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Richard Young

Publications and source records attributed to Richard Young.

At least 19 recordsLinked to original sources
PubMed2006

alpha-Ethyltryptamine (alpha-ET) as a discriminative stimulus in rats.

alpha-Ethyltryptamine (etryptamine, alpha-ET) is a drug of abuse that first appeared on the clandestine market in the mid-1980s. Its pharmacological actions are poorly understood. In this investigation, it is reported for the first time that alpha-ET serves as a training drug in drug discrimination studies. Male Sprague-Dawley rats were trained to discriminate (30-min pretreatment time) 2.5 mg/kg of alpha-ET (ED(50)=1.3 mg/kg) from saline vehicle using a standard two-lever operant paradigm and a VI-15s schedule of reinforcement for appetitive reward. Once established, the alpha-ET stimulus was shown to have an onset to action of 30 min and a duration of effect of at least 4 h. In tests of stimulus generalization (substitution), the alpha-ET stimulus generalized to S(-)alpha-ET (ED(50)=1.6 mg/kg) and R(+)alpha-ET (ED(50)=1.3 mg/kg). Tests of stimulus generalization were also conducted with prototypical phenylisopropylamines: (+)amphetamine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), and N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA). The alpha-ET stimulus generalized to DOM (ED(50)=0.4 mg/kg) and PMMA (ED(50)=0.7 mg/kg), but only partially generalized (ca. 40% maximal drug-appropriate responding) to (+)amphetamine. The results suggest that alpha-ET produces a complex stimulus.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed2006

Effect of the 5-HT(6) serotonin antagonist MS-245 on the actions of (-)nicotine.

The 5-HT(6) serotonin receptor antagonist MS-245 neither substitutes for nor antagonizes the discriminative stimulus effects of (-)nicotine. However, MS-245 was shown to enhance the potency of (-)nicotine in Sprague-Dawley rats trained to discriminate 0.6 mg/kg of (-)nicotine from saline vehicle in a typical two-lever drug discrimination paradigm such that a combination of MS-245 (5.0 mg/kg) plus the ED(50) dose of (-)nicotine caused the animals to respond as if they had received the training dose of (-)nicotine. MS-245 also potentiated the hypolocomotor actions, but not the antinociceptive effects, of (-)nicotine in mice. The results suggest possible involvement of serotonin-regulated signaling mechanisms in certain behavioral effects of nicotine.

Animals↗
PubMed2006

TDIQ (5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline) exhibits anxiolytic-like activity in a marble-burying assay in mice.

Numerous studies have suggested that the central alpha2-adrenergic receptor system may exert an important role in some types of human anxiety. The anxiolytic-like activity and potential side effect-like activities of the novel and purported alpha2-adrenergic compound TDIQ (5,6,7,8-1,3-dioxolo[4,5-g]isoquinoline) were compared to those of the anxiolytic drugs diazepam and buspirone, and the nonselective alpha2-adrenergic agent clonidine. Anxiolytic-like behavior was assessed in an object (marble)-burying assay, a selective test for the evaluation of known anxiolytics and identification of putative antianxiety compounds, that used mice housed either alone or in groups (5/cage). The rodents' antianxiety-like effect was defined as dose-related increases in the number of marbles that remained uncovered in their bedding material without concomitant disruption of their motor activities. Rotarod and inclined screen procedures were employed as potential indicators of side effects. An additional test monitored the heart rate (HR) and blood pressure (BP) of mice after the intravenous (IV) administration of doses of TDIQ. The reference compounds inhibited marble-burying behavior in a dose-related manner and produced various degrees of impairment in the side effect tests. TDIQ also inhibited object burying and displayed a wide separation between doses that produced anxiolytic-like activity and doses that produced some, if any, disruption of coordinated movement and/or motor activity. Moreover, the IV administration of TDIQ, up to 10 mg/kg, produced negligible effects on the HR and BP of mice. TDIQ could be a lead candidate for a new type of structural compound in the treatment of certain forms of anxiety.

Animals↗
PubMed2006

TDIQ (5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline) inhibits the consumption of "snacks" in mice.

