Building a Meaningful Future for Young People with Mental Illness

Transitioning to adulthood is challenging for young people who have a mental illness or substance use disorder, especially those who are transitioning from institutional care. For young people with serious mental illnesses to succeed in the adult world, they need more than treatment.These youth need to be truly integrated into their communities. They need jobs that offer skills, dignity, independence, and peers. They need a responsible and caring older adult who can help them to make better choices, learn from their mistakes, and applaud their successes, no matter how small. Community providers can create these opportunities through their own programs or appropriate community collaborations.

Effects of 8-OH-DPAT and WAY-100635 on performance on a time-constrained progressive-ratio schedule

Rationale. Performance on progressive-ratio schedules has been proposed as a means of assessing the effects of drugs on motivation. We have adopted a mathematical model proposed by Killeen to analyse the effects of drugs acting at 5-HT_1A receptors on progressive-ratio performance. According to this model, the relationship between response rate and ratio size is described by a bitonic (inverted-U) function. One parameter of the function, a, expresses the motivational or "activating" effect of the reinforcer (duration of activation of responding produced by the reinforcer), whereas another parameter, δ, expresses the minimum time needed to execute a response and is regarded as an index of "motor capacity". Objective. To examine the effect of the selective 5-HT_1A receptor agonist 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] and the antagonist WAY-100635 [N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclo-hexanecarboxamide] on progressive-ratio schedule performance. Methods. Sixteen rats responded for a food-pellet reinforcer on a time-constrained progressive-ratio schedule (55-min sessions). In phase 1, they received single doses (s.c.) of 8-OH-DPAT (25, 50, 100, 200 μg kg⁻¹, four treatments at each dose) or the vehicle (0.9% saline solution). In phase 2, they received WAY-100635 (30, 100, 300 μg kg⁻¹) according to the same regimen. In phase 3, they received 8-OH-DPAT (100 μg kg⁻¹) alone or in combination with WAY-100635 (30 μg kg⁻¹). 8-OH-DPAT dose dependently increased the value of a, significant increases being seen with the 50, 100 and 200 μg kg⁻¹ doses. The highest dose also increased δ. WAY-100635 did not significantly alter either a or δ. WAY-100635 significantly attenuated the effect of 8-OH-DPAT on both a and δ. Conclusions. The results suggest that 8-OH-DPAT enhanced the activating effect of the reinforcer (the highest dose may also have induced motor debilitation). The finding that the effect of 8-OH-DPAT on a was attenuated by WAY-100635 implicates 5-HT_1A receptors in this effect. The results are consistent with previous reports that 8-OH-DPAT facilitates feeding and food-reinforced operant responding in rats and suggest that these effects may be brought about by an increase in food motivation. Electronic Publication     

The selective 5-HT3 receptor antagonist,WAY100289, enhances spatial memory in rats with ibotenate lesions of the forebrain cholinergic projection system

The effects of three doses (0.003, 0.03 and 1.0 mg/kg sc) of the 5-HT₃ receptor antagonist, WAY 100289, on spatial learning and memory in the water maze were examined in rats before and after ibotenate lesions to the nucleus basalis and medial septal brain regions at the source of cholinergic projections to cortex and hippocampus. The representative cholinergic nicotinic and muscarinic receptor agonists nicotine (0.1 mg/kg) and arecoline (1.0 mg/kg) were also tested for comparison. Both arecoline and nicotine improved initial acquisition in rats before lesioning, in terms of latency to find a hidden platform and accuracy of search strategy. WAY100289 did not affect the performance of normal rats significantly, apart from some non-significant trends towards improvement with the highest dose. However, in animals showing transient navigational deficits in retention and relearning after lesioning, WAY100289 improved performance at all three doses, though ameliorative effects of nicotine and arecoline were more marked also in lesioned rats. These results show that WAY100289 improved spatial learning in animals impaired after lesions to cholinergic projection nuclei, which may reflect an interaction with cholinergic transmission to enhance cognitive function. However, in the present study, WAY100289 appeared to be less effective than direct cholinergic agonists.     

