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Tire wear microrubber particles (TWMP) are a major source of environmental contamination. Degradation of TWMP is slow and leachates contain toxic constituents including heavy metals, polycyclic aromatic hydrocarbons (PAHs) and organic additives. Few studies have addressed methods to mitigate the potential ecotoxicity of TWMP leachates. This study investigated the effects of UV-C (254 nm) and combined UV-C and vacuum UV (185 nm) treatment (VUV-UV-C) of TWMP leachates on degradation and ecotoxicity. VUV-UV-C treatment mitigated dissolved zinc and degraded the TWMP constituents fluoranthene, pyrene and benzo(a)pyrene by up to 90%, and the additives benzothiazole and phthalates by up to 70%. The potential ecotoxicity and genotoxicity of TWMP constituents were examined before and after UV treatment in bioassays with Escherichia coli, the luminescent bacterium Aliivibrio fischeri, the microalga Raphidocelis subcapitata and the crustacean Daphia magna. VUV-UV-C treatment decreased the potential ecotoxicity up to five-fold as indicated by changes in median effective concentrations (EC50). This was likely due to the formation of less toxic and less bioavailable transformation products. The VUV-UV-C treatment did not require the addition of oxidants or catalysts, and the study indicated a potential of VUV-UV-C as an advanced oxidation process to mitigate toxic compounds in TWMP leachates from urban or industrial sources.

Knowledge about local air temperature variations and extremes in Antarctica is of large interest to many polar disciplines such as climatology, glaciology, hydrology, and ecology and it is a key variable to understand climate change. Due to the remote and harsh conditions of Antarctica's environment, the distribution of air temperature observations from Automatic Weather Stations is notably sparse across the region. Previous studies have shown that satellite-derived land and ice surface temperatures can be used as a suitable proxy for air temperature. Here, we developed a daily near-surface air temperature dataset, AntAir ICE for terrestrial Antarctica and the surrounding ice shelves by modelling air temperature from MODIS skin temperature for the period 2003 to 2021 using a linear model. AntAir ICE has a daily temporal resolution and a gridded spatial resolution of 1 km 2 . AntAir ICE has a higher accuracy in reproducing in-situ measured air temperature when compared with the well-established climate re-analysis model ERA5 and a higher spatial resolution which highlights its potential for monitoring temperature patterns in Antarctica., (© 2023. The Author(s).)

A previously unknown hemoglobin (Hb) variant was detected during measurement of glycosylated Hb (Hb A 1c ) after the introduction of a new high performance liquid chromatography (HPLC) apparatus. Subsequent DNA sequencing revealed a heterozygous single nucleotide substitution at codon 79 (C>A) on the β-globin gene changing an amino acid [β79(EF3)Asp→Glu; HBB : c.240C>A]. The new Hb variant was named Hb Kalundborg after the place of origin of the proband. Heterozygosity for this mutation appears to have no clinical significance in itself except for a possibly slightly lower oxygen affinity. However, it interferes with Hb A 1c measurement by HPLC, causing a falsely high Hb A 1c concentration when using the G11 apparatus with clinical implications possibly to follow.

Objectives: This study was performed to investigate whether an intravenous (IV) strategy based on new-generation midline catheters is an efficacious alternative to a conventional IV strategy consisting of peripheral venous catheters and central venous catheters, for patients needing IV therapy exceeding 5 days., Methods: This was a prospective, randomized, controlled study. Patients requiring more than 5 days of IV treatment were randomized to either a midline catheter-based IV strategy or a conventional strategy. The primary endpoint was the composite of the insertion of a central venous catheter (CVC) or the need for four or more peripheral venous catheter (PVC) insertions. The secondary outcomes included catheter dwell times and reasons for premature removal., Results: One hundred and twenty patients were included. The fraction of patients receiving four or more PVCs or having a CVC inserted was 12/58 (21%) in the midline group versus 38/58 (66%) in the conventional group (p <  0.001); the number needed to treat was 2.2. The median overall catheter dwell time was 7 days (range 0-60 days) in the midline group and 4 days (range 0-84 days) in the conventional group (p =  0.002)., Conclusion: In patients requiring more than 5 days of IV therapy, a midline catheter strategy reduced the need for insertion of a CVC or four or more PVCs., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The additive effect of parental alcohol use disorders (AUD) is conventionally defined as an increasing risk of the offspring developing AUD relative to family history negative, < family history positive with 1 parent (FHP1), < FHP2. The few studies on the additive effect of parental AUD have focused on the risk of development of offspring AUD and not on the degree of multidimensional AUD addiction severity., Aims: The aims of the present study were to examine the frequency of treatment-seeking outpatients exposed to FHP1 and FHP2 and whether addiction severity was impacted by the additive effect of parental AUD among AUD female and male offspring., Methods: This cross-sectional  study was based on 3,361 consecutive treatment-seeking outpatients from 2006 to 2016, assessed by means of the -European Addiction Severity Index (EUROP-ASI). The -EUROP-ASI assessed multidimensional addiction severity, comprising alcohol and other drug use, somatic and psychiatric health status, family and other social status, economy and employment-related problems and criminal status composite scores at treatment entry., Results: Among females, 40.38% had FHP1 and 15.68% FHP2, whereas males had 40.90% FHP1 and 13.24% FHP2. No conventional additive effect was found on the composite scores among both genders. However, another type of synergistic additive effect, only manifesting with exposure to FHP2, was found for employment-related problems and psychiatric status composite scores among male offspring., Conclusions: Exposure to parental AUD is strikingly high among treatment-seeking outpatients. Nonetheless, the additive effect has a modest impact on multidimensional addiction severity and is mostly related to psycho-social impairment among treatment-seeking male offspring., (© 2019 S. Karger AG, Basel.)

