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The trace amine-associated receptor 1 (TAAR1) is a Gs protein-coupled, intracellularly located metabotropic receptor. Trace and classic amines, amphetamines, act as agonists on TAAR1; they activate downstream signal transduction influencing neurotransmitter release via intracellular phosphorylation. Our aim was to check the effect of the catecholaminergic activity enhancer compound ((−)BPAP, (R)-(−)-1-(benzofuran-2-yl)-2-propylaminopentane) on neurotransmitter release via the TAAR1 signaling. Rat striatal slices were prepared and the resting and electrical stimulation-evoked [3H]dopamine release was measured. The releaser (±)methamphetamine evoked non-vesicular [3H]dopamine release in a TAAR1-dependent manner, whereas (−)BPAP potentiated [3H]dopamine release with vesicular origin via TAAR1 mediation. (−)BPAP did not induce non-vesicular [3H]dopamine release. N-Ethylmaleimide, which inhibits SNARE core complex disassembly, potentiated the stimulatory effect of (−)BPAP on vesicular [3H]dopamine release. Subsequent analyses indicated that the dopamine-release stimulatory effect of (−)BPAP was due to an increase in PKC-mediated phosphorylation. We have hypothesized that there are two binding sites present on TAAR1, one for the releaser and one for the enhancer compounds, and they activate different PKC-mediated phosphorylation leading to the evoking of non-vesicular and vesicular dopamine release. (−)BPAP also increased VMAT2 operation enforcing vesicular [3H]dopamine accumulation and release. Vesicular dopamine release promoted by TAAR1 evokes activation of D2 dopamine autoreceptor-mediated presynaptic feedback inhibition. In conclusion, TAAR1 possesses a triggering role in both non-vesicular and vesicular dopamine release, and the mechanism of action of (−)BPAP is linked to the activation of TAAR1 and the signal transduction attached.

Genomic prediction provides an efficient alternative to conventional phenotypic selection for developing improved cultivars with desirable characteristics. New and improved methods to genomic prediction are continually being developed that attempt to deal with the integration of data types beyond genomic information. Modern automated weather systems offer the opportunity to capture continuous data on a range of environmental parameters at specific field locations. In principle, this information could characterize training and target environments and enhance predictive ability by incorporating weather characteristics as part of the genotype-by-environment (G×E) interaction component in prediction models. We assessed the usefulness of including weather data variables in genomic prediction models using a naïve environmental kinship model across 30 environments comprising the Genomes to Fields (G2F) initiative in 2014 and 2015. Specifically four different prediction scenarios were evaluated (i) tested genotypes in observed environments; (ii) untested genotypes in observed environments; (iii) tested genotypes in unobserved environments; and (iv) untested genotypes in unobserved environments. A set of 1,481 unique hybrids were evaluated for grain yield. Evaluations were conducted using five different models including main effect of environments; general combining ability (GCA) effects of the maternal and paternal parents modeled using the genomic relationship matrix; specific combining ability (SCA) effects between maternal and paternal parents; interactions between genetic (GCA and SCA) effects and environmental effects; and finally interactions between the genetics effects and environmental covariates. Incorporation of the genotype-by-environment interaction term improved predictive ability across all scenarios. However, predictive ability was not improved through inclusion of naive environmental covariates in G×E models. More research should be conducted to link the observed weather conditions with important physiological aspects in plant development to improve predictive ability through the inclusion of weather data.

Pharmaceutically available enhancer selegiline/(-)-deprenyl (DEP) in the clinically used dose shows antidepressant effect, but nothing is known about this effect in enhancer dose, and its effect on co-morbid anxiety. Moreover, data about the antidepressant/antianxiety effects of the serotonin-influencing enhancer, (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP) are also missing. The aim of the present paper is to establish the role of enhancer regulation in anxiety and follow the changes in the phosphorylation of glutamate subunits in prefrontal cortex as well as stress-related organ and hormonal changes as possible background mechanism. The effect of 3-week-treatment of rats with specific (0.001 mg/kg for DEP, 0.0001 mg/kg for BPAP) and non-specific (0.1 mg/kg for DEP, 0.05 mg/kg for BPAP) enhancer doses were evaluated on anxiety-like behavior in the elevated plus maze (EPM) and open-field (OF) tests. Phosphorylated glutamatergic GluR1 and GluN2B subunits were analyzed by Western blot. Changes in the stress-regulatory system were evaluated by measuring the organ weights and blood corticosterone concentrations. Non-specific enhancer doses had a tendency for anxiolysis on EPM, while only 0.1 mg/kg DEP elevated motility in OF. Specific enhancer doses significantly increased the expression of both glutamatergic receptor subunits; non-specific doses elevated only pGluR1. Treatments had no effects on stress-like organ weights; however, the specific enhancer doses significantly reduced the dark phase resting corticosterone levels. The study proved the enhancer-sensitivity of the glutamatergic transmitter system and suggested enhancer-induced stabilization of stress-hormone levels without major impact on non-stimulated anxiety-like behavior.

