Previous work has indicated recreational use of methylenedioxymethamphetamine (MDMA or ecstasy) is associated with elevated scores on self-report measures of depression. We sought to examine the long-term effects of consumption on depression in a group of individuals who had consumed large quantities of the drug in the past, but were now leading relatively drug free lives. Respondents to this study (n = 29) had consumed an average of 1.5 ecstasy tablets in the last month, 8.4 in the last 6 months and 23.3 in the last 12 months. The estimated total consumed was 527 tablets, indicating that these respondents were indeed former chronic users of the drug. None of the respondents had consumed ecstasy in the last 14 days. Levels of depression (Beck's Depression Inventory) were significantly (p < 0.01) elevated compared to a matched non-drug using control group. Within the group of former chronic users, these levels of depression were not significantly affected by current use of alcohol, cannabis or amphetamine, but were positively correlated with an external locus of control (p < 0.05), infrequent but severe- (p < 0.05) and frequent but mild- (p < 0.005) self-report measures of life stress. Multiple regression indicated that levels of frequent but mild life stress (p < 0.005) and the quantity of ecstasy tablets respondents consumed over a 12-h period (p < 0.05) were the only variables that were significant predictors of self-reported levels of depression. The results of this study indicate that former chronic ecstasy users report higher levels of depression than their matched controls.

1 This study examined whether group III metabotropic glutamate (mGlu) receptor agonists injected into the globus pallidus (GP), substantia nigra pars reticulata (SNr) or intracerebroventricularly (i.c.v.) could reverse reserpine-induced akinesia in the rat. 2 Male Sprague -Dawley rats, cannulated above the GP, SNr or third ventricle, were rendered akinetic with reserpine (5 mg kg À1 s.c.). 18 h later, behavioural effects of the group III mGlu receptor3 In reserpine-treated rats, unilateral injection of L-SOP (2000 and 2500 nmol in 2.5 ml) into the GP produced a significant increase in net contraversive rotations compared to vehicle, reaching a maximum of 83721 rotations 120 min À1 (n ¼ 8). Pretreatment with the group III mGlu receptor antagonist methyl-serine-O-phosphate (M-SOP; 250 nmol in 2.5 ml) inhibited the response to L-SOP (2000 nmol) by 77%. 4 Unilateral injection of L-SOP (250-1000 nmol in 2.5 ml) into the SNr of reserpine-treated rats produced a dose-dependent increase in net contraversive rotations, reaching a maximum of 4776 rotations 30 min À1 (n ¼ 6). M-SOP (50 nmol in 2.5 ml) inhibited the response to L-SOP (500 nmol) by 78%. 5 Following i.c.v. injection, L-SOP (2000 -2500 nmol in 2.5 ml) or L-AP4 (0.5 -100 nmol in 2 ml) produced a dose-dependent reversal of akinesia, attaining a maximum of 45717 (n ¼ 8) and 7273 (n ¼ 9) arbitrary locomotor units 30 min À1 , respectively. 6 These studies indicate that injection of group III mGlu receptor agonists into the GP, SNr or cerebral ventricles reverses reserpine-induced akinesia, the mechanism for which remains to be established.

1 The molecular nature and functions of the I 2 subtype of imidazoline binding sites are unknown but evidence suggests an association with monoamine oxidase (MAO). Rats can distinguish the selective imidazoline I 2 -site ligand 2-BFI from vehicle in drug discrimination, indicating functional consequences of occupation of these sites. We have used drug discrimination to investigate the nature of the discriminable stimulus, especially in relation to MAO inhibition. 2 Following training to distinguish 2-BFI 7 mg kg 71 i.p. from saline vehicle in two-lever operantchambers, male Hooded Lister rats underwent sessions where test substances were given instead and the proportion of lever presses on the 2-BFI-associated lever (substitution) recorded. 3 2-BFI; its cogeners BU216, BU224, BU226 and LSL60101; the reversible MAO-A inhibitors moclobemide and RO41-1049; the b-carbolines harmane, norharmane and harmaline which also reversibly inhibit MAO-A, and the anti-addictive substance ibogaine exhibited potent, dosedependent substitution for 2-BFI. 4 Agmatine, and LSL60125 substituted at one dose only. The reversible MAO-B inhibitors lazabemide and RO16-1649; the s 2 -site ligand SKF10,047 and the I 2A -site ligand, amiloride, failed to substitute. The irreversible inhibitor of MAO, deprenyl, substituted for 2-BFI while clorgyline did not. 5 These results suggest imidazoline I 2 site ligands produce a common discriminable stimulus that appears associated with reversible inhibition of MAO-A rather than MAO-B, possibly through increases in extracellular concentration of one or more monoamines. Ibogaine exhibits a commonality in its subjective e ects with those of I 2 -site ligands.

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1 The present study examined the ability of the selective imidazoline I 2 -site ligands 2-(-2-benzofuranyl)-2-imidazoline (2-BFI) and 2-[4,5-dihydroimidaz-2-yl]-quinoline (BU224) and selected monoamine oxidase (MAO) inhibitors to evoke locomotor activity in rats bearing a lesion of the nigrostriatal pathway. 2 Male Sprague-Dawley rats were injected with 12.5 mg 6-hydroxydopamine (6-OHDA) into the right median forebrain bundle to induce a unilateral lesion of the nigrostriatal tract. After 6 weeks, test drugs were administered either alone or in combination with L-DOPA (L-3,4-dihydroxyphenylamine) and the circling behaviour of animals was monitored as an index of anti-Parkinsonian activity. ) significantly increased either the duration or total number of contraversive rotations emitted over the testing period in comparison to L-DOPA alone. 5 These data suggest that I 2 -specific ligands have dual effects in the 6-OHDA-lesioned rat model of Parkinson's disease; a first effect associated with an increase in activity in the intact hemisphere, probably via an increase in striatal dopamine content, and a secondary action which, through the previously documented inhibition of MAO-A and/or MAO-B, increases the availability of dopamine produced by L-DOPA.

Dementia with Lewy bodies (DLB) accounts for 15-20% of the millions of people worldwide with dementia. In the current work we investigate the association between proteasome dysfunction and the development of cortical Lewy body pathology. Analysis of post-mortem cortical tissue indicated levels of the alpha-subunit of the 20S proteasome were significantly reduced in DLB cortex, but not Alzheimer's, in comparison to control and this reduction correlated with both the severity and duration of dementia. Application of proteasome inhibitors to rodent cortical primary neurones in vitro and by direct injection onto rodent cholinergic forebrain neurons in vivo gave rise to dose dependent neuronal death and in rodent cortex -- marked cholinergic deficits accompanied by the accumulation of inclusions that stained positive for alpha-synuclein and ubiquitin. These findings suggest that proteasomal abnormalities are present within cortical Lewy body disease and the experimental inhibition of proteasomal function mirrors the neuropathological changes seen within the disorder.

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