There is considerable evidence that alpha2-adrenergic receptor activity exerts a pivotal role in initiation of feeding behavior. The appetite suppressant and monoamine release effects of TDIQ (5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline), a putative selective alpha2-adrenergic compound, were compared to those of fenfluramine, a reference drug that produces an anorectic effect via presynaptic release and reuptake inhibition of serotonin. The drugs were administered to two groups of mice that had learned to consume either sweet milk or chocolate pellets (i.e. "snacks") during the low-activity/reduced-feeding "light" portion of their light/dark cycle. The selectivity of the drugs to suppress the consumption of snacks was determined by comparing doses of each drug that inhibited the animals' consumption of snacks to doses of each drug that have been shown, or were shown, to impact the motor (i.e. locomotor, rotarod, and inclined-screen side effect-like tests) or conditioned taste aversion (CTA) behavior of mice. An evaluation of TDIQ as a releaser of monoamines was determined in rodent brain synaptosomes. The administration of TDIQ or fenfluramine inhibited the consumption of the snacks, and a comparison of their ED50 doses indicated that TDIQ is about 3 times more potent than fenfluramine (1.3 mg/kg vs. 4.2 mg/kg, respectively) in the sweet milk test and almost equipotent to fenfluramine (19.4 mg/kg vs. 18.4 mg/kg, respectively) in the chocolate pellet assay. The selectivity of the appetite suppressant effect of TDIQ was differentiated from that of fenfluramine on the basis that TDIQ exhibited a wide separation between its dose-response effects that suppressed snack consumption and its minimal effects in tests that measured behavioral impairment. Moreover, TDIQ was distinguished from fenfluramine in that it displayed very low potencies as a presynaptic releaser of monoamines. Finally, TDIQ (0.3 mg/kg-30.0 mg/kg) did not induce a conditioned taste aversion. TDIQ may represent a novel chemical entity that exhibits a significantly favorable therapeutic-like (i.e. appetite suppressant) effect to side effect-like ratio.

Animals↗
PubMed2006

Modulation of a (+)amphetamine discriminative stimulus in rats by 8-hydroxy-2-(N,N-di-n-propylamino)tetralin (8-OH DPAT).

It is well established that the discriminative stimulus (DS) effect of amphetamine involves a dopaminergic and/or noradrenergic mechanism. These catecholamines can be modulated by the 5-HT(1A) serotonin receptor agonist 8-hydroxy-2-(N,N-di-n-propylamino)tetralin (8-OH DPAT). The present study was conducted to determine whether 8-OH DPAT could influence the DS effects of (+)amphetamine. Administration of 8-OH DPAT doses to Sprague-Dawley rats trained to discriminate 1 mg/kg of (+)amphetamine (ED(50)=0.33 mg/kg) using a two-lever operant paradigm (VI-15 s schedule of reinforcement for appetitive reward) failed to result in stimulus generalization when administered alone, and failed to antagonize the stimulus effect when administered in combination with the training dose of (+)amphetamine. However, administration of 8-OH DPAT doses that produced saline-like responding (i.e., 0.01-0.1 mg/kg; <20% amphetamine-appropriate responding) in combination with the ED(50) dose of (+)amphetamine resulted in the animals' making a progressively greater number of responses on the drug-appropriate lever such that a combination of 0.1 mg/kg of 8-OH DPAT plus (+)amphetamine (0.33 mg/kg) elicited 91% (+)amphetamine-appropriate responding. In a separate study, administration of (+)amphetamine doses in combination with fixed doses of 8-OH DPAT (either 0.01 or 0.1 mg/kg) resulted in an apparent leftward shift of the dose-response curve. The results indicate that (+)amphetamine can be more effective as a discriminative stimulus in the presence of 8-OH DPAT than in its absence.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2006

Prevalence rate of myopia in schoolchildren in rural Mongolia.