Cool temperatures during the early-growing season are a major limitation to growing sorghum [Sorghum bicolor (L.) Moench] in temperate areas. Several landraces from China have been found to exhibit higher emergence and greater seedling vigor under cool conditions than most breeding lines currently available, but tend to lack desirable agronomic characteristics. The introgression of desirable genes from Chinese landraces into elite lines could be expedited by marker-assisted selection. Using a population of 153 RI lines, developed from a cross between Chinese landrace 'Shan Qui Red,' (SQR, cold-tolerant) and SRN39 (cold-sensitive), QTL associated with early-season performance under both cold and optimal conditions were identified by single marker analysis, simple interval mapping (SIM), and composite interval mapping (CIM). Germination was observed under controlled conditions, and other traits were measured in field plantings. Two QTL for germination were identified: one on linkage group SBI-03a, derived from SRN39, was significant under cold and optimal temperatures. The other, on group SBI-07b, showed greater significance under cold temperatures and was contributed by SQR. A region of group SBI-01a, derived from SQR, showed strong associations with seedling emergence and seedling vigor scores under early and late field plantings. A QTL for both early and late emergence was identified by CIM on SBI-02 which favored the SRN39 allele. SIM identified a QTL for early vigor on SBI-04 favoring the SQR genotype. Further studies are needed to validate the effects of these QTL, but they represent the first step in development of a marker-assisted breeding effort to improve early-season performance in sorghum.

R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane [(-)-BPAP] is a potent "catecholaminergic and serotonergic activity enhancer (CAE/SAE)", which enhances the impulse-evoked catecholamines and serotonin release, e.g. (-)-BPAP enhances in vitro norepinephrine efflux from the slices of locus coeruleus in a bipolar manner with the two effective ranges of low (fM-pM level) and high (nM-microM level) concentrations. Here, the effects of (-)-BPAP and selegiline on the cultured mouse astrocytes were studied. The protein levels of the neurotrophic factors (NGF, BDNF and GDNF) in the conditioned medium of cultured astrocytes were determined by using ELISA. In the cultured astrocytes incubated for 24 h with selegiline, the synthesis of NGF and BDNF was significantly enhanced in the concentration dependent manner, with minimum effective concentrations of 4 x 10(-4) and 5 x 10(-4) M, respectively. (-)-BPAP also enhanced the NGF, BDNF and GDNF synthesis, with minimum effective concentrations of 5 x 10(-5), 1 x 10(-5), and 1 x 10(-6) M, respectively. Although the effects of (-)-BPAP on the NGF synthesis was tested in the range of 1 x 10(-15)-5 x 10(-4) M, the concentration response curve of (-)-BPAP was a single bell shape with the peak effect at 1 x 10(-4) M, and did not show any effects in low concentrations such as fM-pM level. Each concentration response curve of (-)-BPAP on BDNF and GDNF synthesis was a single bell shape with peak effects at 1 x 10(-3) M and 1 x 10(-4) M, respectively.

R-(–)-1-(Benzofuran-2-yl)-2-propylaminopentane hydrochloride [(–)-BPAP], a highly potent enhancer of impulse propagation-mediated release of catecholamines and serotonin in the brain, and significantly increased the locomotor activity of normal rats at the doses of 0.3 and 1 mg/kg s.c. (P < 0.05), while l-DOPA (200 and 400 mg/kg i.p.) had no significant effect. The locomotor activity of rats simultaneously administered l-DOPA and (–)-BPAP was significantly higher than with (–)-BPAP alone (P < 0.05). In rats pretreated with reserpine (1 mg/kg i.v.), the hypolocomotion was significantly reversed by 400 mg/kg i.p. l-DOPA, or 1 or 3 mg/kg s.c. (–)-BPAP (P < 0.05). Furthermore, the combined administration of subthreshold doses of 200 mg/kg i.p. l-DOPA and 0.3 mg/kg s.c. (–)-BPAP highly potentiated the locomotor activity in the reserpine-pretreated rats. However, (–)-BPAP failed to reverse the hypolocomotion in rats pretreated with reserpine + α-methyl-dl-p-tyrosine. Thus, (–)-BPAP was demonstrated to possess the l-DOPA-sparing effect in normal and reserpine-pretreated rats.

This review is to summarize experimental evidence and theoretical consideration in support of the concept that a mesencephalic enhancer regulation is the basis of the limited number of innate drives indispensable for the survival of the individual and the species, while a specifically organized telencephalic enhancer regulation is the basis of the acquired drives to reach an unlimited number of dispensable goals. The study is also an overview of the experimental and clinical data supporting the proposal that, due to the progressive decay of the mesencephalic enhancer regulation with the passing of time, the prophylactic administration of a synthetic enhancer substance [(-)-deprenyl, (-)-BPAP] during postdevelopmental life could significantly slow the age-related decay of behavioral performances, prolong life, and prevent the precipitation or delay the onset of Parkinson's disease and Alzheimer's disease.