Background: Plasma viscosity (PV) is used in the investigation of hyperviscosity syndrome. We have evaluated the performance of a new bench-top free oscillation rheometer, ReoRox from Medirox, and established a new reference range., Methods: Performance of the free oscillation rheometry (FOR) method was evaluated examining within-run and between-run imprecision, duration of measurement and operator simplicity. Furthermore, influence of storage on the PV measurements was assessed and a reference range based on plasma from 585 healthy men and women was established., Results: Imprecision of the free oscillation rheometer was comparable to other viscometers and performance of the instrument was satisfying. The non-parametrical reference range established was 1.22-1.44 mPa s at 37℃ (2.5th and 97.5th percentiles)., Conclusions: We have established a FOR PV reference range to support clinical decision-making. Furthermore, we found high pre-analytical stability of the samples and an analytical imprecision comparable to other PV methods., (© The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Rationale: Psychosis susceptibility is mediated in part by the dopaminergic neurotransmitter system. In humans, individual differences in vulnerability for psychosis are reflected in differential sensitivity for psychostimulants such as amphetamine. We hypothesize that the same genes and pathways underlying behavioral sensitization in mice are also involved in the vulnerability to psychosis., Objectives: The aim of the current study was to investigate which genes and pathways may contribute to behavioral sensitization in different dopaminergic output areas in the mouse brain., Methods: We took advantage of the naturally occurring difference in psychostimulant sensitivity in DBA/2 mice and selected animals displaying extremes in behavioral sensitization to amphetamine. Subsequently, the dopamine output areas, prefrontal cortex, nucleus accumbens, and cornu ammonis 1 (CA1) area of the hippocampus, were isolated by laser microdissection and subjected to DNA microarray analysis 1 h after a challenge dose of amphetamine., Results: A large number of genes with differential expression between high and low responders were identified, with no overlap between brain regions. Validation of these gene expression changes with real-time quantitative polymerase chain reaction demonstrated that the most robust and reproducible effects on gene expression were in the CA1 region of the hippocampus. Interestingly, many of the validated genes in CA1 are members of the cAMP response element (CRE) family and targets of the glucocorticoid receptor (GR) and myocyte enhancer factor 2 (Mef2) transcription factors., Conclusion: We hypothesize that CRE, Mef2, and GR signaling form a transcription regulating network, which underlies differential amphetamine sensitivity, and therefore, may play an important role in susceptibility to psychosis.

A real-time PCR assay, which enables simultaneous detection and differentiation of all three serotypes of Marek's disease virus, without the need for post-PCR sequencing, has been developed. The assay is based on the primer-probe energy transfer real-time PCR, which has a relatively high tolerance towards point mutations in the probe region. The PCR is followed by a probe melting point analysis, which enables confirmation of identity of amplicon and differentiation of serotypes. The assay targets the MDV031 gene, encoding UL19 major capsid protein-like protein and was shown to be quantitative, with a detection limit below 10TCID(50)/ml starting material. This sensitivity is similar to the one obtained with traditional virus cultivation. However, the PCR method can provide a laboratory result within a day, while the virus cultivation method takes more than a week to perform. The new method will be useful for testing of avian live viral vaccines and screening for extraneous agents., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

(5R,6R)-6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[ 3.2.1]octane (PTAC) is a selective muscarinic receptor ligand. The compound exhibits high affinity for central muscarinic receptors with partial agonist mode of action at muscarinic M(2) and M(4) and antagonist mode of action at muscarinic M(1), M(3) and M(5) receptor subtypes. The compound was earlier reported to exhibit functional dopamine receptor antagonism in rodents despite its lack of affinity for dopamine receptors. In the present study, we report that PTAC, as well as the muscarinic receptor agonists pilocarpine and oxotremorine, dose-dependently decreased rates of intravenous self-administration (fixed ratio 1) of the indirect dopamine receptor agonist cocaine in drug naive mice. Similar decreases in cocaine self-administration rates were obtained with the dopamine receptor antagonists olanzapine, clozapine, risperidone, fluphenazine and haloperidol. These findings suggest that compounds with partial muscarinic receptor agonist mode of action may be used in the medical treatment of cocaine abuse.

Use of a cell culture model of a specific epithelium requires documentation of its differentiation. This study reports permeability of mannitol concurrent with a profile of differentiation markers of filter-grown TR146 cells, a cell line originating from a human buccal carcinoma, cultivated submerged or at the air-liquid interface for 23 to 31 d. A multilayered squamous epithelial-like tissue was found. The maximal permeability barrier and the most distinct stratification were obtained at day 23, when cultured submerged (apparent permeability coefficient 4.08 +/- 0.15 (x 10(-6)) cm/s; transepithelial electrical resistance 102 +/- 5 omega x cm2). The profile of differentiation markers demonstrated similarities to normal human buccal epithelium by expression of K4, K10, K13, K16, and K19 keratins, plasma membrane-associated transglutaminase, involucrin, and epidermal growth factor receptor. Uniform expression of K5, K8 and K18 was consistent with the carcinogenic origin of TR146 cells. Identical profiles of differentiation markers were obtained irrespective of method or time of culture. Karyotyping proved the human origin of TR146 cells. Three different passages had near triploid (3n+-) chromosome compliments and consistent occurrence of four marker chromosomes [mar4, mar5, mar9, and add(5)(p)], while differences between them defined them as subclones. The results indicate that a submerged filter-grown TR146 cell culture at day 23 of culture has the potential to model the human buccal epithelial barrier for permeation of drugs.

In the present study we investigated the in vivo pharmacological profile of the benz[e]indole cis-8-hydroxy-3-(n-propyl)],2,3a,4,5,9b-hexahydro-1H-benz[e]indole (cis-8-OH-PBZI), which has been described as a preferential dopamine D3 receptor agonist in vitro. The compound inhibited spontaneous locomotor activity in mice, an effect which was antagonized by the dopamine D3 receptor antagonist 5,6-dimethoxy-2-(di-u-propylamino) indan (U99194A). Moreover, cis-8-OH-PBZI inhibited conditioned avoidance responding in rats, a preclinical test indicative of antipsychotic efficacy, at doses which did not induce catalepsy. Doses of cis-8-OH-PBZI (6 and 12 mg/kg) that inhibited spontaneous locomotor activity in rats did not affect interstitial levels of dopamine and dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens or dorsolateral striatum. In contrast to the effect of the dopamine receptor agonist (+/-)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphythalene (7-OH-DPAT), cis-8-OH-PBZI did not induce locomotor activity in reserpinized mice. In conclusion, cis-8-OH-PBZI exhibits a pharmacological profile that suggests it has antipsychotic activity but lacks the motoric side effects often associated with antipsychotic medication. The data suggest a mechanism requiring the activation of postsynaptic dopamine D3 receptors and support the hypothesis that these receptors mediate inhibitory behavioral effects.

