) depletion of striatal 5-HT content, had no effect on GLU efflux in the striatum.

A Review of Sunscreen Safety and Efficacy

The use of sunscreen products has been advocated by many health care practitioners as a means to reduce skin damage produced by ultraviolet radiation (UVR) from sunlight. There is a need to better understand the efficacy and safety of sunscreen products given this ongoing campaign encouraging their use. The approach used to establish sunscreen efficacy, sun protection factor (SPF), is a useful assessment of primarily UVB (290–320 nm) filters. The SPF test, however, does not adequately assess the complete photoprotective profile of sunscreens specifically against long wavelength UVAI (340–400 nm). Moreover, to date, there is no singular, agreed upon method for evaluating UVA efficacy despite the immediate and seemingly urgent consumer need to develop sunscreen products that provide broad‐spectrum UVB and UVA photoprotection. With regard to the safety of UVB and UVA filters, the current list of commonly used organic and inorganic sunscreens has favorable toxico‐logical profiles based on acute, subchronic and chronic animal or human studies. Further, in most studies, sunscreens have been shown to prevent the damaging effects of UVR exposure. Thus, based on this review of currently available data, it is concluded that sunscreen ingredients or products do not pose a human health concern. Further, the regular use of appropriate broad‐spectrum sunscreen products could have a significant and favorable impact on public health as part of an overall strategy to reduce UVR exposure.

Carrier‐Mediated Release of Serotonin by 3,4‐Methylenedioxymethamphetamine: Implications for Serotonin‐Dopamine Interactions

Abstract: In vivo microdialysis was used to determine whether the 3,4‐methylenedioxymethamphetamine (MDMA)‐induced release of serotonin (5‐HT) in vivo involves a carrier‐mediated process and to investigate further the state‐dependent interaction between 5‐HT and dopamine. MDMA produced a dose‐dependent increase in the extracellular concentration of 5‐HT in the striatum and prefrontal cortex that was attenuated by treatment with fluoxetine but not by tetrodotoxin. Suppression by fluoxetine of the MDMA‐induced release of 5‐HT was accompanied by a suppression of the MDMA‐induced release of dopamine. Administration of MDMA to rats treated with carbidopa and l‐5‐hydroxytryptophan resulted in a synergistic elevation of the extracellular concentration of 5‐HT that was much greater than that produced by either treatment alone. The MDMA‐induced release of dopamine by MDMA also was potentiated in 5‐hydroxytryptophan‐treated rats. These data are consistent with the view that MDMA increases the extracellular concentration of 5‐HT by facilitating carrier‐mediated 5‐HT release, which can be enhanced greatly under conditions in which 5‐HT synthesis is stimulated. Moreover, these data are supportive of a state‐dependent, stimulatory role of 5‐HT in the regulation of dopamine release.

Potentiation of 3,4-methylenedioxymethamphetamine-induced dopamine release and serotonin neurotoxicity by 5-HT2 receptor agonists.

The effects of the 5-HT2 receptor agonists 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) on 3,4-methylenedioxymethamphetamine (MDMA)-induced dopamine release and 5-HT depletion in the striatum were studied. The MDMA-induced increase in the extracellular concentration of dopamine in the striatum was enhanced significantly in rats treated with either DOI (2 mg/kg, ip.) or 5-MeODMT (15 mg/kg, ip.), as assessed using in vivo microdialysis. Neither DOI nor 5-MeODMT alone altered the extracellular concentration of dopamine in the striatum. The striatal concentration of 5-HT was decreased, but not significantly, 7 days following a single administration of MDMA (10 mg/kg, sc.). However, 7 days following the concomitant treatment with DOI and MDMA the striatal concentration of 5-HT was significantly less than that in rats treated with MDMA alone or the vehicle-treated controls. It is concluded that activation of 5-HT2 receptors is an important determinant of the acute increase in extracellular dopamine and, consequently, the long-term depletion of brain 5-HT produced by MDMA.

Ketanserin pretreatment attenuates MDMA-induced dopamine release in the striatum as measured by in vivo microdialysis

Systemic administration of the amphetamine analogue, 3,4-methylenedioxymethamphetamine (MDMA) produced a dose-dependent increase in the extracellular concentration of dopamine (DA) in the striatum as measured by in vivo microdialysis in awake, freely-moving rats. The extracellular concentration of the DA metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), was significantly decreased in dialysate samples following the administration of MDMA (10 and 20 mg/kg, i.p.). The serotonin-2 (5-HT2) antagonist ketanserin (3 mg/kg, i.p.) had no effect on the extracellular concentration of DA or DOPAC in the striatum of vehicle- treated rats. The administration of ketanserin (3 mg/kg) 1 hr prior to MDMA (20 mg/kg) significantly attenuated the MDMA- induced increase in the extracellular concentration of DA without affecting the decrease in DOPAC concentrations. These data are suggestive that MDMA administration increases DA release in the striatum of awake, freely-moving rats. In addition, MDMA-induced increase in the extracellular concentration of DA in the striatum is mediated, in part, via 5-HT2 receptor mechanisms.

