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PubMed1985

Effects of chalcone derivatives on lipoxygenase and cyclooxygenase activities of mouse epidermis.

The effects of chalcone derivatives on 12-lipoxygenase and cyclooxygenase of mouse epidermis were investigated. The chalcone derivatives which have 3,4-dihydroxycinnamoyl structure in the molecule, such as 3,4-dihydroxychalcone, 3,4,2'-trihydroxychalcone, 3,4,4'-trihydroxychalcone and 3,4,2'4'-tetrahydroxychalcone, potently inhibited epidermal 12-lipoxygenase activity. Although some of them also inhibited cyclooxygenase activity at relatively high concentrations, the inhibitory effects of these chalcone derivatives on 12-lipoxygenase were 10 times or more potent than their effects on cyclooxygenase. The chalcone derivatives which have cinnamoyl or 4-hydroxycinnamoyl structure, instead of 3,4-dihydroxycinnamoyl structure, in the molecule, showed little or no inhibitory effects on either 12-lipoxygenase or cyclooxygenase activities. The inhibitory effects of chalcone derivatives on 12-lipoxygenase and cyclooxygenase of mouse epidermis are dependent on the particular structure, i.e. 3,4-dihydroxycinnamoyl structure, of the chalcone derivatives.

Animals↗
PubMed1980

Anorexigenic effects of two amines obtained from Catha edulis Forsk. (Khat) in rats.

The anorexigenic effects of cathine (phenylpropanolamine) and cathinone (alpha-aminopropiophenone), both amines obtained from Catha edulis Forsk. (Khat) were investigated by acute and chronic experiments in rats. Amphetamine was included for comparison purposes. Both khat amines reduced food intake when administered acutely and body weight when given chronically. Cathinone was more effective than cathine, and both were less active than amphetamine. Partial or total cross-tolerance was observed among the 3 drugs.

Alkaloids↗
PubMed1981

Drug alterations of punished responding after chlordiazepoxide: possible screen for agents useful in minimal brain dysfunction.

In the present study, the effect of various stimulant drugs on the action of chlordiazepoxide to increase punished responding was studied. Drugs such as d-amphetamine, methylphenidate and imipramine that are effective in attentional deficit disorder (MBD) were found to reverse this benzodiazepine-induced increase in responding. Phenobarbital which worsens this condition enhanced the benzodiazepine effect. Since the impairment caused by chlordiazepoxide may be analogous to the lack of impulse control noted in MBD, the bupropion antagonism of this action of chlordiazepoxide suggests that bupropion may be useful in MBD.

Animals↗
PubMed1982

Animal model of depression: tests of three structurally and pharmacologically novel antidepressant compounds.

Previous studies have identified behavioral and neuroendocrine abnormalities in chronically stressed rats which resemble some of the more prominent features of clinical depression. These abnormalities have proved responsive to pharmacotherapy by standard antidepressant drugs and related somatic treatments. Several structurally and pharmacologically atypical compounds, resembling neither standard agents, nor each other, have recently been identified as clinically effective antidepressants. There drugs do not show typical preclinical response profiles in other drug screening tests and, therefore, represent critical instances for evaluating the selectivity of the chronic stress model. Three drugs were tested, these being iprindole, bupropion, and mianserine; a tricyclic indole, propriophenone, and tetracyclic compound respectively. Four circulating measures, which previously proved most useful in discriminating antidepressant potential, and a measure of circulating corticosterone were obtained for subjects examined factorially in a 2x2x2 experimental design (chronic stress vs none, acute stress vs none, and drugs vs control). All compounds proved capable of reversing chronic stress induced behavioral deficits, and all but one compound reversed the attendant basal hypersecretion of corticosterone. These findings argue that the chronic stress model provides an accurate and selective assessment of the therapeutic potential of both standard and structurally novel compounds.

Animals↗
PubMed1982

Differential effects of d-amphetamine, pipradrol and bupropion on shuttlebox self-stimulation.

The shuttlebox self-stimulation test is claimed by Atrens to differentiate drug effects on brain stimulation reward from those on performance variables. Thus, for example, drug-induced enhancement of the reward value of stimulation should be reflected in a selective reduction of the latency to initiate stimulation (the ON latency), as compared with the latency to terminate stimulation (the OFF latency). The effects of the psychostimulant drugs, d-amphetamine and pipradrol, and the antidepressant, bupropion, were evaluated in this procedure as well as in a bar-pressing test of self-stimulation. Pipradrol (3 and 10 mg/kg) and bupropion (54 mg/kg) reduced ON latencies by 40% or more but failed to shorten OFF latencies, indicating that performance variables were not involved in the ON latency decrements. Although d-amphetamine (0.3 and 1.0 mg/kg) shortened ON latencies, the 1.0 mg/kg dose also reduced OFF latencies. Drug doses that reduced ON latencies also increased bar-pressing self-stimulation. The shuttlebox self-stimulation test appears to be capable of discriminating drug-induced enhancement in brain stimulation reward from performance variables.