Tiagabine is a novel antiepileptic drug which has clinical efficacy against complex refractory and myoclonic seizures. The anticonvulsant mechanism of action of tiagabine results from its blockade of neuronal and glial GABA-uptake, thereby increasing GABA levels in the synaptic cleft. Here we present a comparison of the preclinical anticonvulsant profile of tiagabine with that of lamotrigine, gabapentin and vigabatrin in the following tests (all antiepileptic drugs were administered i.p.): seizures induced by pentylentetrazol (PTZ), 6,7-dimethoxy-4-ethyl-b-carboline-3-carboxylate (DMCM) and maximal electroshock (MES); sound induced seizures in DBA/2 mice and finally acute amygdala kindled seizures. Tiagabine was the most potent drug in antagonizing tonic convulsions induced by PTZ, DMCM and sound induced seizures in DBA/2 mice with ED50 values of 2, 2 and 1 mumol/kg, respectively, followed by lamotrigine with ED50 values of 9, 43 and 6 mumol/kg, respectively. Gabapentin and vigabatrin had ED50 values in the same tests of 185, 452, 66 mumol/kg and 2322, > 7740, 3883 mumol/kg, respectively. Tiagabine was the only drug capable of blocking PTZ-induced clonic convulsions (ED50 = 5 mumol/kg), an effect seen at low but not high doses of tiagabine. Lamotrigine was the only drug which antagonized tonic convulsions in the MES test (ED50 = 36 mumol/kg). Therapeutic index (TI) of antiepileptic drugs in NMRI- and DBA/2-mice ranked with decreasing TI lamotrigine > gabapentin > vigabatrin > tiagabine. All drugs reduced the generalized seizures in amygdala kindled rats, but tiagabine and gabapentin furthermore attenuated afterdischarge duration of amygdala kindled seizures. However, an ED50 value against amygdala kindled focal seizures was only obtained for tiagabine (36 mumol/kg). The data here presented show that tiagabine, lamotrigine, gabapentin and vigabatrin possess different preclinical anticonvulsant profiles which is of relevance to the clinical anticonvulsant profiles of the drugs.

Tiagabine (TGB) is a novel antiepileptic drug whose anticonvulsant effects are due to inhibition of gamma-aminobutyric acid (GABA) transport mediated by the GABA transporter-1. We have previously shown that TGB is effective in acute amygdala kindled seizures, and consequently we wanted to test the hypothesis that TGB also could suppress the development of kindling epileptogenesis. Rats had stereotaxically implanted stimulating/recording electrodes in the basolateral amygdala and recording electrode in the contralateral occipital cortex. Rats were divided in three groups (n = 8 for each group) intraperitoneally (i.p.) administered vehicle, TGB 7.3 micromol/kg and TGB 24.3 micromol/kg, respectively, 30 min before stimulation. TGB dose-dependently suppressed the development of the behavioral seizure score and afterdischarge (AD) duration recorded from the amygdala and cortex. Vehicle treated animals displayed at the 16th stimulation an average behavioral score of 4.7 +/- 0.2 (mean +/- SEM) compared to 3.9 +/- 0.2 in the 7.3 micromol/kg TGB treated group and 1.4 +/- 0.3 in the 24.3 micromol/kg TGB treated group. Amygdaloid AD in controls on the 16th stimulation was 92 +/- 10 s compared to 56 +/- 12 s in group 2 and 25 +/- 3 s in group 3. Cortical AD was at the same time 92 +/- 10, 55 +/- 13 and 20 +/- 5 s, respectively. Groups 2 and 3 required four and seven further stimulations, respectively, without TGB administration to reach the AD level in the control group. At the 17th stimulation, rats in group 1 were administered TGB 24.3 micromol/kg and displayed an average behavioral score of 0.5 +/- 0.2. Amygdaloid and cortical AD were both 6 +/- 1 s. Tiagabine 24.3 micromol/kg suppresses both the kindling process and the expression of the fully kindled seizure.

NNC 19-1228 [1-(3(6-methylenedioxyphenylcarbamoyloxy) propyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl) piperidine] and NNC 22-0031 [4-(6-fluoro-1,2-benzisoxazol-3-yl) -1-(3-(3,4-methylenedioxyphenylcarbamoyloxy) propyl)piperidine] are newly developed compounds with an in vitro pharmacologic profile similar to that of clozapine, i.e., mixed dopamine (DA), 5-hydroxytryptamine (5-HT)2 and alpha 1-adrenergic antagonist action. In pharmacological experiments in mice, the compounds inhibited DA D2 receptor binding in vivo at doses that produced only moderate antagonism of methylphenidate (MPD)-induced stereotyped gnawing. However, the compounds were markedly more potent in blocking MPD-induced motility, a model which showed a high degree of sensitivity to alpha 1-adrenergic antagonism, but not 5-HT2 antagonism. In rats, the NNC-compounds blocked conditioned avoidance responding and attenuated the discriminative stimulus effects of amphetamine, but failed to induce catalepsy. These results are discussed in terms of adrenergic, serotonergic and dopaminergic interactions which suggest that the NNC compounds may act as DA antagonists with mesolimbic selectivity, and thus may have efficacy as antipsychotics without coincident extrapyramidal side effects.

