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2614W94 [3-(1-trifluoromethyl)ethoxyphenoxathiin 10,10-dioxide] is a selective, reversible inhibitor of monoamine oxidase-A with a competitive mechanism of inhibition and a Ki value of 1.6 nM with serotonin as substrate. In pretreated rats, the ED50 value after single oral dosing was 1.7 mg/kg, similar to an ED50 value of 1.1 mg/kg estimated in the 5-hydroxytryptophan potentiation test. Maximal inhibition of monoamine oxidase-A (MAO-A) was observed by 0.5 h after dosing, suggesting rapid transport to brain. Inhibition in brain was maintained for several hours, followed by a gradual reversal with a half-time of 7.2 h. Brain levels of parent compound were higher than plasma levels at all times after dosing. No significant inhibition of MAO-B was observed. After preincubation of MAO with 2614W94 at 37°C, the inhibition was reversed by dialysis. Concentrations of serotonin, norepinephrine, and dopamine were clearly elevated in brains of rats after single oral doses, whereas levels of MAO metabolites were decreased. In a rat model designed to show blood pressure elevations in response to a threshold dose of orally administered tyramine, 2614W94 compared well with moclobemide, an MAO-A selective inhibitor that has not been associated with problems relating to dietary tyramine. The two stereoisomers of 2614W94 were both potent MAO-A inhibitors. In vitro and in vivo properties of 2614W94 suggest that this compound and its close analogs are among the most potent MAO-A inhibitors known and that they may have therapeutic potential as safe new antidepressant/anxiolytic agents. Drug Dev. Res. 45:1–9, 1998. © 1998 Wiley-Liss, Inc.

A series of bicyclo analogues of several 2-phenylmorpholines were synthesized and tested for anti-tetrabenazine activity in mice. Most of the target compounds were prepared by reaction of 2-bromopropio-phenone (22) with the appropriate amino alcohol to form 2-phenylmorpholinols. Reduction of the 2-phenyl-morpholinols with sodium borohydride gave amino diols, which were cyclized to morpholines with acid. Alternatively, oxazines 17 and 18 were synthesized by alkylation of phenyl-(2-pyrrolo)carbinol (32a) and phenyl-(2-piperidyl)carbinol (32b) with 2-bromoethanol, followed by cyclization of the resulting amino diols with acid. Only the spirocyclic compounds 8 and 9 had i.p. anti-tetrabenazine activity comparable to the non-cyclic compounds 2a-3b, but 8 and 9 were less active by the oral route of administration.

A series of 6-(alkylamino)-9-alkylpurines was synthesized and evaluated for the property of antagonizing the behavioral effects in animals of the dopamine agonist apomorphine. This model for identifying potential antipsychotic agents is based on the hypothesis that agents that antagonize apomorphine-induced aggressive behavior in rats and apomorphine-induced climbing in mice, but that do not block stereotyped behavior, could have an antipsychotic effect in humans without producing extrapyramidal side effects. The antiaggressive-behavior activity of lead compound 1 (6-(dimethylamino)-9-(3-phenylalaninamidobenzyl)-9H-purine) was improved 48-fold with 6-(cyclopropylamino)-9-(cyclopropylmethyl)-2-(trifluoromethyl)-9H- purine (80) (po ED50 of 2 mg/kg), which was obtained through an iterative sequence of structure--activity relationship studies that encompassed evaluation of the effects of structure variations at the purine 9-, 6-, and 2-positions. Potency was enhanced with a 9-cyclopropyl group, the duration of action was improved with the 6-(cyclopropylamino) substituent, potency was further enhanced with an N-formyl prodrug, and an agent with reduced cardiovascular effect emerged with the 2-trifluoromethyl purine 80. This potential antipsychotic agent was not developed further due to undesirable effects on the stomach.

Extracts of Ginkgo biloba leaves produce reversible inhibition of rat brain monoamine (MAO). Both MAO-A and -B types were inhibited to a similar extent. The MAO inhibitory compound(s) were present in dried or fresh Ginkgo biloba leaves as well as in commercially available capsules of Ginkgo biloba and appear to be heat stable with relatively low molecular weight. MAO inhibition by Ginkgo biloba may be a mechanism underlying reported anti-stress and anxiolytic activities of this natural product.