The subcutaneous administration of 1 mg/kg tetrabenazine, once daily for 5 days, which depletes the catecholamine stores in the brain, significantly inhibits in rats the acquisition of a two-way conditioned avoidance reflex in the shuttle box. Enhancer substances, the tryptamine-derived selective and highly potent enhancer, R -(−)-1-(benzofuran-2-yl)-2-propylaminopentane HCl [(−)-BPAP] (0.05–10 mg/kg), the β-phenylethylamine (PEA)-derived enhancer, (−)-deprenyl (1–5 mg/kg) and the (−)-deprenyl analogue, free of MAO-B inhibitory potency, (−)-1-phenyl-2-propylaminopentane HCl [(−)-PPAP], (1–5 mg/kg), antagonize in a dose-dependent manner the inhibition of learning caused by tetrabenazine. 1-(Benzofuran 2 yl)-2-(3,3,3-trifluoropropyl)aminopentane HCl [3 F BPAP], a newly synthetized analogue of (−)-BPAP with low specific activity, significantly antagonized the enhancer effect of (−)-BPAP but left the effect of (−)-deprenyl and (−)-PPAP unchanged. This is the first proof for a difference in the mechanism of action between a PEA-derived enhancer substance and its tryptamine-derived peer.

R-(-)-1-(Benzofuran-2-yl)-2-propylaminopentane HCl, (-)-BPAP, the recently developed selective and much more potent catecholaminergic/serotoninergic enhancer (CAE/SAE) substance than (-)-deprenyl enhances the performance of midbrain neurons, both in vivo and ex vivo, in a characteristic complex manner, presenting one bell shape dose/concentration effect curve in the low nanomolar range and another at higher micromolar range. For example, 4.7 +/- 0.10 nmol/g wet weight noradrenaline was released within 20 min from the quickly removed locus coeruleus of saline treated rats. This amount was increased 30 min after the subcutaneous administration of 0.0005 mg/kg (-)-BPAP to 15.4 +/- 0.55 nmol/g (P < 0.001). However, following the injection of a hundred times higher, 0.05 mg/kg, dose of (-)-BPAP, the amount of noradrenaline (4.3 +/- 0.25 nmol/g) released from the locus coeruleus did not differ from the control value. In ex vivo experiments, when the isolated locus coeruleus was soaked in an organ bath containing (-)-BPAP, the release of noradrenaline was significantly enhanced from 10(-16) M concentration, reached a peak effect at 10(-13) M concentration, but 10(-10) M (-)-BPAP was ineffective. A significant enhancer effect was detected also in the high concentration range from 10(-8) M, the peak effect was reached at 10(-6) M concentration and 10(-5) M (-)-BPAP was ineffective. (-)-BPAP enhanced in the low concentration range the performance of dopaminergic and serotoninergic neurons with a peak effect at 10(-13) and 10(-12) M concentration, respectively. The results with (-)-BPAP, the highly specific artificial enhancer substance, suggest that (i) high and low affinity "enhancer" receptors may exist in the brain, and (ii) that they may be identified with the recently cloned family of the "trace amine" receptors, activated by beta-phenylethylamine and tryptamine, the prototypes of the endogenous enhancer substances.

Enantioselective synthesis and absolute configuration of (-)-1-(benzofuran-2-yl)-2-propylaminopentane ((-)-BPAP), which is a highly potent and selective catecholaminergic activity enhancer (CAE) substance, are described. The synthetic approach consists of the coupling reaction of benzofuran with (R)-N-tosyl-2-propylazirizine or (R)-N-methoxy-N-methylnorvaliamide, followed by appropriate modifications of the resulting coupling products. As the results, (-)-BPAP turned out to have the R configuration, which was finally confirmed by X-ray crystallographic analysis.

The brain constituents β-phenylethylamine (PEA) and tryptamine enhance the impulse propagation mediated transmitter release (exocytosis) from the catecholaminergic and serotoninergic neurons in the brain (‘catecholaminergic/serotoninergic activity enhancer, CAE/SAE, effect’). (−)Deprenyl (Selegiline) and (−)1-phenyl-2-propylaminopentane [(−)PPAP] are amphetamine derived CAE substances devoid of the catecholamine releasing property. By changing the aromatic ring in PPAP we developed highly potent and selective CAE/SAE substances, structurally unrelated to the amphetamines. Out of 65 newly synthetized compounds, a tryptamine derived structure, (−)1-(benzofuran-2-yl)-2-propylaminopentane [(−)BPAP] was selected as a potential follower of (−)deprenyl in the clinic and as a reference compound for further analysis of the CAE/SAE mechanism in the mammalian brain. (−)BPAP significantly enhanced in 0.18 μmol 1−1 concentration the impulse propagation mediated release of [3H]-noradrenaline and [3H]-dopamine and in 36 nmol 1−1 concentration the release of [3H]-serotonin from the isolated brain stem of rats. The amount of catecholamines and serotonin released from isolated discrete rat brain regions (dopamine from the striatum, substantia nigra and tuberculum olfactorium, noradrenaline from the locus coeruleus and serotonin from the raphe) enhanced significantly in the presence of 10−12–10−14 M (−)BPAP. BPAP protected cultured hippocampal neurons from the neurotoxic effect of β-amyloid in 10−14 M concentration. In rats (−)BPAP significantly enhanced the activity of the catecholaminergic and serotoninergic neurons in the brain 30 min after acute injection of 0.1 μg kg−1 s.c. In the shuttle box, (−)BPAP in rats was about 130 times more potent than (−)deprenyl in antagonizing tetrabenazine induced inhibition of performance. British Journal of Pharmacology (1999) 128, 1723–1732; doi:10.1038/sj.bjp.0702995