Effect of acute monoamine depletion on 3,4-methylenedioxymethamphetamine-induced neurotoxicity

The effect of acute, reversible depletion of either serotonin [5-hydroxytryptamine (5-HT)] or dopamine (DA) on the long-term (7-day) decrease of brain 5-HT content produced after 3,4-methylenedioxymethamphetamine (MDMA) administration was investigated. The tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (alpha-MPT) significantly attenuated the acute increase in DA efflux produced by MDMA in the striatum as measured by in vivo microdialysis. Treatment with alpha-MPT had no effect on MDMA-induced 5-HT release. alpha-MPT treatment blocked the long-term (7-day) depletion of striatal 5-HT content after MDMA administration. The tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) completely blocked the acute increase in the extracellular concentration of 5-HT produced by MDMA. Although PCPA significantly attenuated the increase in DA efflux produced by MDMA, the effect was small in magnitude. More importantly, treatment with PCPA had no effect on MDMA-induced decrease of 5-HT uptake sites in the frontal cortex. These data are suggestive that acute depletion of DA but not 5-HT protects against the long-term neurotoxic effects of MDMA on 5-HT axon terminals. In addition, these data are supportive of the hypothesis that DA plays a major role in the neurotoxic effects of MDMA.

Microdialysis studies on 3,4-methylenedioxyamphetamine and structurally related analogues

The acute effect of 3,4-methylenedioxyamphetamine (MDA) and three structural analogues on the extracellular concentrations of dopamine (DA) and its major metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum was studied using in vivo microdialysis in awake, freely moving rats. MDA significantly (P less than 0.001) increased and decreased the extracellular concentrations of DA and its metabolites, respectively, following i.p. administration. Similarly, acute administration of the N-methyl (MDMA) and N-ethyl (MDE) derivatives of MDA significantly (P less than 0.05) increased the concentration of DA in the striatum. The alpha-ethyl homologue of MDMA, MBDB, increased the extracellular concentration of DA but significantly (P less than 0.05) less than MDA, MDMA, or MDE. The rank order of potency for these amphetamine derivatives to increase the extracellular concentration of DA was: MDA greater than MDMA greater than MDE greater than MBDB greater than vehicle. The increase in extracellular DA concentration following a single administration of these compounds was negatively correlated with the level of serotonin (5-HT) and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in the contralateral striatum measured 7 days following drug administration. Thus, extending the alkyl group on the nitrogen or alpha-carbon of MDA reduces the ability of these compounds both to increase acutely the extracellular concentration of DA and to produce long-lasting depletions of 5-HT in the brain.

Antagonism of serotonin receptor mediated neuroendocrine and temperature responses by atypical neuroleptics in the rat

The ability of atypical and typical antipsychotics to antagonize serotonin (5-HT) receptor-mediated temperature and neuroendocrine responses was tested in rats. Clozapine, melperone and setoperone, three atypical neuroleptics, blocked in a dose-dependent manner, the hyperthermic response to the 5-HT agonist, MK-212, whereas chlorpromazine and haloperidol were ineffective. The hypothermic response to the 5-HT1A agonist, 8-OH-DPAT, was unaltered by any of the atypical neuroleptics tested. Similarly, MK-212-induced corticosterone secretion was blocked in a dose-related manner by clozapine, melperone and setoperone but was relatively unaffected by either haloperidol or chlorpromazine. The increase in corticosterone secretion observed following 8-OH-DPAT administration was not attenuated by pretreatment with the atypical or typical antipsychotics tested. These data indicate that atypical neuroleptics are effective 5-HT2 but not 5-HT1A antagonists in vivo. Conversely, the typical neuroleptics, haloperidol and chlorpromazine do not block the 5-HT receptors involved in activation of the hypothalamic-pituitary-adrenal axis or thermoregulation.

Inhibitory effect of ritanserin on the 5-hydroxytryptophan-mediated cortisol, ACTH and prolactin secretion in humans

Oral administration of the serotonin (5-HT) precursorl-5-hydroxytryptophan (5-HTP), 200 mg, significantly increased plasma cortisol levels in man.l-5-HTP had no significant effect on the plasma prolactin levels. A borderline effect of 5-HTP on plasma ACTH levels was found. Pretreatment with the 5-HT2/5-HT1C antagonist ritanserin (5 mg, PO, b.i.d. for 2 days) significantly inhibited 5-HTP-induced cortisol secretion. Ritanserin had no effect on the basal plasma cortisol or prolactin levels. These data are suggestive that 5-HTP stimulates cortisol secretion in man via 5-HT2/5-HT1C receptor mechanisms.

Effect of 3,4‐Methylenedioxymethamphetamine on 3,4‐Dihydroxyphenylalanine Accumulation in the Striatum and Nucleus Accumbens

Abstract: The effect of the racemic mixture of 3,4‐methy‐lenedioxymethamphetamine (MDMA) on the synthesis of dopamine in the terminals of nigrostriatal and mesolimbic neurons was estimated by measuring the accumulation of 3,4‐dihydroxyphenylalanine (DOPA) in the striatum and nucleus accumbens 30 min following the administration of the l‐aromatic amino acid decarboxylase inhibitor, 3‐hydroxybenzylhydrazine. MDMA produced an increase in DOPA accumulation in the striatum which was greater in magnitude and longer in duration than that in the nucleus accumbens. Although the concentrations of serotonin (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) in both the striatum and nucleus accumbens were reduced 3 h following an injection of MDMA (20 mg/kg), 5‐HT and 5‐HIAA concentrations were significantly reduced only in the striatum 7 days after the administration of MDMA. Pretreatment with a 5‐HT2 antagonist, ketanserin, significantly attenuated the reduction in 5‐HT concentration in the striatum 3 h following MDMA administration and completely blocked 5‐HT depletion at 7 days post administration. Moreover, ketanserin completely blocked MDMA‐induced DOPA accumulation in the striatum. The results obtained in these studies suggest that MDMA activates nigrostriatal dopaminergic pathways via 5‐HT2 receptors. In addition, these data are supportive of the hypothesis that dopamine plays a role in MDMA‐induced 5‐HT depletion.