Synergism between 5-HT1B/1D and 5-HT1A receptor antagonists on turnover and release of 5-HT in guinea-pig brain in vivo

The effects on 5-HT turnover (5-HIAA/5-HT ratio) and extracellular 5-HT and 5-HIAA levels (in vivo microdialysis in freely moving animals) were analysed in guinea-pig brains following the 5-HT_1B receptor antagonist, GR 127935 {N-[4-methoxy-3-(4-methyl-1-piper_{azinyl)phenyl]-2’-methyl-4’-(5-methyl-1,2,4-oxadiazol-3-}yl) [1,1-biphenyl]-4-carboxamide}, or the 5-HT_1A receptor antagonist, WAY-100635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride), administered alone or in combination. GR 127935, injected alone, increased 5-HT turnover with maximal effects approximately 50% above the control levels in the four brain regions examined (hypothalamus, hippocampus, striatum and frontal cortex). GR 127935 significantly increased extracellular concentrations of 5-HT and 5-HIAA in frontal cortex (40%), whereas 5-HIAA, but not 5-HT, was elevated in striatum (20–30%). WAY-100635 did not significantly change 5-HT turnover but caused a small significant increase in the extracellular 5-HT and 5-HIAA concentrations in both striatum and frontal cortex. The combined treatment with GR 127935 and WAY-100635 resulted in an increased 5-HT turnover reaching maximal effects of 70–90% above the control values in all brain regions tested and produced a significant elevation of striatal and frontal cortex extracellular 5-HT (40% and 60%, respectively) and 5-HIAA (60% and 70%, respectively) concentrations. The synergistic effect of the two receptor antagonists on the 5-HT turnover and the terminal release of 5-HT indicate somatodendritic 5-HT release and stimulation of inhibitory 5-HT_1A receptors at this level. Extracellular 5-HIAA seems to be a better marker than 5-HT itself for the evoked 5-HT release when the reuptake mechanism is intact. Received: 2 September 1998 / Accepted: 19 November 1998     

Antidepressant-like effect of coadministration of sulpiride and fluvoxamine in mice

We have recently reported that coadministration of sulpiride, an antipsychotic drug, and fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor, selectively increases in vivo dopamine release in the prefrontal cortex. This study examined the effects of coadministration of these drugs on duration of immobility in the tail suspension test using mice. Neither sulpiride (3 or 10 mg/kg) nor fluvoxamine (10 or 20 mg/kg) alone affected immobility time, whereas coadministration significantly reduced immobility time. WAY100635, a 5-HT_1A receptor antagonist, did not affect the effects of sulpiride and fluvoxamine coadministration, but reduced immobility time in combination with fluvoxamine (20 mg/kg). A high dose of fluvoxamine alone (60 mg/kg) also reduced immobility time. These results suggest that the antidepressant-like effects of fluvoxamine in combination with sulpiride or WAY100635 in the tail suspension test are mediated by the activation of dopamine or 5-HT systems, respectively.     

WAY-100635 is a potent dopamine D4 receptor agonist

Rationale and objectives WAY-100635 is a prototypical 5-HT_1A receptor antagonist and has been used widely as a pharmacological probe to investigate the distribution and function of 5-HT_1A receptors. Results from our studies suggested that WAY-100635 was potently inducing effects unrelated to its 5-HT_1A receptor affinity. In the present work, we evaluated the in vitro pharmacology of this compound at two D₂-like receptor subtypes.Method The functional properties and binding affinities of WAY-100635 were evaluated in HEK 293 cells stably expressing dopamine D_2L or D_4.4 receptors.Results Initial screens performed by the NIMH Psychoactive Drug Screening Program indicated that WAY-100635 displayed 940, 370, and 16 nM binding affinities at D_2L, D₃, and D_4.2 receptors, respectively. Subsequent saturation analyses demonstrated that the K _d of [³H]WAY-100635 at D_4.2 receptors was 2.4 nM, only tenfold higher than 5-HT_1A. WAY-100635 and its major metabolite, WAY-100634, were potent agonists in HEK-D_4.4 cells (EC₅₀=9.7±2.2 and 0.65±0.2 nM, respectively). WAY-100635 behaved as a full agonist, and WAY-100634 was a nearly full agonist. In HEK-D_2L cells, WAY-100635 weakly antagonized the effects of 300 nM quinpirole. Subsequent radioligand binding studies confirmed that WAY-100635 possesses high affinity for D_4.4 receptors but binds weakly to D_2L receptors (3.3±0.6 and 420±11 nM, respectively).Conclusions This study demonstrates that WAY-100635 is not a “selective” 5-HT_1A receptor antagonist, as previously reported, and conclusions drawn from studies that employed WAY-100635 as a selective 5-HT_1A antagonist may need to be reevaluated.     