beta-Phenylethylamine and its long acting derivatives, the amphetamines, are mixed-acting stimulants of the sympathetic system in the brain. They enhance the impulse propagation mediated release of catecholamines (catecholaminergic activity enhancer effect) and displace catecholamines from their stores (catecholamine releasing effect). (-)Deprenyl (selegiline), a close structural relative to (-)methamphetamine, is the first catecholaminergic activity enhancer substance in clinical use devoid of catecholamine releasing property, being therefore free of the 'cheese effect' and of the dependence capacity of the amphetamines. (-)Deprenyl is also a highly potent and selective, irreversible inhibitor of monoamine oxidase type B. (-)Deprenyl enhances superoxide dismutase and catalase activity in the striatum, protects the nigrostriatal dopaminergic neurons against selective neurotoxins (6-hydroxy-dopamine, MPTP, 4-N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) and prevents characteristic age-related morphological changes in the neurocytes of the substantia nigra. Maintenance of rats on (-)deprenyl during the postdevelopmental phase of their life slows the age-related decline of sexual and learning performances and prolongs life significantly. Patients with early, untreated Parkinson's disease maintained on (-)deprenyl need levodopa significantly later than their placebo-treated peers, and when on levodopa plus (-)deprenyl, they live significantly longer than patients on levodopa alone. In patients with moderately severe impairment from Alzheimer's disease, treatment with (-)deprenyl slows the progression of the disease. It may be supposed that a prophylactic low dose administration of a safe catecholaminergic activity enhancer substance during the postdevelopmental phase of life will slow the age-related decline of behavioral performances, delay natural death and decrease susceptibility to Parkinson's disease and Alzheimer's disease.

On the helical strip of a capacitance vessel, the pulmonary artery of the rabbit, phenylethylamine (PEA) and tyramine act solely via displacement of noradrenaline from their storage sites and this effect is inhibited by desmethylimipramine (DMI). In contrast, on a resistance vessel, the perfused central ear artery of the rabbit, PEA enhances stimulation induced contractions in 0.2-0.8 microgram/ml concentration [catecholaminergic activity enhancer (CAE) effect], and increases smooth muscle tone (noradrenaline displacing effect) in 4-6 micrograms/ml concentration. This latter effect only is blocked by DMI. Tyramine acts similarly and is more potent than PEA. On the isolated brain stem PEA, tyramine and (-)methamphetamine are, in the presence of cocaine and DMI, highly potent enhancers of stimulation induced release of 3H-noradrenaline, 3H-dopamine and 3H-serotonin. Compounds with specific CAE effect in the brain, (-)deprenyl and 1-phenyl-2-propylaminopentane [(-)PPAP], antagonize tetrabenazine-induced depression of performance of rats in the shuttle box. PEA and tyramine, which are rapidly metabolized in vivo, are ineffective in this test up to 40 mg/kg, whereas (-)methamphetamine, the stable PEA derivative, is highly effective. Compounds with CAE effect enhance at low concentrations the slow inward Ca2+ current in the sino-auricular fibers of the frog heart and inhibit it in high concentration. PEA and tyramine enhance Ca2+ influx from 0.05 to 4 micrograms/ml and inhibit it in 8 micrograms/ml. In conclusion, PEA and tyramine stimulate primarily coupling of action potential to transmitter release in the catecholaminergic neurons in the brain and displace catecholamines in higher concentration only.

The activity of the catecholaminergic neurons in the rat brain is enhanced significantly 30 min after the subcutaneous injection of very small doses of (-)deprenyl (threshold doses: 0.01 mg/kg for noradrenergic neurons and 0.025 mg/kg for dopaminergic neurons). As a catecholaminergic activity enhancer (CAE) substance (-)deprenyl is about ten times more potent than its parent compound, (-)methamphetamine. While the (+)methamphetamine is 3-5 times more potent than (-)methamphetammine in releasing catecholamines, the (-)methamphetamine is the more potent CAE substance. The mechanism of the CAE effect of (-)deprenyl and (-)PPAP, a deprenyl-derived substance devoid of MAO inhibitory potency, was studied in rats by measuring: a) the release of catecholamines from striatum, substantia nigra, tuberculum olfactorium and locus coeruleus; b) the stimulation induced release of 3H-noradrenaline from the isolated brain stem; and c) the antagonistic effect against tetrabenazine-induced depression of learning in the shuttle box. The CAE effect was found to be unrelated: a) to the inhibition of MAO activity; b) to the inhibition of presynaptic catecholamine receptors; c) to the inhibition of the uptake of catecholamines; and d) to the release of catecholamines. It was concluded that (-)deprenyl and (-)PPAP act primarily as potent stimulants of action potential-transmitter release coupling in the catecholaminergic neurons of the brain. We show that both (-)deprenyl and (-)PPAP enhance the inward Ca2+ current in sino-auricular fibers of the frog heart. (-)PPAP was much more potent than either (+)PPAP or (-)deprenyl in this test.