Animals↗
PubMed1983

Bupropion, d-amphetamine, and amitriptyline-induced conditioned taste aversion in rats: dose effects.

Nine groups of rats (n = 6 per group) were adapted to a daily one-half hour period of water availability. When intake had stabilized, they were allowed access to a 0.1% (w/v) solution of saccharin, and immediately afterward were given IP injections of isotonic saline; bupropion HCl (10.0, 20.0, or 40.0 mg/kg); d-amphetamine-sulfate (0.5, 1.0, 2.0 mg/kg); or amitriptyline HCl (5.0, 10.0, or 20.0 mg/kg) in a volume of 1 ml. The lowest dose of each compound as chosen to be equipotent in screening tests used to identify potential antidepressants. Following 2 days of access to water alone, all groups were given a choice between water and saccharin for 3 consecutive days. All compounds induced taste aversions in a dose-related manner, but amitriptyline induced greater and longer-lasting aversions than either bupropion or d-amphetamine which were equipotent over the dose range studied. As such, this is the first demonstration that bupropion and amitriptyline, two clinically effective antidepressants, can induce taste aversions and replicates as well the common finding that d-amphetamine has substantial taste aversion-inducing properties. The ability of these compounds to induce taste aversions could be mediated through their effects on central catecholaminergic processes although amitriptyline has significant peripheral anticholinergic effects.

Amitriptyline↗
PubMed1986

Dopamine-norepinephrine interactions in the development of hyperphagia and obesity following medial hypothalamic lesions.

Conflicting evidence exists on the ability of central 6-hydroxydopamine (6-OHDA) injections to alter the subsequent development of hyperphagia and obesity following medial hypothalamic lesions (MHL) in rats. An initial study found no effects of prior intracisternal (IC) 6-OHDA on the subsequent development of this MHL syndrome, while later work reported that a dopamine (DA) depletions induced by intracerebral 6-OHDA effectively blocked it. The present study reexamined this issue by investigating the effects of depleting brain dopamine, norepinephrine (NE), or both DA and NE, on overeating and obesity induced by subsequent MH lesions. Different patterns of DA and NE depletions were achieved by IC 6-OHDA in combination with systemic pretreatments designed to protect central NE, DA, or neither amine, respectively. It was found that 6-OHDA regimens that selectively depleted forebrain DA did prevent the development of hyperphagia and obesity following MHL. However, when such forebrain DA depletions were accompanied by NE depletions no such blockade occurred. Manipulations which selectively depleted forebrain NE had no effect on MHL-induced hyperphagia and obesity. These results offer a framework for resolving previous discrepancies in the literature concerning brain monoamines and MHL effects. They also indicate that the effectiveness of brain DA depletions in blocking the MHL syndrome is critically dependent on the functional status of NE systems.

Animals↗
PubMed1986

Effects of acute and chronic bupropion on locomotor activity and dopaminergic neurons.

Acute administration of bupropion (10 or 30 mg/kg) to rats increased locomotor activity in a dose-related manner. The highest dose increased the dopamine (DA) concentration while both doses reduced the concentration of dihydroxyphenylacetic acid (DOPAC) in the striatum. The enhancement of locomotor activity and the decrease of striatal DOPAC concentrations were increased with chronic administration (up to 40 days) of bupropion. The rate of DA synthesis in the striatum was increased by the acute administration of d-amphetamine but was not altered by acute or chronic administration of bupropion.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Methcathinone: a new and potent amphetamine-like agent.