The aim of the present study was: 1) to determine the effects of the novel selective inhibitor of guanylyl cyclase, ODQ (1H-[1,2,4]oxadiazolo[4,3,-a]quinoxaline-1-one) on basal and agonist-stimulated cyclic GMP levels in cultured porcine aortic endothelial cells and bovine pulmonary artery strips; 2) to determine its effects on agonist-induced relaxations of bovine pulmonary artery strips; and 3) to compare pulmonary artery cyclic GMP levels with vessel relaxation. ODQ (1 nM-30 microM) inhibited cyclic GMP accumulation in endothelial cells stimulated with S-nitrosoglutathione, nitroprusside and 3-morpholine-sydnonimine at IC50 values of 40 to 100 nM. Complete suppression of cyclic GMP generation was observed at approximately 10 microM. Relaxation of pulmonary artery strips induced by S-nitrosoglutathione, nitroprusside, glycerol trinitrate, nitrite (all endothelium-independent), bradykinin and the Ca++ ionophore A23187 (endothelium-dependent) were antagonized by ODQ (1-10 microM) in a concentration-dependent way. A consistent feature of the inhibitor was that maximal relaxant effects also were reduced. Basal levels and agonist-induced increases in arterial tissue cyclic GMP were inhibited in the same concentration range. However, tissue cyclic GMP production correlated poorly with pulmonary artery relaxation in that relaxations induced by S-nitrosoglutathione were only inhibited in part (50%), whereas rises in cyclic GMP were abolished completely by ODQ (10 microM). Furthermore, at 1 microM, ODQ had no effect on relaxation induced by endothelium-dependent agonists, but prevented entirely stimulation of cyclic GMP accumulation in arterial tissue. These results suggest that ODQ inhibits nitrovasodilator-induced and endothelium-dependent relaxation through inhibition of guanylyl cyclase activation, but also point to the presence of a cyclic GMP-independent component of relaxation in bovine pulmonary artery.

The effect of 'typical' and 'atypical' neuroleptics on interstitial levels of the dopamine metabolite 3,4- dihydroxyphenylacetic acid ([DOPAC]e) in the dorsolateral striatum (DLSt), the nucleus accumbens (NAc) and the medial prefrontal cortex (PFC) was investigated in awake rats by use of the microdialysis technique. All neuroleptics increased [DOPAC]e in the DLSt, NAc and in PFC. However, the 'atypical' neuroleptics clozapine, risperidone, sertindole and NNC 22-0031 showed an apparent cortical selectivity by preferentially elevating [DOPAC]e in the PFC compared with the DLSt and NAc, a feature which was not observed with the 'typical' neuroleptic haloperidol. Our data suggest that 'atypical' neuroleptics can be differentiated from the 'typical' neuroleptic, haloperidol, with respect to their ability to increase [DOPAC]e in PFC relative to DLSt and NAc.

In brain and other tissues, nitric oxide (NO) operates as a diffusible second messenger that stimulates the soluble form of the guanylyl cylase enzyme and so elicits an accumulation of cGMP in target cells. Inhibitors of NO synthesis have been used to implicate NO in a wide spectrum of physiological and pathophysiological mechanisms in the nervous system and elsewhere. The function of cGMP in most tissues, however, has remained obscure. We have now identified a compound, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), that potently and selectively inhibits NO-stimulated guanylyl cyclase activity. In incubated slices of cerebellum, ODQ reversibly inhibited the NO-dependent cGMP response to glutamate receptor agonists (IC50 approximately nM) but did not affect NO synthase activity. The compound did not affect synaptic glutamate receptor function, as assessed in hippocampal slices, nor did it chemically inactivate NO. ODQ did, however, potentially inhibit cGMP generation in response to NO-donating compounds. An action on NO-stimulated soluble guanylyl cyclase was confirmed in studies with the purified enzyme. ODQ failed to inhibit NO-mediated macrophage toxicity, a phenomenon that is unrelated to cGMP, nor did it affect the activity of particulate guanylyl cyclase or adenylyl cyclase. ODQ is the first inhibitor that acts selectively at the level of a physiological NO "receptor" and, as such, it is likely to prove useful for investigating the function of the cGMP pathway in NO signal transduction.

The tritiated dopamine reuptake inhibitor [3H]NNC 12-0781 ([1-[2-(bis(4-fluorophenyl)-methoxy)-ethyl]-4-(3-(2-furanyl)-2,3-[3H] - propyl)-piperazine) was radiolabelled in one step starting from 1-[2-(bis(4-fluorophenyl)-methoxy)-ethyl]-4-(3-(2-furanyl)-2-propenyl)- piperazine, using tritium gas and PdO as catalyst. The radiochemical purity of [3H]NNC 12-0781 was higher than 99% after HPLC purification with a specific radioactivity of 21 Ci/mmol. [3H]NNC 12-0781 bound specifically to rat striatum in vitro at +4 degrees C with a Kd of 1.76 nM and Bmax of 587 fmol/mg tissue. The nonspecific binding was about 10% at Kd. At +37 degrees C no acceptable binding was observed. The association of [3H]NNC 12-0781 thus has the characteristics of a radioligand for the dopamine transporter in vitro at +4 degrees C.

The anesthetic, isoflurane, has been shown to potentiate the ability of the dopamine (DA)-uptake inhibitor, nomifensine, to increase the brain interstitial dopamine level ([DA]e). Since the effect of the more commenly used anesthetic, halothane, on this system is unknown, we determined [DA]e by microdialysis in the striatum of rats, conscious or anesthetized with halothane, in the presence of the more selective DA uptake inhibitor, vanoxerine (GBR 12909), or the DA releaser, d-amphetamine. Basal [DA]e was not changed by halothane. However, in halothane-anesthetized rats, the vanoxerine (3 mg/kg i.v.)-induced DA response increased severalfold compared to the response in conscious rats. The initial peak response to d-amphetamine (1 mg/kg i.v.) did not change, but the late response (1-3 h after injection) was augmented in anesthetized rats. Halothane is believed to increase firing of DA neurons in the substantia nigra and, hence, to release striatal DA. We hypothesize that [DA]e is maintained at a normal level during the increased firing by equally increased activity of the DA transporter. However, when the DA transporter is blocked by vanoxerine, the increased DA release is unimpaired and [DA]e rises.

NNC 12-0722 (1-[2-(bis(4-fluorophenyl)-methoxy)ethyl]-4-methyl piperazine) is a new selective inhibitor of the dopamine transporter. [11C]NNC 12-0722 was prepared by N-methylation of the desmethyl compound with [11C]methyl iodide. The total radiochemical yield of [11C]NNC 12-0722 was 40%-50% with an overall synthesis time of 30-35 min. The radiochemical purity was higher than 99% and the specific radioactivity about 1500 Ci/mmol (55 GBq/mumol). Autoradiographic examination of [11C]NNC 12-0722 binding on whole hemisphere cryosections from human brain post mortem demonstrated specific binding in the caudate nucleus and putamen. In a positron emission tomographic examination of [11C]NNC 12-0722 in a cynomolgus monkey there was a rapid uptake of radioactivity in the brain. In the striatum, a region with a high density of dopamine transporters, the radioactivity was two times higher than in the cerebellum. These results indicate that [11C]NNC 12-0722 may be a useful radioligand for labelling of the dopamine transporter in man.