The selective monoaminooxidase (MAO)-B inhibitor (−)deprenyl facilitates the nigrostriatal dopamine (DA)-ergic system by a complex mechanism that includes inhibition of DA reuptake and increase of DA turnover. In this study, DA reuptake and DA turnover were measured in the olfactory tubercle of rats treated with 0.25 mg/kg (−)deprenyl for 28 days. There was no difference between these rats and the saline-treated group. In another series of experiments, we analysed how (−)deprenyl influences the action of some indirectly acting DA agonists, such as amphetamine (AM) and phenylethylamine (PEA). The effect on different behavioral patterns related either to the nigrostriatal (stereotyped behaviour) or the mesolimbic (rearing, locomotion) DAergic system was investigated. As expected, the PEA-induced stereotyped behaviour was tremendously potentiated by (−)deprenyl and the AM-induced stereotypy was reduced. At the same time there was no change in locomotion and rearing. The results give futher biochemical and behavioural proof that (−)deprenyl enhances the function of the nigrostriatal DAergic system and leaves the mesolimbic DAergic neurons unaffected.

Sorghum [Sorghum bicolor (L.) Moench] is an important food and feed crop in many parts of the world, and has potential uses in the biofuels industry. Compared to most other cereals, sorghum is more tolerant to many abiotic stresses, including heat, drought, and flooding, making it an ideal crop for growing on marginal lands as demands for food, feed, and energy increase. Though it is generally stress-tolerant, the true potential of sorghum can only be realized through concerted genetic improvement programs. The use of DNA-based markers for the genetic analysis and manipulation of important agronomic and stress-tolerance traits is becoming an increasingly useful tool in sorghum improvement. The known germplasm of sorghum is incredibly diverse, and molecular markers are being used to assess this diversity to help manage large germplasm collections, and to make these collections more useful to breeders. Molecular markers have been used in sorghum to identify quantitative trait loci (QTL) for many complex traits, including pre-flowering and post-flowering drought tolerance, early-season cold tolerance, and resistance to the parasitic weed Striga. However, progress in utilizing these QTL had been limited by the lack of a standard genetic map and a common nomenclature for the various linkage groups of sorghum. Fortunately, the genetic map of sorghum has recently become standardized, and has also been linked to physical chromosomes. The use of a common map will facilitate the exchange of marker and QTL information between sorghum research groups. This will allow independent validation of QTL and should expedite efforts to use these QTL for the development of improved sorghum cultivars through marker-assisted selection and trait introgression. Newer, faster marker technologies based on single nucleotide polymorphisms (SNPs), and mapping methods based on linkage disequilibrium (association mapping), will soon become useful tools for future efforts to improve this important crop.

Sorghum [Sorghum bicolor (L.) Moench] landraces from China generally exhibit excellent emergence and seedling vigor under cool conditions, and are being used as sources of genes for improvement of seedling cold tolerance in other cultivars. Marker-assisted selection (MAS) could expedite the introgression of genes from landraces into elite lines, however, only a few studies have empirically demonstrated efficacy of MAS for quantitatively inherited agronomic traits. In a preceding study we identified quantitative trait loci (QTL) for early-season performance in a recombinant inbred (RI) population, one parent of which was a cold-tolerant Chinese line, 'Shan Qui Red' (SQR). In this study, three SSR markers (Xtxp43, Xtxp51, and Xtxp211), each representing a QTL, were tested in two new populations: (Tx2794 x SQR F(3)) and (Wheatland x SQR BC(1)F(3)). Individual families were genotyped, and early-season field performance was measured for two years. Statistical analyses showed that the SQR allele of Xtxp43 had favorable effects on seedling vigor in both populations, and on emergence in the Tx2794 population. A large positive effect of the SQR allele of Xtxp51 was observed in the Tx2794 population for vigor and emergence. Slight genotype by environment interaction was observed for Xtxp51 in the Wheatland population. Marker Xtxp211 had small but significant effects on seedling vigor and emergence in both populations. Various interactions between loci were also significant. This study validated QTL markers in various genetic backgrounds, and demonstrated the utility of MAS for a quantitative trait, early-season cold tolerance, evaluated in the field.

This review is to summarize experimental evidence and theoretical consideration in support of the concept that a mesencephalic enhancer regulation is the basis of the limited number of innate drives indispensable for the survival of the individual and the species, while a specifically organized telencephalic enhancer regulation is the basis of the acquired drives to reach an unlimited number of dispensable goals. The study is also an overview of the experimental and clinical data supporting the proposal that, due to the progressive decay of the mesencephalic enhancer regulation with the passing of time, the prophylactic administration of a synthetic enhancer substance [(-)-deprenyl, (-)-BPAP] during postdevelopmental life could significantly slow the age-related decay of behavioral performances, prolong life, and prevent the precipitation or delay the onset of Parkinson's disease and Alzheimer's disease.