The purpose of the present investigation was to examine the effect of N-monomethylation of phenylisopropylamine derivatives on amphetamine-like activity. In tests of stimulus generalization using rats trained to discriminate 1.0 mg/kg of (+)-amphetamine from saline, the N-monomethyl derivatives of 1-(X-phenyl)-2-aminopropane, where X = 2,4-dimethoxy (2,4-DMA), 3,4-dimethoxy (3,4-DMA), 2,4,5-trimethoxy (2,4,5,-TMA), and 2-methoxy-4,5-methylenedioxy (MMDA-2), did not produce amphetamine-appropriate responding at the doses evaluated. However, the N-monomethyl derivative of cathinone (i.e., methcathinone), like cathinone, resulted in stimulus generalization. Further studies with this agent revealed that (a) in the amphetamine-trained animals, methcathinone (ED50 = 0.37 mg/kg) is more potent than racemic cathinone or racemic amphetamine (ED50 = 0.71 mg/kg in both cases), (b) methcathinone is capable of inducing release of radioactivity from [3H]dopamine-prelabeled tissue of rat caudate nucleus in a manner similar to that observed with cathinone, amphetamine, and methamphetamine, and (c) methcathinone is more potent than cathinone as a locomotor stimulant in mice as determined by their effect on spontaneous activity. The results of the present study provide evidence for a structural analogy between the prototypic psychostimulants amphetamine/methamphetamine and cathinone/methcathinone, and lend further support to the concept that amphetamine and cathinone correspond in their pharmacological effects.

Alkaloids↗
PubMed1990

Chronic antidepressant and clonidine treatment effects on conflict behavior in the rat.

The present studies examined the effects of chronic treatment with several antidepressants and clonidine on conflict behavior. In daily ten-minute sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.25 or 0.5 mA). Electrification was signalled by a tone. Chronic desipramine (5 mg/kg, IP, b.i.d.) or clonidine (40 micrograms/kg, b.i.d.) treatment resulted in time-dependent anticonflict effects, with a latency to onset of approximately 3-4 weeks. In contrast, chronic buproprion (up to 10 mg/kg, IP, b.i.d.), mianserin (up to 10 mg/kg, IP, b.i.d.) or trazodone (up to 40 mg/kg, IP, b.i.d.) treatment resulted in at best only a weak anticonflict effect. The efficacy of these antidepressants and clonidine to increase punished responding when administered chronically correlates well with their efficacy as antipanic agents in man.

Animals↗
PubMed1990

Effects on opioid-induced rate reductions by doxepin and bupropion.

Twelve pigeons key-pecked under a multiple variable interval 15-second, variable interval 150-second schedule of food reinforcement. Effects of two opioid drugs, buprenorphine and methadone, were determined alone and in combination with chronic daily administration of the antidepressants doxepin or bupropion. Methadone initially produced dose-dependent key-pecking rate reductions when administered acutely, prior to the session, while buprenorphine produced key-pecking rates that reached a plateau at 50-80% of baseline rate and were not reduced further by higher doses. Neither doxepin nor bupropion, given alone, had lasting effects on key-pecking rates. Chronic daily doxepin administration significantly attenuated methadone-induced response rate reductions. Bupropion reduced the effect of the highest methadone dose, but this effect was mitigated by the development of opioid tolerance. Unlike bupropion, doxepin interfered with the development of opioid tolerance. Neither antidepressant systematically altered effects of buprenorphine on key-pecking.

Animals↗
PubMed1993

Cocaine-stimulus generalization to two new designer drugs: methcathinone and 4-methylaminorex.

Rats were trained to discriminate 8 mg/kg cocaine from saline vehicle for the purpose of examining the stimulus properties of two novel and structurally related drugs of abuse recently confiscated on the illicit market: (+/-)methcathinone and cis(+/-)4-methylaminorex. The stimulus properties of these controlled substance analogs were compared with those of their parent compounds (+/-)cathinone and aminorex, respectively. All agents resulted in cocaine-stimulus generalization with the following rank order of potency: aminorex (ED50 value = 0.8 microM/kg) > methcathinone (1.9 microM/kg) > cathinone (3.7 microM/kg) > 4-methylaminorex (5.2 microM/kg) > cocaine (7.6 microM/kg).

Animals↗
PubMed1995

Methcathione ("cat"): an enantiomeric potency comparison.

With regard to its chemical structure, methcathinone is to cathinone what methamphetamine is to amphetamine. Although it is a drug of abuse outside the United States, methcathione is only recently making an appearance on the clandestine market in this country and has just been classified a Schedule I substance under the Emergency Scheduling Act. We have previously demonstrated that racemic methcathinone produces locomotor stimulation in mice, and substitutes for cocaine and (+)amphetamine in rats trained to discriminate either cocaine or (+)amphetamine, respectively, from saline in tests of stimulus generalization. Because an enantiomeric potency comparison has never been reported for the optical isomers of methcathinone, in the present investigation we synthesized samples of S(-)- and R(+)methcathinone and compared them for their ability: a) to produce locomotor stimulation in mice, b) to elicit cocaine-like responding in rats trained to discriminate 8.0 mg/kg of cocaine from saline vehicle, and c) to elicit (+)-amphetamine-appropriate responding in rats trained to discriminate 1.0 mg/kg of (+)amphetamine from saline vehicle. S(-)Methcathinone was about twice as potent as S(+)amphetamine and three to five times more potent than R(+)methcathinone in the three pharmacologic assays. We conclude that both optical isomers possess central stimulant character, but that S(-)methcathinone is somewhat more potent than R(+)methcathinone.