PURPOSE: The prevalence of myopia among some young Asian populations has been reported to be increasing to near epidemic proportions. Mongolia is an emerging Asian economy with limited ophthalmic resources. The purpose of this study was to define a level of myopia for school-aged children in rural Mongolia. METHODS: A total of 1057 schoolchildren, aged between 7 and 17 years, were examined in two remote, rural suums (districts) of Mongolia: one situated in the western aimag (province) of Khovd and the other in the central steppe's aimag of Zavkhan. The examination included retinoscopy, subjective refraction, best-corrected visual acuity, and direct ophthalmoscopy. RESULTS: The total prevalence of myopia (more than -0.5 D spherical equivalent) was 5.8% (95% confidence intervals [CIs], 4.4-7.2%). Female students exhibited a significantly higher prevalence of myopia in comparison to male students: 8.3% (95% CIs, 6.0-10.6%) compared with 3.1%, respectively (95% CIs, 1.6-4.6%): p < 0.001). For those with myopia, the median level of myopia for both genders was -0.75 D spherical equivalent (SE) and ranged from -0.50 to -28.00 D SE in girls and from -0.50 to -6.50 D SE in boys. CONCLUSIONS: To the authors' knowledge, this is the first study to report a level of myopia for schoolchildren in Mongolia. The prevalence rate is low in comparison to reported studies for other Far Eastern countries.

Adolescent↗
PubMed2006

Plasma cell-free DNA as an indicator of severity of injury in burn patients.

BACKGROUND: Raised levels of plasma cell-free DNA have been detected in various patient groups, including trauma patients. We hypothesized that plasma DNA is increased in burn patients and may represent an objective indicator of burn severity and have predictive as well as prognostic significance. METHODS: This was a prospective clinical study with full ethical approval. With informed consent, blood samples were collected from 28 burn patients within 24 h of injury and from 12 control subjects. Plasma cell-free DNA was measured by real-time quantitative polymerase chain reaction (PCR) assay for the beta-globin gene. Descriptive analysis, non-parametric data comparison tests (Mann-Whitney) and correlation tests (Spearman rank) were performed on the data. RESULTS: Samples were taken at a mean time of 5.7 h after injury from 13 patients with flame/flash burns and 15 patients with scalds. Median plasma DNA levels in the control, scald and flame/flash burn patient groups were 287, 648 and 2685 kilogenome-equivalents/L, respectively. Plasma DNA levels correlated with the length of hospital stay, but not with admission to the intensive care unit (ICU) nor the length of ICU stay. DNA levels correlated with the burn surface area (Spearman rank r = 0.54, p = 0.04) and the number of operations needed (Spearman rank r = 0.55, p = 0.03) for scalds, but not for flame/flash burns. CONCLUSIONS: Plasma DNA is increased after burn injury and is significantly correlated with some outcome measures, including the length of hospital stay. DNA levels are higher in flame/flash patients than in scald patients; the difference may provide an objective indication of burn depth and inhalation injury.

Body Surface Area↗
PubMed2005

S(+)- and R(-)N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) as discriminative stimuli: effect of cocaine.

Racemic N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (methylenedioxymethamphetamine, MDMA), a central stimulant and empathogenic agent, and cocaine are drugs of abuse that function as training drugs in drug discrimination studies. In tests of stimulus generalization (substitution), asymmetric generalization occurs between the two agents: a (+/-)MDMA stimulus generalized to cocaine, but a cocaine stimulus did not generalize to (+/-)MDMA. A possible explanation may be found, at least in part, in the stimulus effects of the optical isomers of MDMA. In the present study, groups of male Sprague-Dawley rats were trained to discriminate either S(+)MDMA (training dose=1.5 mg/kg, i.p.; n=10; ED50=0.6 mg/kg) or R(-)MDMA (training dose=1.75 mg/kg, i.p.; n=7; ED50=0.4 mg/kg) from saline vehicle using a VI-15s schedule of reinforcement. Tests of stimulus generalization with cocaine were conducted in each of the two groups. Cocaine only partially substituted for the S(+)MDMA stimulus (maximum=39% drug-appropriate responding), and various doses of cocaine did not enhance the percent drug-appropriate responding produced by a low dose (0.5 mg/kg) of S(+)MDMA. In contrast, the R(-)MDMA stimulus generalized completely to cocaine (ED50=1.3 mg/kg). Taken together with an earlier report that a (+/-)MDMA stimulus generalizes to cocaine, it would seem that the stimulus actions of cocaine might share greater similarity with R(-)MDMA than with S(+)MDMA.