A series of analogues of 2-phenylmorpholines with alkyl substituents at the C-3 position were synthesized for anti-tetrabenazine (anti-TBZ) testing in mice. The target compounds were prepared by reaction of (2-bromoalkyl) phenyl ketones 21a-h with the appropriate aminoalcohol 20a-b to form morpholinols 22a-h. Hydride reduction of the morpholinols gave aminodiols 23a-h which were cyclized to morpholines 6, 8, 10–12, 14–16, 18 and 19 by acid catalaysis. Compounds 7, 9, 13 and 17 were prepared by reductive formylation. The smaller straight chain substituents of 6, 8, 12 and 15, and the beta branching of the iso-butyl group of 16 were well tolerated; anti-tetrabenazine ED50′s were comparable to compounds 2–5. The α-branched, N-methylated, and side chain aryl derivatives were less active.

The imidazo[4,5-d]-1,2,3-triazine and pyrazolo[3,4-d]-1,2,3-triazine analogues of the potent anticonvul-sant purine, BW 78U79 (9-(2-fluorobenzyl)-6-methylamino-9H-purine, 1), were synthesized and tested for anticonvulsant activity. The imidazo[4,5-d]-1,2,3-triazines 11–13 were prepared in four steps from 5-aminoimidazole-4-carboxamide (2) and the pyrazolo[3,4-d]-1,2,3-triazines 18–21 were synthesized starting with 5-amino-1-(2-fluorobenzyl)pyrazole-4-carbonitrile (14). The intermediate 1,2,3-triazin-4-ones 6 and 16 were converted to the 4-substituted targets via the 4-(4-dimethylaminopyridinium) salts 10 and 17. Imidazotriazine 11 had potent anticonvulsant activity against maximal electroshock-induced seizures, but its propensity to cause emesis precluded further development.

A series of novel 4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl) cyclic amides was prepared and evaluated as potential antipsychotic agents. The target compounds were examined in vitro for their binding affinities to the dopamine D2, serotonin 5-HT2, and serotonin 5-HT1a receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. Derivatives that exhibited good D2/5-HT2 selectivity in vitro and good potency in vivo were selected for further evaluation in tests designed to assess their potential extrapyramidal side effect liability. Structural modifications discussed herein focus on the bicyclic amide subunit leading to the preparation of a variety of heterocyclic ring systems (i.e., phthalimide, isoindolinone, isoquinolinone, benzazepinone, indazolone, phthalazinone, 4-methyl phthalazinone, benzisothiazolone 1,1-dioxide, benzotriazinone, homophthalimide, benzisothiazolone, phthalazinedione, quinazoline, and saturated phthalazinones). The potency and selectivity within this series was found to be dependent on ring size, nature of the covalent linking unit, relative position of the functional groups, degree of unsaturation, and relative stereochemistry. In general, the cyclic benzamides examined in this investigation exhibited receptor binding activities indicative of potential atypical antipsychotic agents. Several of these derivatives possessed in vivo activities that suggest they would be useful in the treatment of schizophrenia and would have a low propensity to induce extrapyramidal side effects. Two potent analogues were identified and selected for further evaluation: 2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-1-isoind olinone (31) and (+-)-cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)- 4a,5,6,7,8,8a-hexahydro-1(2H)-phthalazinone hydrochloride (52).

Eleven substituted 8-amino-3-benzyl-1,2,4-triazolo[4,3-a] pyrazines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures (MES) in rats. The compounds were prepared in four stages from the phenylacetonitriles. I. The intermediate (2,2,2-triethoxyethyl)benzenes III were condensed with 2-chloro-3-hydrazinopyrazine (IV) to provide the 3-benzyl-8-chloro-1,2,4-triazolo[4,3-a]pyrazines V. The latter were converted to the 8-amine targets VI with methylamine or ammonia. Several compounds exhibited potent activity against MES; the 3-(2-fluorobenzyl)-8-(methylamino) and 3-(2,6-difluorobenzyl)-8-(methylamino)congeners (4 and 12) exhibited the best anticonvulsant activity with oral ED50S of 3 mg/kg. The 1,2,4-triazolo[4,3-a]pyrazine ring system serves as a bioisostere of the purine ring for anticonvulsant activity; however, these agents exhibit less propensity to cause emesis.