“Catecholaminergic and serotoninergic activity enhancer” effects are newly found mechanisms of action of a class of compound that enhance impulse propagation-mediated release of catecholamines and serotonin in the brain. In the present study, (−)-1-(benzofuran-2-yl)-2-propylaminopentane hydrochloride [(−)-BPAP HCl], a compound with selective and potent “catecholaminergic and serotoninergic activity enhancer” effects, was tested for its efficacy to potentiate locomotor activity in normal rats and to attenuate hypolocomotion in reserpine-treated rats. (−)-BPAP HCl potentiated locomotor activity in non-habituated rats during a 2-h observation period dose-dependently (0.3–10 mg/kg). (−)-BPAP HCl (1–3 mg/kg) was also effective to reverse reserpine-induced hypolocomotion. The effects of (−)-BPAP HCl in normal and reserpine-treated rats were attenuated by the dopamine D1 receptor antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390), suggesting that the effects of (−)-BPAP HCl were mediated by activation of the dopaminergic system. In addition, the administration of (−)-BPAP HCl increased ipsilateral turning in unilaterally 6-hydroxydopamine-lesioned rats, implying presynaptic activation of nigrostriatal dopaminergic terminals by (−)-BPAP HCl. Furthermore, although antiparkinsonian agents, such as apomorphine and amantadine, failed to improve reserpine-induced ptosis, (−)-BPAP HCl significantly improved ptosis. These findings suggested that a “catecholaminergic and serotoninergic activity enhancer” compound, (−)-BPAP, stimulates motor function in rats and improves motor deficits in animal models of Parkinson's disease due to its ability to induce dopamine release.

The amount of dopamine released from the striatum, substantia nigra and tuberculum olfactorium, noradrenaline from locus coeruleus and serotonin from the raphe, was significantly higher in four and five weeks old rats than in three month old ones, proving that the catecholaminergic/serotoninergic activity enhancer (CAE/SAE) regulation works unrestrained during developmental longevity and is restricted thereafter. As the dampening of the CAE/SAE regulation (end to the second month of age) coincided temporally with the appearance of sexual hormones, we castrated three weeks old male and female rats and measured at the end of the third month of their life the release of catecholamines and serotonin from selected discrete brain regions. The amount of catecholamines and serotonin released from the neurons was significantly higher in castrated than in untreated or sham operated rats, signalting that sexual hormones inhibit the CAE/SAE regulation in the brain. We therefore treated male and female rats s.c. with oil (0.1 ml/rat), testosterone, (0.1 mg/rat), estrone (0.01 mg/rat) and progesterone (0.5 mg/rat), respectively, and measured their effect on the CAE/SAE regulation. Twenty-four hours after a single injection with the hormones, the release of noradrenaline, dopamine and serotonin was significantly inhibited in the testosterone or estrone treated rats, but remained unchanged after progesteron treatment. In rats treated with a single hormone injection, testosterone in the male and estrone in the female was the significantly more effective inhibitor. Remarkably, the reverse order of potency was found in rats treated with daily hormone injections for 7 or 14 days. After two-week treatment with the hormones estrone was in the male and testosterone in the female the significantly more potent inhibitor of the CAE/SAE regulation. The data indicate that sexual hormones terminate the hyperactive phase of adolescence by dampening the impulse propagation mediated release of catecholamines and serotonin in the brain.

Two breeds of rats, Charles River Wistar [Crl(Wi)Br.] and HSD Wistar [Wistar per LATI (Budapest) Br.], with remarkable difference in learning performance were selected. The rats were trained in the shuttle box with 100 trials per day and the number of conditioned avoidance responses (CARs), the escape failures (EFs) to the unconditioned stimulus and the intersignal reactions (IRs) were counted and evaluated by multi-way analysis of variance (ANOVA). Rats of the Crl (Wi) breed proved to be the 'low performing' (LP) animals and rats of the Wistar per LATI (Budapest) breed the 'high performing' (HP) ones. The HP rats produced higher number of CARs (p0.001), lower number of EFs (P0.05) and higher number of IRs (P0.01) than their LP peers. Significantly higher amounts of noradrenaline from the locus coeruleus and serotonin from the raphe were released in the HP than in the LP rats (p0.01). There was no difference between HP and LP rats in the amount of dopamine released from the striatum, the substantia nigra and the tuberculum olfactorium. The catecholaminergic activity enhancer (CAE) substance, 1-phenyl-2-propylaminopentane HCl, [(-)PPAP], which enhances action potential-transmitter release coupling in the catecholaminergic neurons, fully antagonized in a dose of 1 mg/kg, tetrabenazine-induced learning depression in HP rats and this dose was ineffective in LP rats. The findings were regarded as further support for the view that endogenous CAE substances regulate catecholaminergic activity in the brain and (-)PPAP acts via this regulation.

(-)Deprenyl (selegiline, jumex, eldepryl, movergan) which is closely related to phenylethylamine (PEA) is a drug with a unique pharmacological spectrum. Single dose effects: (a) It is a highly potent and selective inhibitor of B-type monoamine oxidase (MAO). (b) In contrast to other MAO inhibitors it inhibits the noradrenaline releasing effect of tyramine, is therefore free of the 'cheese effect'. Multiple dose effects unrelated to MAO inhibition: (a) It enhances superoxide dismutase and catalase activity in the striatum. (b) It facilitates the activity of the nigrostriatal dopaminergic neurones. (c) It prevents age-related morphological changes in the neurocytes of the substantia nigra. Consequences of multiple dose effects: Compared to salt solution-treated rats, male rats maintained on (-)deprenyl loose their capacity to ejaculate later on; retain for longer their learning ability; and live longer. Freshly diagnosed Parkinson's patients maintained on (-)deprenyl, required levodopa later than their placebo-treated peers. Patients treated with levodopa plus (-)deprenyl live longer than those on levodopa alone. Chronic treatment with (-)deprenyl improves the performance of patients with Alzheimer's disease.