Animals↗
PubMed2005

Pizotyline effectively attenuates the stimulus effects of N-methyl-3,4-methylenedioxyamphetamine (MDMA).

MDMA (N-methyl-3,4-methylenedioxyamphetamine) produces a discriminative stimulus (DS) effect in animals, but attempts to completely block this action with selective neurotransmitter antagonists have not been very successful. Biochemically, MDMA can increase synaptic levels of serotonin, dopamine, and norepinephrine that, conceivably, might interact with multiple populations or subpopulations of neurotransmitter receptors. The present study attempted to antagonize the DS effects of MDMA using the nonselective agents clozapine, cyproheptadine, and pizotyline. An extensive and comparative radioligand binding profile was also obtained for the latter two agents. The purported antagonists were administered in combination with the training dose of MDMA to groups of Sprague-Dawley rats trained to discriminate 1.5 mg/kg of MDMA from saline vehicle in a standard two-lever operant paradigm using a VI-15s schedule of reinforcement. Clozapine was without effect at the doses evaluated, and cyproheptadine only partially attenuated MDMA-appropriate responding. In contrast, pizotyline (AD50=2.5 mg/kg), in combination with the MDMA training dose, resulted in a dose related decrease in percent drug-appropriate responding to saline levels. In a separate group of animals trained to discriminate the structurally-related agent N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA) from vehicle, pretreatment with pizotyline also resulted in a substantial decrease in drug-appropriate responding. The results with cyproheptadine and pizotyline in the binding assays confirmed that these agents display high affinity for multiple subpopulations of serotonergic, dopaminergic, adrenergic, histaminergic, and cholinergic receptors. The overall results of the present investigation indicate that pizotyline, which is clinically available in some countries, might be of clinical utility in the treatment of MDMA overdose.

Animals↗
PubMed2005

6-(2-Phenylethyl)nicotine: a novel nicotinic cholinergic receptor ligand.

6-(2-Phenylethyl)nicotine (1b; K(i)=15 nM) was unexpectedly found to bind at alpha4beta2 nicotinic cholinergic (nACh) receptors. Although this compound failed to produce nicotine-like agonist action in several functional assays, 1b antagonized the antinociceptive effects of nicotine (mouse tail-flick assay) in a dose-dependent fashion when administered via an intrathecal route.

Analgesics↗
PubMed2005

Pocket protein complexes are recruited to distinct targets in quiescent and proliferating cells.

Biochemical and genetic studies have determined that retinoblastoma protein (pRB) tumor suppressor family members have overlapping functions. However, these studies have largely failed to distinguish functional differences between the highly related p107 and p130 proteins. Moreover, most studies pertaining to the pRB family and its principal target, the E2F transcription factor, have focused on cells that have reinitiated a cell cycle from quiescence, although recent studies suggest that cycling cells exhibit layers of regulation distinct from mitogenically stimulated cells. Using genome-wide chromatin immunoprecipitation, we show that there are distinct classes of genes directly regulated by unique combinations of E2F4, p107, and p130, including a group of genes specifically regulated in cycling cells. These groups exhibit both distinct histone acetylation signatures and patterns of mammalian Sin3B corepressor recruitment. Our findings suggest that cell cycle-dependent repression results from recruitment of an unexpected array of diverse complexes and reveals specific differences between transcriptional regulation in cycling and quiescent cells. In addition, factor location analyses have, for the first time, allowed the identification of novel and specific targets of the highly related transcriptional regulators p107 and p130, suggesting new and distinct regulatory networks engaged by each protein in continuously cycling cells.

Acetylation↗
PubMed2004

Beta-oxygenated analogues of the 5-HT2A serotonin receptor agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane.