A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of nipecotic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties. The in vitro value for inhibition of [3H]-GABA uptake in rat synaptosomes was determined for each compound. It was found that the most potent examples are those having a substituent in an "ortho" position in one or both aromatic/heteroaromatic groups. The majority of the compounds described are structurally related to tiagabine, (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidinecarboxylic acid hydrochloride (NNC 05-0328) and some of the reasoning behind the selection of this compound as a drug candidate is summarized.

NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride) is a novel, potent and selective gamma-aminobutyric acid (GABA) uptake inhibitor. NNC-711 inhibited synaptosomal (IC50 = 47 nM), neuronal (IC50 = 1238 nM) and glial (IC50 = 636 nM) GABA uptake in vitro NNC-711 lacked affinity for other neurotransmitter receptor binding sites, uptake sites and ion channels examined in vitro. In vivo, NNC-711 was a potent anticonvulsant compound against rodent seizures induced by methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (ED50 (clonic) = 1.2 mg/kg i.p.), pentylenetetrazole (PTZ) (ED50 (tonic) = 0.72 mg/kg i.p., mouse; and ED50 (tonic) = 1.7 mg/kg, rat), or audiogenic (ED50 (clonic and tonic) = 0.23 mg/kg i.p.). At higher doses NNC-711 produced behavioral side effects characterized by inhibition of traction (ED50 = 23 mg/kg i.p.), rotarod (ED50 = 10 mg/kg i.p.) and exploratory locomotor activity (ED50 = 45 mg/kg i.p.) in the mouse. Following acute (3-h) in vivo pretreatment with NNC-711, behavioral tolerance developed to its motor impairing side effects (inhibition of traction, rotarod or exploratory locomotor activity) without corresponding tolerance to the anticonvulsant effects. These data suggest that NNC-711 will be useful for future in vitro and in vivo experiments to elucidate the role of the GABA uptake carrier in the central nervous system.

The neurochemical properties of three novel benzazepine derivatives NNC-112, NNC-687 and NNC-756 were assessed. These compounds inhibited dopamine D1 receptor binding in vitro with low nanomolar to picomolar dissociation constants whereas those for the D2 receptor were in the micromolar range. Contrary to classical neuroleptics, but similar to the atypical neuroleptics, clozapine and fluperlapine, NNC-112, NNC-687 and NNC-756 were relatively more potent in inhibiting dopamine-stimulated adenylyl cyclase than [3H]SCH 23390 binding. Both NNC-112 and NNC-756 had high affinity for the 5-HT2 receptor whereas NNC-687 had low affinity for this receptor. The affinity for other receptors or neurotransmitter transporters was very low. In vivo, the dopamine D1 receptor selective profile of NNC-112, NNC-687 and NNC-756 was evident from the potent inhibition of D1 receptor binding whereas no effect on D2 receptor binding was apparent. In addition, the compounds blocked D1 receptor-mediated rotation in unilaterally 6-hydroxydopamine-lesioned rats, but had no effect on D2-induced rotation. Thus, NNC-112, NNC-687 and NNC-756 are potent and selective dopamine D1 receptor antagonists that may be useful in the treatment of schizophrenia.

The ability of dopamine D2, mixed D1/D2 and selective D1 receptor antagonists, including NNC-112, NNC-687, NNC-756, to inhibit the in vivo binding of [3H]SCH 23390 or [3H]raclopride to dopamine receptors was studied in mice and rats. Furthermore, the dopamine-antagonistic effects of these drugs were also studied in various behavioral models. Significant levels of in vivo receptor blockade were required for antagonism of typical dopamine agonist-mediated behaviors. However, fewer D1 than D2 receptors had to be blocked to produce similar antagonistic effects. Thus, there may be a greater receptor reserve for D2 receptors than for D1 receptors.

Tiagabine (NO-328) (R(-)-N-[4,4-bis(3-methylthien-2-yl)but-3-enyl]nipecotic acid, hydrochloride) is a new centrally acting GABA uptake inhibitor. The anticonvulsant activity of tiagabine was evaluated against seizures induced by methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), pentylenetetrazol, bicuculline, maximal electrostimulation (MES), or high intensity sound. The sedative actions of tiagabine were evaluated in tests for traction, rotarod performance and exploratory behavior. Finally, interoceptive properties of tiagabine were assessed using diazepam-, CGS 9896-, pentylenetetrazol-, or amphetamine-discriminating rats. Tiagabine was an effective anticonvulsant in doses which did not produce sedation or motor debilitation, although it was not potent against MES. In a manner similar to other anti-epileptic drugs, tiagabine potentiated dopaminergic function (methylphenidate-induced gnawing in mice) although it did not substitute for amphetamine in amphetamine-trained animals. Furthermore, although tiagabine antagonized DMCM-induced convulsions, it exhibited neither CGS 9896 or diazepam-like interoceptive effects, nor did it block (or potentiate) pentylenetetrazol-discrimination. Thus, GABA uptake inhibition represents a novel rationale for a valproate-like anticonvulsant drug therapy.