Animals↗
PubMed1994

Intravenous self-injection of methcathinone in the baboon.

Methcathinone is a phenylisopropylamine that has been produced by clandestine laboratories and identified in illicit drug traffic. The present study evaluated the intravenous self-administration of methcathinone in three baboons using a cocaine substitution procedure. Intravenous self-injections were available 24 h/day according to a fixed-ratio (FR) schedule with a 3-h timeout following each injection. Doses of racemic methcathinone HCl (0.01-1.0 mg/kg/injection) and its vehicle were substituted for cocaine for 15 or more days. A concurrent FR schedule of food pellet delivery allowed evaluation of any changes in food intake. Self-injection of methcathinone was dose dependent. The lower doses of methcathinone, 0.01 and 0.032, maintained low and intermediate rates of self-injection, respectively, while the higher doses, 0.1, 0.32, and 1.0, maintained rates above vehicle control and comparable to those maintained by cocaine. Acute administration of 3.2 mg/kg to two baboons produced signs of psychomotor stimulant toxicity. Systematic changes in food intake were not observed. The present data indicate that methcathinone functions as a positive reinforcer in baboons and suggests that methcathinone may have abuse potential.

Animals↗
PubMed1985

Activity of dopamine-containing substantia nigra neurons in freely moving cats.

The present series of studies examined the activity of presumed dopamine-containing neurons in the substantia nigra of freely moving cats. These neurons were found to have a slow (1-9 spikes/sec) discharge rate, unusually long duration action potentials (2-4 msec) and frequently fired in bursts with progressive decreases in the amplitude of the action potential within the burst. These neurons showed no significant change in their activity across the sleep-waking cycle, and showed no changes in activity with phasic movement. Most units were unresponsive to olfactory, noxious, tactile, auditory and visual stimulation, when unit activity was integrated over several seconds following stimulus presentation. However, phasic auditory and visual stimuli produced a period of excitation lasting approximately 120 msec after a delay of about 80 msec. The period of excitation was followed by a period of inhibition lasting approximately 60 msec. Presumed dopamine-containing substantia nigra units showed no significant circadian changes in activity. The firing rates of these units were inhibited by dopamine agonists, including the direct-acting agonist, apomorphine, the dopamine precursor, L-dihydroxyphenylalanine, a dopamine releasing agent, d-amphetamine, and a dopamine reuptake blocker, bupropion, and were excited by a dopamine receptor blocker, haloperidol. Thus, these neurons show many similarities to dopamine units recorded in anesthetized rats; however, they showed several notable differences as well. Recording the activity of these units in behaving animals allows one to examine behavioral correlates of unit activity. Furthermore, the data (sensory stimulation, pharmacological, etc.) obtained in the unanesthetized preparation are far more relevant to the physiological and pharmacological effects that may occur in humans.

Action Potentials↗
PubMed1986

Structure-mutagenicity relationships of chalcones and their oxides in the Salmonella assay.

31 p-monosubstituted chalcones (E-1, 3-diphenylpropene-1-one) and the corresponding oxides (E-1-benzoyl-2-phenyloxirane) were tested for mutagenic activity on two strains of Salmonella typhimurium (TA98 and TA100) with and without rat liver microsomal and cytosolic enzymes. Highest mutagenicity (3.0 revertants/nmole in either strain) was seen with the 4-nitrochalcone, especially after S9 activation. Epoxidation, in general, increased the mutagenic activity of the respective chalcone. Benzoyl (4') substituted chalcones and their oxides with an electron-withdrawing substituent (e.g., nitro, fluoro) usually had higher activity than their phenyl (4) substituted counterparts, whereas the converse was the case with electron-donating substituents (e.g., acetamido, methoxy). Further multiple factorial analysis revealed that increasing hydrophilicity as indicated by the Hansch pi parameter, and resonance electronic contributions were more important than other factors including steric terms in explaining the mutagenicity of these compounds. Mutagenic effects of some chalcone oxides, particularly the 4-methoxy derivative, were markedly decreased by S9 treatment. The consequence of the weak-to-moderate mutagenicity of these compounds to dietary intake of hydroxylated and methoxylated chalcones is discussed.

Animals↗