Activation of 5-HT(2A) serotonin receptors represents a novel approach to lowering intraocular pressure. Because 5-HT(2A) serotonin receptor agonists might also produce undesirable central effects should sufficient quantities enter the brain, attempts were made to identify 5-HT(2) serotonin receptor agonists with reduced propensity to penetrate the blood-brain barrier. 1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropan-1-ol (6), an analogue of the 5-HT(2) serotonin receptor agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB; 1a) bearing a benzylic hydroxyl group, was identified as a candidate structure. Of the four optical isomers of 6, the 1R,2R-isomer (6d; K(i) = 0.5 nM) was found to bind at 5-HT(2A) receptors with an affinity similar to that of R(-)DOB (K(i) = 0.2 nM). Like R(-)DOB, 6d behaved as a partial agonist (efficacy ca. 50%) in a 5-HT(2)-mediated calcium mobilization assay. However, in an in vivo test of central action (i.e., stimulus generalization with rats as subjects), 6d was >15 times less potent than R(-)DOB. O-Methylation of 6d (i.e., 7d; 5-HT(2A) K(i) = 0.3 nM) resulted in an agent that behaved as a full (93% efficacy) agonist. Intraocular administration of 300 microg of 6d and 7d to ocular hypertensive monkeys was shown to reduce intraocular pressure by 20-27%. Given the route of administration (i.e., topical), and concentrations necessary to reduce intraocular pressure, compounds such as 6d should demonstrate minimal central effects at potentially useful therapeutic doses and offer useful leads for further development.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed2004

A common set of gene regulatory networks links metabolism and growth inhibition.

Using genome-wide analysis of transcription factor occupancy, we investigated the mechanisms underlying three mammalian growth arrest pathways that require the pRB tumor suppressor family. We found that p130 and E2F4 cooperatively repress a common set of genes under each growth arrest condition and showed that growth arrest is achieved through repression of a core set of genes involved not only in cell cycle control but also mitochondrial biogenesis and metabolism. Motif-finding algorithms predicted the existence of nuclear respiratory factor-1 (NRF1) binding sites in E2F target promoters, and genome-wide factor binding analysis confirmed our predictions. We showed that NRF1, a factor known to regulate expression of genes involved in mitochondrial function, is a coregulator of a large number of E2F target genes. Our studies provide insights into E2F regulatory circuitry, suggest how factor occupancy can predict the expression signature of a given target gene, and reveal pathways deregulated in human tumors.

Amino Acid Motifs↗
PubMed2004

Features of sentinel lymph nodes for melanoma may lead to re-diagnosis of the cutaneous primary: an unusual case and review of literature.

Although sentinel lymph-node biopsy is accepted as a reliable method of staging of melanoma, it is not without problems to the pathologist. It has been re-emphasised that aggregates of benign naevus cells are not uncommon. Usually these are easily identified by a combination of their benign cytology and location in the fibrous skeleton of lymph nodes. This case represents a combination of an unusual pseudo-malignant pattern in the primary lesion with unusual morphology of the sentinel lymph node. The latter prompted reassessment of the cutaneous lesion as a benign naevus. Confirmation of the diagnosis as cutaneous melanoma by a positive sentinel-node biopsy was averted only by a careful comparison of unusual features of the putative primary and the sentinel lymph node. This case illustrates the need for a rigorous protocol for pathological assessment of sentinel lymph nodes for melanomas to assure detection of all metastases but also to avoid misdiagnosis and over-treatment. It also supports "benign metastases" as the mechanism underlying at least some melanocytes in regional lymph nodes.

Adult↗
PubMed2004

Comparison of the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) and cocaine: asymmetric generalization.