(R)-N-[4,4-Bis(3-methyl-2-thienyl)but-3-en-1-yl]nipecotic acid (NO 328) has previously been shown to be a potent anticonvulsant in both mice and rats. Here, we report that NO 328 is a potent inhibitor of gamma-[3H]aminobutyric acid [( 3H]GABA) uptake in a rat forebrain synaptosomal preparation (IC50 = 67 nM) and in primary cultures of neurons and astrocytes. Inhibition of [3H]GABA uptake by NO 328 is apparently of a mixed type when NO 328 is preincubated before [3H]GABA uptake; the inhibition is apparently competitive without preincubation. NO 328 itself is not a substrate for the GABA uptake carrier, but NO 328 is a selective inhibitor of [3H]GABA uptake. Binding to benzodiazepine receptors, histamine H1 receptors, and 5-hydroxytryptamine1A receptors was inhibited by NO 328 at 5-30 microM, whereas several other receptors and uptake sites were unaffected. [3H]NO 328 showed saturable and reversible binding to rat brain membranes in the presence of NaCl. The specific binding of [3H]NO 328 was inhibited by known inhibitors of [3H]GABA uptake; GABA and the cyclic amino acid GABA uptake inhibitors were, however, less potent than expected. This indicates that the binding site is not identical to, but rather overlapping with, the GABA recognition site of the uptake carrier. The affinity constant for binding of [3H]NO 328 is 18 nM, and the Bmax is 669 pmol/g of original rat forebrain tissue. The regional distribution of NaCl-dependent [3H]NO 328 binding followed that of synaptosomal [3H]GABA uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Schizophrenia-like symptoms have been experimentally produced in humans by a single, large dose of amphetamine or by relatively low level, but continuous administration of the drug. In animal studies of the psychotomimetic properties of amphetamine, high doses and, in particular, repeated daily-injection drug schedules have often been used. However, amphetamine psychosis is not always a prominent effect of repeated intake drug schedules in humans and available clinical evidence suggests that psychosis develops more readily when the drug is taken in a continuous fashion over longer periods. The state produced by single large doses of amphetamine, although clearly abnormal, has been said to bear less resemblance to schizophrenia than the delayed paranoid symptoms developing after longer periods of continuous intake. In the present experiments we have studied the behavioral effects of 7 to 14 days of continuous administration of amphetamine to monkeys (Cercopithecus aethiops) using subcutaneously implanted silicone capsules releasing approximately .7 to 1.5 mg/kg/day of d-amphetamine base. Around-the-clock TV monitoring of the animals revealed a general biphasic sequence of drug effects, although considerable individual variation occurred: a) an "acute" phase dominated by stereotyped movements and/or prolonged staring, lasting for 2 to 5 days; b) a "late" phase peaking during days 5 to 10 after capsule implantation and characterized by highly individual, but striking sequences of: (1) Attack or sudden threat reactions directed at invisible objects; (2) rapid orienting and flight behavior without apparent cause; (3) sudden startle reactions; (4) prolonged vocalization; (5) visual tracking of invisible objects, sometimes involving coordinated patterns of "eating behavior" and (6) prolonged and rapid grooming directed at various parts of the body. These behaviors might be termed "hallucinatory" since no eliciting stimuli could be determined for their occurrence. Motor disturbances, including whole-body shakes, were often present at the same time. The animals were generally sleepless throughout the drug treatment period. Reimplantation of amphetamine capsules 2 to 8 months after the first capsule treatment produced the same effects in an individual-specific manner, but the "late phase" behaviors generally appeared sooner. The delayed occurrence of apparent hallucinatory behaviors and other abnormal "late" phase behaviors in the present experiment may be a close parallel to the delayed development of psychosis in humans induced by a similar drug regimen. Furthermore, the hallucinogenic nature of the late amphetamine state is consonant with other reports in the literature that hallucinogen-characteristic behaviors are present at this time.

Specific [3H]flunitrazepam binding was determined for five brain regions in both sexes of the three Roman rat strains. Small strain differences and a large Sex-Region interaction were detected, benzodiazepine receptor binding being significantly higher in females in the two cortical areas and the cerebellum, but significantly lower in the striatum and hippocampus. These findings are discussed in the context of sex and strain differences in behavior and benzodiazepine sensitivity.

Rats (N = 8) were trained to discriminate the stimulus properties of the potent benzodiazepine (BZ) receptor inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) from saline in a two-lever operant task. The initial training dose of DMCM was 0.4 mg/kg at which the discrimination developed slowly; increasing the dose to 0.8 mg/kg resulted in rapid acquisition. However, since convulsions eventually developed during further training (sensitization), the training dose was finally individualized below the convulsive threshold (0.4-0.7 mg/kg). The DMCM cue was mimicked by FG 7142 (10 mg/kg), a non-convulsant anxiogenic beta-carboline, by pentylenetrazol (20-30 mg/kg), and by the GABA antagonist bicuculline (2 mg/kg). The DMCM cue was not, or marginally, blocked by diazepam (2.5 mg/kg) or pentobarbital (10-15 mg/kg). Furthermore, the BZ receptor antagonists CGS 8216 (2.5 mg/kg), ZK 93426 (20 mg/kg), and Ro 15-1788 (20-80 mg/kg) also did not, or only marginally, block the DMCM cue. However, the receptor antagonists (alone) substituted for DMCM although Ro 15-1788 was less effective. The partial BZ receptor agonist ZK 91296 (25 mg/kg), which is structurally similar to DMCM, blocked completely the DMCM stimulus effect. THIP (4 mg/kg) did not block the DMCM cue. To explain these results, we suggest that the repeated DMCM treatment, necessary for maintaining the discrimination, shifts the balancing point ("set-point") for positive (i.e., BZ-like) agonist efficacy versus inverse agonist efficacy, towards inverse action. This hypothesis was supported by the finding of an enhanced ability of GABA to reduce 3H-DMCM binding to cortical neuronal membranes of animals treated chronically with DMCM in a regimen similar to that used to maintain the DMCM discrimination. Furthermore, this treatment did not affect baseline 3H-DMCM binding, baseline or GABA stimulated 3H-diazepam binding, or 35S-TBPS binding (to chloride channels).

Rats were implanted with a silicone tubing pellet continuously releasing amphetamine base for several days. After five days of this treatment specific binding of spiroperidol (dopamine receptors) and LSD (serotonin receptors) was decreased in the corpus striatum and frontal cortex. In the striatum the number of dopamine receptors was decreased while the affinity was unchanged. These results indicate that dopamine and serotonin receptors can be regulated by the release of their own neurotransmitter.

In two groups of rats trained to discriminate 0.08 or 0.16 mg/kg of lysergic acid diethylamide (LSD) from saline, pirenperone and ketanserin completely blocked the stimulus effect of LSD. Pizotifen (BC-105) blocked the LSD cue when the training dose was 0.08 mg/kg, but had variable effects in the 0.16 mg/kg of LSD-trained group. The antagonism of the 0.08 mg/kg cue occurred at doses of the antagonists which blocked [3H]spiroperidol labeled 5-HT2 receptors in the frontal cortex in vivo; binding in the striatum was unaffected by the LSD antagonists. However, in doses which produce the LSD cue, neither LSD nor the 5-HT agonist, 5-methoxy-N,N-dimethyltryptamine, which substitutes for LSD, inhibited the binding in either the cortex or the striatum. The results are discussed in relation to the possible neuropharmacological basis for the LSD cue.