With the aid of TV-image analysis the number, the area and the density features of melanin granules in neurocytes of the substantia nigra in a group of 3-month-old naive male rats and in a 21-month-old group of male rats treated for 18 months with saline, (-)deprenyl and (-)parafluorodeprenyl, respectively, were determined. According to the Kolmogorov 2-sample test the two drug-treated groups do not differ significantly from each other in the number, total area and area of one pigment granule. In the aged saline-treated group the number of melanin granules decreased significantly and the area of the melanin granules increased in comparison to young controls as well as to the drug-treated groups.

With the aid of a Robotron A6471 type TV-image analyser the number, total area, area of one granule and density features (sum, average of gray values and average gray value of one pigment granule) of melanin granules in neurocytes of the substantia nigra in 3-month-old and 3-year-old male rats were determined. The number of cells in sections of identical areas was similar in the young and old rats. A statistically non-significant difference between the two age cohorts in the proportion of neurocytes with and without melanin was found; 773 (48.1%) and 853 (51.8%), in the young rats and 1219 (65.1%) and 652 (34.8%) in the old ones. Within the melanin containing neurocytes, however, statistically conspicuous, age-related differences in the number, area and density features of melanin granules were discovered. The majority of the neurocytes in young rats contained numerous, small sized neuromelanin granules, whereas in the majority of the neurocytes of old rats smaller numbers of large sized, neuromelanin granules were detected.

The effect of tetanus on the twitch responses of the longitudinal muscle-myenteric plexus preparation of the guinea-pig ileum to electrical stimuli was investigated in the presence of naloxone and indomethacin. Naloxone was used to prevent post-tetanic twitch inhibition due to the release of endogenous opiate ligands, and indomethacin to diminish pretetanic twitch height. Twitch contractions following tetanus were potentiated in the presence of both drugs. The optimal stimulation parameters for the manifestation of post-tetanic potentiation (PTP) were determined; tetanic stimulation: 30 Hz for 25 s, supramaximal impulse intensity; twitches: 0.04 Hz, low impulse intensity. PTP was also obtained when indomethacin was replaced by noradrenaline or adenosine, i.e. by drugs whose mechanism of action also includes a presynaptic effect. Postsynaptic changes in contractility cannot fully account for the observed PTP of twitches judging from the smaller effect of tetanus on acetylcholine-evoked contractions. The hypothesis of a presynaptic origin of PTP at this muscarinic synapse was corroborated in the experiments where acetylcholine stores were labelled with [ 3 H]choline and the release of the label was increased during PTP. Furthermore, a bioassay showed that the output of endogenous acetylcholine in the post-tetanic interval was increased in the presence of naloxone plus indomethacin but not in their absence. The fact that PTP was also observed in the absence of any drug, if the tetanic stimulation was short (10 s) and of low impulse intensity, suggested its possible physiological significance.

Male rats were treated from the end of their 2nd year of life either with saline (1 ml/kg, s.c.) (n = 66) or with deprenyl (0.25 mg/kg, s.c.) (n = 66) three times a week until death. Whereas none of the two-year-old saline-treated rats displayed full scale sexual activity, this appeared in 64 out of 66 rats on deprenyl. The longest living rat in the saline-treated group lived 164 weeks. The average lifespan of the group was 147.05 +/- 0.56 weeks. The shortest living animal in the (-)deprenyl-treated group lived 171 weeks and the longest living rat died during the 226th week of its life. The average lifespan was 191.91 +/- 2.31 weeks. This is the first instance that a well-aimed medication prolonged lifespan of members of a species beyond their maximum age of death (182 weeks in the rat). A close relation between sexual activity and lifespan was detected. Male rats (n = 94) selected from an 8-month old population as sexually inactive ones were found to be miserable learners. This group was treated either with saline (1 ml/kg, s.c.) (n = 46) or with (-)deprenyl (0.25 mg/kg, s.c.) (n = 48) three times a week for 36 weeks. Their performance in the shuttle box during 5 consecutive days was tested before and after treatment. The total number of conditioned avoidance responses (CAR) which remained unchanged in the saline-treated group (6.53 +/- 1.41 before and 5.98 +/- 1.15 after treatment) increased from 5.57 +/- 0.65 to 20.73 +/- 1.39 (p less than 0.001) in the (-)deprenyl-treated group of rats. (-)Deprenyl-treatment (0.25-2 mg/kg, s.c., daily for 21 days) increased superoxide dismutase (SOD) activity in the striatum of CFY rats, whereas clorgyline-treatment (0.1-1 mg/kg) inhibited it.

A substance named satietin, capable of reducing food intake drastically in rats deprived of food for 96 hr, was discovered in human serum. The substance was extracted and purified by gelchromatographic techniques. The purified satietin containing samples exerted a dose-dependent anorexogenic effect both at intravenous and intracerebroventricular injection. The C-terminal octapeptide of cholecystokinin (CCK-OP) and pGlu-His-GlyOH, the peptides described to reduce food intake in nonstarving rodents, were found to be devoid of satietin-like effect in rats deprived of food for 4 days.