Evidence suggests that +/- 3,4-methylenedioxymethamphetamine (MDMA) and psychostimulants produce similar but non-identical stimulus effects in animals. To examine this hypothesis, groups of rats were trained to discriminate either MDMA (1.5 mg/kg) or cocaine (8 mg/kg) from saline vehicle using a two-lever operant procedure under a variable interval (VI) 15 s schedule of reinforcement. Once the animals were trained, tests of stimulus generalization were conducted with +/- MDMA, cocaine, S+ MDMA, and R- MDMA. As previously demonstrated, both S+ MDMA and R- MDMA (ED50 = 0.8 and 1.2 mg/kg, respectively) substituted for +/- MDMA. Stimulus generalization also occurred upon administration of cocaine (ED50 = 4.6 mg/kg) to the +/- MDMA-trained animals. In the cocaine-trained animals, however, stimulus generalization did not occur to +/- MDMA, S+ MDMA nor R- MDMA. Receptor binding profiles for MDMA and cocaine were compared in an effort to identify any novel and common receptor-based mechanism(s) to explain stimulus generalization of MDMA-trained animals to the effects of cocaine, but only their actions on neurotransmitter transporters seem applicable. Taken together, the results indicate that stimulus substitution between MDMA and cocaine is asymmetric and suggest that although similarities exist between the stimulus actions of MDMA and cocaine, differences might be explained by their differential effects on increasing synaptic concentrations of serotonin (5-HT), dopamine (DA), and/or norepinephrine (NE).

Animals↗
PubMed2004

Modulation of the stimulus effects of (+)amphetamine by the 5-HT6 antagonist MS-245.

5-HT(6) serotonin receptors are distributed within some dopamine terminal regions in the brain leading to suggestions that they might influence dopaminergic function. In the present study, the 5-HT(6) antagonist 5-methoxy-N,N-dimethyl-N(1)-benzenesulfonyltryptamine (MS-245) was without effect when administered (3.0-7.5 mg/kg) to rats trained to discriminate (+)amphetamine (1.0 mg/kg) from saline vehicle in a two-lever drug discrimination task. Administered in combination, 0.3 mg/kg (i.e., the ED(50) dose) of (+)amphetamine plus 5.0 mg/kg of MS-245 elicited 95% amphetamine-appropriate responding. Similar studies were conducted using rats trained to discriminate cocaine (8.0 mg/kg) from saline vehicle, but a combination of 2.0 mg/kg (i.e., the ED(50) dose) of cocaine together with relatively low doses of MS-245 resulted in the percent response (approximately 50%) expected from administration of this dose of cocaine or in disruption of the animals' behavior. The present results confirm findings from other laboratories that 5-HT(6) antagonists can modulate amphetamine-induced behavioral actions, and further extend these findings to an example of a different structural class of 5-HT(6) antagonists and to a different behavioral paradigm. Taken together, the data suggest that 5-HT(6) serotonin agents (or at least MS-245) could have potential clinical application in therapies that involve modulation of dopamine neurotransmission.

Amphetamine↗
PubMed2004

Stimulus effects of three sulfur-containing psychoactive agents.

Two agents gaining popularity on the illicit drug market are the phenylalkylamines 4-MTA and 2C-T-7 [or 1-(4-methylthiophenyl)-2-aminopropane and 2-(2,5-dimethoxy-4-n-propylthiophenyl)-1-aminoethane, respectively]. At this time, there exists a paucity of information on the behavioral actions of these sulfur-containing agents. The present investigation examined these agents, and the N-monomethyl analog of 4-MTA (i.e., 4-MTMA), in tests of stimulus generalization (substitution) using a two-lever drug discrimination task with groups of rats trained to discriminate either the hallucinogen DOM [1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane], the stimulant cocaine, or the empathogen MDMA from vehicle. 4-MTA and its N-monomethyl analog 4-MTMA (ED50 = 0.8 mg/kg in both cases) substituted only for the MDMA stimulus, whereas 2C-T-7 (ED50 = 0.8 mg/kg) substituted only for the DOM stimulus. Thus, at the doses examined, 4-MTA and 4-MTMA appear to be MDMA-like agents, and 2C-T-7 seems best classified as a DOM-like hallucinogen. These results provide additional data that extend the structure-activity relationships of phenylalkylamines and that are consistent with what little is currently known about the action of 4-MTA and 2C-T-7 in humans.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