The fact that SCH 23390, a selective dopamine (DA) D1 antagonist, blocks the effects of D2 agonists suggests a functional coupling of D1 and D2 receptors. Therefore, the binding of SCH 23390 to D2 receptors was investigated in vivo using 3H-N-n-propylnorapomorphine (NPA), a D2 agonist, and 3H-spiperone and 3H-raclopride, both D2 antagonists. SCH 23390 failed to inhibit 3H-spiperone or 3H-raclopride binding; however, SCH 23390 was relatively potent in inhibiting 3H-NPA binding. These results suggest that (some) antidopaminergic effects of SCH 23390 may result from antagonism of a D2 agonist conformation of the D2 receptor.

The mechanisms underlying CNS-stimulant drug discrimination are discussed. Although different doses of CNS stimulants may produce qualitatively different cues, it appears that a relatively low dose of d-amphetamine (e.g., 1 mg/kg) elicits a "general" CNS-stimulant cue. Presynaptically, this cue may primarily depend on release of endogenous dopamine whereas inhibition of dopamine reuptake, per se, is insufficient to elicit the cue. Postsynaptically, the involvement of both dopamine D-1 and D-2 receptors is implicated. Furthermore, in the drug discrimination situation, D-1/D-2 receptors may be coupled differently than in dopamine-dependent locomotor activation. Anatomically, CNS-stimulant drug discrimination may depend primarily on mesolimbic dopamine systems.

Four monkeys (Cercopithecus aethiops) were trained to discriminate 0.06 mg/kg of lysergic acid diethylamide (LSD) from saline in a two-key task in which correct responding was reinforced with food under a fixed ratio 32 schedule. The ED50 of LSD was 0.011 mg/kg. The nonhallucinogenic ergot, lisuride, and the hallucinogen, 5-methoxy-N,N-dimethyltryptamine, substituted completely for LSD (ED50 values were 0.0098 and 0.45 mg/kg, respectively). Mescaline (1-40 mg/kg), d-amphetamine (0.1-0.625 mg/kg) and apomorphine (0.1-0.5 mg/kg) did not substitute for LSD. In antagonism testing with ketanserin (1-10 mg/kg) or pirenperone (0.025 and 0.05 mg/kg), only the highest dose of pirenperone attenuated the LSD stimulus effect (to 55%). A 0.1-mg/kg dose of pirenperone produced nonresponding in three of four animals. The LSD cue was unaffected by clozapine (1 and 2 mg/kg), haloperidol (0.1 mg/kg) and pizotifen (0.6-1.8 mg/kg). The fact that lisuride does not readily cause hallucinations in humans, but yet substituted for LSD in primates, indicates that the LSD cue may not reflect the hallucinogenic properties of LSD. It is suggested that the LSD stimulus effect may depend on receptors (e.g., serotonergic) that, at the moment, are only poorly characterized.

The continuous presence of endogenous psychotomimetic compounds has frequently been hypothesized in human psychopathology. In related drug-based animal models it would be necessary to demonstrate accumulating behavioral abnormalities despite a low constant drug-level. Using subcutaneously implanted slow-release capsules containing a d-amphetamine base, we studied behavioral effects during 11-weeks of low level but continuous release of this psychotomimetic drug in a socially housed family group of monkeys (drugged father and mother with undrugged infant). Following implantation, locomotion was only slightly affected throughout the drug period. Among visual behaviors, staring gradually increased and, after 5-7 weeks, peaked at a level ten-fold higher than pre-implant levels. Except for infant/female contact, social behaviors were decreased throughout the drug period. Sleep during nights declined by about one-third for the first 8 weeks. In vitro measurements of this capsule type confirmed amphetamine release at 1st-week levels for ca. 8 weeks. Low level prolonged amphetamine intoxication apparently can lead to increasing behavioral abnormalities despite relatively stable drug-release levels.

Six pigeons were trained in a chamber with three response keys. Following an observing response on the center key, either colored or noncolored (white) lights were projected on that key. A second center key observing response provided an opportunity to respond on one of the side keys, appropriate to the stimuli presented, to obtain food; responding on the incorrect side produced a 30-s time-out. A delay period of varying duration with no stimuli followed stimulus presentation; the length of the delay was determined 'on-line', such that performance would be maintained at about 80% correct. Lysergic acid diethylamide (LSD, 0.04-0.2 mg/kg) had no significant effect on the accuracy of the discrimination (overall percent correct responses), even at doses that produced cessation of responding in some animals. Amphetamine (1-4 mg/kg) and morphine (0.5-4 mg/kg) decreased accuracy by decreasing sensitivity (A') and had little effect on reaction time. Haloperidol (0.5-2 mg/kg) had no significant effect on any measure of performance. None of the drugs altered response bias (B").

Six pigeons were trained to respond under concurrent fixed-ratio extinction schedules of food reinforcement (FR 50) on the side keys of a three key chamber. Presence or absence of continuously-flashing, colored lights on the center key signalled which key pecking response (left or right) would be reinforced over the course of an entire experimental session; thus, the lights were analogous to a drug cue in drug-discrimination situations. In test (generalization) sessions of one FR in duration, the percentage of light on the center key was varied from 0 to 100%. During these sessions, saline, lysergic acid diethylamide (LSD; 0.04-0.20 mg/kg) and morphine (3.75 mg/kg) produced orderly, log-linear light generalization gradients, but only LSD shifted the gradient to the right (by approximately 50%). These results demonstrate the potential value of the method for assessing the effects of drugs on both exteroceptive (light) and interoceptive (drug) stimulus control. The method has the additional advantage that the effects of drugs on such control (i.e., on stimulus generalization) are relatively unaffected by corresponding effects on response control (e.g., rate of responding).