The antidepressive efficacy of 1-deprenyl (5-10 mg daily) plus 1-phenylalanine (250 mg/day) has been evaluated in 155 unipolar depressed patients. Both oral and intravenous administration showed beneficial effects in 90% of outpatients and 80.5% of inpatients. It is concluded that this combined treatment has a potent antidepressive action based on the accumulation of 1-phenylethylamine in the brain.

Rats were treated subcutaneously with different doses of the “B form” selective monoamine oxidase (MAO) inhibitors deprenyl (phenylisopropylmethylpropargylamine), U-1424 ( N -methyl- N -propargyl-[2-furyl-1-methyl]-ethylammonium) and J-508 ( N -methyl- N -propargyl-[1-indenyl]-ammonium. HCl) in order to study the changes of their selectivity during 21 days of treatment. When the daily dose of (−) deprenyl and U-1424 was 0.05 or 0.25 mg/kg body wt (similar to the human dosage of deprenyl in clinical trials), in spite of their repeated administration, a fairly selective inhibition pattern was maintained. In this case at a low rate of oxidation of beta-phenylethylamine (MAO-B form specific substrate) the conversion of serotonin (MAO-A form specific substrate) was near to the untreated value. When 1.0 mg/kg of these inhibitors were repeatedly administered they also inhibited the A form of MAO. As J-508 is a more potent MAO inhibitor than deprenyl and U-1424. even the lowest dose (0.05 mg/kg) used in this study proved to inhibit MAO-A. All the compounds tested were less effective on liver than on brain MAO; thus their selectivity was more pronounced on liver homogenate.

Deprenyl inhibits MAO-B selectively in different animal species and in man. Its safety margin is remarkable. We were able to block MAO-B activity in the brain selectively in vivo in four species (mouse, rat, cat, dog) with s.c. administration of 0.17-0.31% of LD50. The usual oral dose range in clinical practice, 5-20 mg daily (0.05-0.2 mg/kg), is about ten times lower than the orally active dose in the rat. Deprenyl proved to be safe drug in man. Neither hypertensive reactions nor the need for any special dietary care were ever encountered during long-term (2-8 years) daily administration of the drug. The most important effect of deprenyl in the brain is the sensitization of dopaminergic neurons to physiological and pharmacological influences, but in contrast to levodopa or bromocrytine, deprenyl does not elicit an acute increase in dopaminergic activity. The effect of deprenyl is due, on the one hand, to the inhibition of MAO-B and, on the other hand, to inhibition of the uptake of dopamine. In agreement with its peculiar spectrum of pharmacological activity, deprenyl proved to be a useful adjuvant to levodopa alone or in combination with a peripheral decarboxylase inhibitor. In addition, a supplement of deprenyl in Parkinson's disease led to significant prolongation of the duration of the illness. This has not been observed so far with other antiparkinsonian drugs. The dopamine content of the human caudate nucleus decreases by 13% per decade over the age of 45. The hypothesis has been put forward that the significant increase of incidence of depression in the elderly, the age-dependent decline in male sexual vigour and the frequent appearance of parkinsonian symptoms in the later decades of life might be attributed to a decrease of dopamine and 'trace amines' in the brain. The possibility of countering these biochemical lesions of ageing by long-term administration of deprenyl, a selective inhibitor of MAO-B which facilitates dopaminergic and 'trace-aminergic' activity in the brain, and is a safe drug in man, is considered in detail.

Isolated Auerbach's plexus-longitudinal muscle preparations from guinea-pig ileum and slices of the rat cerebral cortex have been used to study the effect of adenine nucleotides on the release of acetylcholine. The release of acetylcholine evoked by cholecystokinin was completely inhibited by adenosine. The effect of nucleotides on neuro-effector transmission of electrically stimulated longitudinal muscle strip was also studied. Adenosine and adenosine triphosphate reduced the release of acetylcholine provided a low frequency of stimulation was applied. While the three adenine nucleotides (adenosine mono-, di- and triphosphate) dose-dependently reduced neuro-effector transmission in Auerbach's plexus-longitudinal muscle preparation, adenine, guanosine triphosphate and dibutyryl-cyclic AMP had no effect. Theophylline, an adenosine receptor antagonist, prevented the inhibitory effect of the nucleotides. In addition, theophylline alone enhanced the release of acetylcholine both from Auerbach's plexus and from the nerve terminals of the cortical slice. This indicates that there might be a continuous control of ACh release by an adenine nucleotide. These results are discussed in relation to the release of adenosine triphosphate from purinergic nerves in the intestine and of adenosine from slices of cerebral cortex; the possibility is raised that adenine nucleotides released from nerves might act as a type of presynaptic inhibitory transmitter on cholinergic neurons. Furthermore, if some of the released nucleotide originates from the synaptic vesicles of cholinergic neurons, it might serve as a negative feed-back transmitter for acetylcholine release. The inhibitory effect of adenosine and related nucleotides on the cholecystokinin-induced release of acetylcholine from the gut might be of physiological importance since gastrointestinal polypeptides play a very important role in maintaining gastrointestinal motility.