N-Methyl-d-aspartate receptors regulate 5-HT release in the raphe nuclei and frontal cortex of freely moving rats: differential role of 5-HT1A autoreceptors

The effects of infusing N-methyl-

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-aspartate (NMDA) into the raphe nuclei on release of 5-HT in this brain region and also the frontal cortex of the same animal were studied using in vivo microdialysis in freely moving rats. Infusion of 25 μM NMDA into the raphe led to a substantial decrease in dialysate 5-HT in this region and a prolonged increase in terminal 5-HT release in the frontal cortex. These effects were blocked by the specific NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (D-AP5; 100 μM). When 25 μM NMDA was co-infused into the raphe with the selective 5-HT_1A receptor antagonist (N-{2-{4-(2-methoxyphenyl)-1-piperazinyl}ethyl-N-(2-pyridinyl)cyclohexanecarboxamide) (WAY-100635; 1.0 μM) the effect of NMDA infusion was unaltered. WAY-100635 infused alone into the raphe did not alter local 5-HT or extracellular 5-HT in the cortex. Infusion of 100 μM NMDA into the raphe was followed by an increase in local dialysate 5-HT and a decrease in 5-HT release in the cortex. These changes were reversed by D-AP5. Following infusion of 100 μM NMDA with 1.0 μM WAY-100635 into the raphe local 5-HT release was still increased, however, the decrease in 5-HT observed in the frontal cortex was abolished. These data suggest that the degree of NMDA receptor activation leads to dramatically different outcomes with regard to serotonergic transmission to the frontal cortex. Furthermore, there appears to be a differential role of the 5-HT_1A autoreceptor in regulating these effects. These data are discussed in relation to other studies on the regulation of serotonergic transmission in ascending pathways.     

Inhibition of median and dorsal raphe neurones following administration of the selective serotonin reuptake inhibitor paroxetine

Acute systemic injection of selective serotonin reuptake inhibitors (SSRIs) decreases 5-HT neuronal firing in the dorsal raphe nucleus (DRN). Recent data, however, question whether these drugs also inhibit the firing of 5-HT neurones in the median raphe nucleus (MRN). Using in vivo extracellular electrophysiological recording techniques in the chloral hydrate anaesthetised rat, we have tested the effect of acute administration of the SSRI, paroxetine, on 5-HT neuronal activity in the MRN and DRN. Presumed 5-HT neurones in the MRN displayed the same electrophysiological characteristics as those in the DRN, the only detectable difference being that MRN neurones showed a significantly (p < 0.001) slower mean ( ± SEM(n)) spontaneous firing rate (MRN, 5.6 ± 0.9 (14) spikes/10 s; DRN, 13.5 ± 1.6 (24) spikes/10 s). Paroxetine caused a dose-related (0.1–0.8 mg/kg i.v.) inhibition of all MRN neurones tested (n = 8), producing a complete cessation of cell-firing at the highest doses. DRN neurones (n = 9) responded in a similar fashion. Furthermore, paroxetine inhibited MRN and DRN neurones with almost identical potency (MRN ED₅₀ 259 ± 57 g/kg i.v.: DRN ED₅₀ 243 ± 49 g/kg i.v.). In the majority of cells tested, the effect of paroxetine was reversed by the 5-HT_1A receptor antagonists spiperone or (+)WAY100135, implicating the involvement of the 5-HT_1A autoreceptor. The selective 5-HT_1A receptor agonist 8-OH-DPAT also inhibited the firing of MRN (n = 5) and DRN (n = 12) neurones and with equal potency (MRN ED₅₀, 1.32 ± 0.40 g/kg i.v.: DRN ED₅₀, 1.19 ± 0.23 g/kg i.v.). Our data indicate that paroxetine not only inhibits the firing of 5-HT neurones in the MRN but does so with equal potency to those in the DRN.