Dopamine (DA) D-1 and D-2 receptor agonists and antagonists were characterized in receptor binding and adenylate cyclase assays with respect to affinity, selectivity and efficacy. The ability of the ligands to interact with the discriminative stimulus effects of d-amphetamine (AMPH) was then assessed. The D-2 agonists, quinpirole, pergolide and CH 29-717, substituted completely for AMPH while neither partial (SKF 38393 and SKF 75670) nor full D-1 receptor agonists (SKF 89626 and SKF 81297) substituted. On the other hand, the selective D-1 and D-2 antagonists all blocked AMPH. The substitution for AMPH by pergolide was blocked by raclopride but not by SCH 23390, indicating D-2 mediation. In contrast, the motor effects of pergolide were blocked by both raclopride and SCH 23390, indicating mixed D-1/D-2 receptor involvement. These results suggest that D-1 and D-2 are equally involved in the expression of functional effects in the DAergic motor systems. Conversely, D-2 receptors may play a primary role in the DA systems involved in the AMPH cue; furthermore, the D-1 and D-2 receptors in the systems are relatively uncoupled.

Photochemotherapy with psoralen and long-wave ultraviolet light, so-called PUVA-treatment, is currently being evaluated in many dermatologic departments. Side effects such as nausea, pruritus and erythema are well known. Recently the development of acneiform eruptions was reported in a British patient treated with PUVA (3). We found that 4 out of 80 patients treated in our clinic with 8-methoxy-psoralen according to the usual weight schedule (6) and long-wave ultraviolet irradiation developed perioral dermatitis, in 2 cases, together with acneiform eruptions localised to the forehead.

Rats and mice were exposed to several different stress situations to investigate whether brain benzodiazepine receptors were sensitive to altered external or internal environmental circumstances. All stresses were applied for several days. Electrical foot shock and post-natal isolation of newborn pups resulted in small (7--25%; P less than 0.05--0.001) decreases in benzodiazepine receptor binding in some cerebral cortex or hippocampal areas while immobilization stress resulted in a small (9%; P less than 0.05) increase in frontal cortex. Other brain areas (i.e., striatum, cerebellum, pons-medulla, and occipital cortex) and other stress forms (isolation of male mice, forced swimming in cold water, or chronic amphetamine intoxication) did not change receptor binding. The effect of prolonged stress on benzodiazepine receptors is complex and not very pronounced.

The binding of the selective dopamine uptake inhibitor [3H]GBR 12935 was studied in vivo in mouse brain. The binding was reversible with t1/2 = 80 min. The localisation of [3H]GBR 12935 binding and of dopaminergic receptors did not overlap. The binding of [3H]GBR 12935 was distributed almost uniformly throughout the brain. Also, the in vitro inhibition of dopamine uptake and the inhibition of in vivo [3H]GBR 12935 binding did not correlate when a series of relevant reference compounds was used. The potencies of various dopamine uptake inhibitors to induce stereotyped behavior did not correspond to the inhibitory potencies in the [3H]GBR 12935 binding assay. In conclusion, [3H]GBR 12935 labels in vivo a site which is different from the dopamine uptake complex. We have recently obtained results for the in vitro binding of [3H]GBR 12935 that indicate that this site could be a piperazine acceptor site.

Rats were trained to press a lever under a variable-interval (VI) schedule of water reinforcement. After stable responding had developed, a 4.5-KHz tone (CS) was conditioned classically to a 2.5-mA electric shock (US) in groups of animals which had been given various psychoactive drugs or saline. Twenty-four hours later, a stimulus generalization test was conducted in the absence of drug; during this session, tones that varied in frequency around 4.5 KHz were presented while the animals were responding under the VI schedule. In animals conditioned under saline, all tones (non-differentially) suppressed responding which, however, recovered gradually over time. This suppressive effect was eliminated by lysergic acid diethylamide (LSD; 0.2 and 0.32 mg/kg), cocaine (20 mg/kg), diazepam (2.5 mg/kg), lisuride (0.08 mg/kg), mescaline (20 mg/kg) and 5-methoxy-N,N-dimethyltryptamine (4 mg/kg), and was attenuated by amphetamine (4 mg/kg), pentobarbital (15 mg/kg) and morphine (4 mg/kg). Atropine (10 mg/kg), scopolamine (1 mg/kg), clonazepam (0.5 mg/kg), and chlorpromazine (4 mg/kg) did not alter the suppressive effect of the tone. The serotonin antagonist BC-105 (6 mg/kg) reversed the effect of 0.2 mg/kg of LSD. These results suggest (1) that drug-induced stimuli may "overshadow" other (e.g., external) stimuli during classical conditioning and, (2) that drugs might affect behavior by altering processes (stimulus control or others) that do not simultaneously involve response or motor control.

Two groups of rats were trained to discriminate either d-amphetamine sulphate (AMPH; 1 mg/kg) or d-lysergic acid diethylamide bitartrate (LSD; 0.16 mg/kg). Microinjection of AMPH into the nucleus accumbens elicited a cueing effect which was similar to that of systemically administered AMPH in AMPH-trained animals (ED50 was 0.24 micrograms). Co-injection of (-)-sulpiride (50 or 100 ng) into the accumbens antagonized the effect of a fixed dose of AMPH (1 microgram) which, alone, produced 76% of the systemic AMPH cue effect. Microinjections of AMPH (1-5 micrograms) into either the anterior dorsomedial or the anterior ventrolateral striatum failed to elicit the cueing effect of AMPH. In LSD-trained animals a dose of 1 microgram LSD injected into the accumbens produced 84% of the systemic cueing effect of LSD. These results suggest that dopamine (DA) receptors in the nucleus accumbens are involved in AMPH discrimination. Furthermore, since both classical and atypical antipsychotic drugs block the AMPH cue, the results provide indirect evidence for involvement of mesolimbic DA in antipsychotic drug action.

Rats injected with LSD or mescaline show the behavioral syndrome which has been previously reported following injections of hallucinogens in higher mammals: limb flicks and whole body shakes. Although these behaviors are not elicited by acute injections of amphetamine, they are present in rats which have been pretreated for 108 h with a slow-release amphetamine pellet, given a 12 h rest period, and then injected with d-amphetamine. Such pellet-pretreated animals also groom their body surface excessively. We propose that this novel syndrome which follows continuous amphetamine administration can serve as an animal model of the type of amphetamine psychosis that is produced by a similar drug regimen in humans.