A series of (fluorobenzyl)triazolo[4,5-c]pyridines was synthesized and tested for activity against maximal electroshock-induced seizures in rodents. The most promising compound, 14 (BW 534U87), which is a carbon-nitrogen isoster of a purine anticonvulsant, has a profile in rodents that suggests 14 will be free of emesis and useful in the treatment of seizure disorders for which phenytoin is presently indicated.

The 3H-imidazo[4,5-c]pyridazine, 1H-imidazo[4,5-d]pyridazine, and 1H-benzimidazole analogues of the potent anticonvulsant purine 9-(2-fluorobenzyl)-6-methylamino-9H-purine (1, 78U79) were synthesized and tested for anticonvulsant activity. The 3H-imidazo[4,5-c]pyridazines 8 and 9 were prepared in five stages from 3,4,5-trichloropyridazine (2). The 1H-imidazolo[4,5-d]pyridazine 15 was synthesized in four stages from 5-[(benzyloxy)methyl]-1,5-dihydro-4H-imidazo[4,5-d] pyridazin-4-one (10a). The benz-imidazole analogues 18 and 20 were prepared from 2,6-dinitroaniline in three stages. These compounds were one-tenth or less as active as 1 in protecting rats against maximal electroshock-induced seizures.

Analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine (1) containing isosteric replacements of the imidazole ring atoms were synthesized and tested for anticonvulsant activity. The pyrrolo[2,3-d]-, pyrazolo[3,4-d]-, and triazolo[4,5-d]pyrimidines were less active than 1 against maximal electroshock-induced seizures (MES) in rats when given po. The differences in anti-MES activity for these analogues was not explained by differences in pKa or lipophilicity. However, the four classes of heterocycles have distinctly different calculated electrostatic isopotential maps, which may be related to optimum anticonvulsant activity.

Monoamine oxidase (MAO) inhibitors increase brain concentrations of biogenic amines and decrease concentrations of the acidic metabolites of biogenic amines. It has been suggested that the magnitude of these effects is an indicator of MAO inhibition. Oral doses of BW 1370U87, moclobemide, and brofaromine were given to rats at doses previously shown to induce brain MAO-A inhibition by at least 80%. The effects on brain biogenic amines and their metabolites were quantified 2 and 4 hr after oral dosing using HPLC with electrochemical detection. Moclobemide and BW 1370U87 induced larger increases in 5HT, NE, and DA and larger decreases in DOPAC, 5HIAA, and HVA than did brofaromine at the doses tested. At 8 hr post-dose the effects of BW 1370U87 on 5HT, NE, DOPAC, and HVA were still significant (P≤0.05), and the time course was similar to that seen following moclobemide and brofaromine treatment. Only BW 1370U87 increased brain concentrations of biogenic amines at a dose that does not significantly potentiate pressor effects of orally administered tyramine.

The design of rigid cyclic analogues derived from cinnamamide 1, (E)-N-cyclopropyl-3-(3-fluorophenyl)prop-2-enamide, and beta-methylcinnamamide 2, (E)-N-cyclopropyl-3-(3-fluorophenyl)but-2-enamide, has led to the discovery of the potent, centrally acting muscle relaxant (E)-2-(4,6-difluoro-1-indanylidene)acetamide, 17. Compound 17 also possesses potent antiinflammatory and analgesic activity. This paper describes the synthesis and the muscle relaxant, antiinflammatory, and analgesic structure-activity relationships of 17 and 67 of its analogues. Compound 17 has been taken into phase I clinical trials.

Extension of the structure-activity relationship studies that led to the discovery of the nonsedating potent muscle relaxant, antiinflammatory, and analgesic agent (E)-2-(4,6-difluoro-1-indanylidene)acetamide, 1, has given rise to (E)-2-(4-chloro-6-fluoro-1-indanylidene)-N-methylacetamide, 2. Compound 2 is a potent antiinflammatory and analgesic agent without centrally acting muscle relaxant activity.

A series of (fluorobenzyl)triazolo[4,5-c]pyridines was synthesized and tested for activity against maximal electroshock-induced seizures in rodents. The most promising compound, 14 (BW 534U87), which is a carbon-nitrogen isoster of a purine anticonvulsant, has a profile in rodents that suggests 14 will be free of emesis and useful in the treatment of seizure disorders for which phenytoin is presently indicated.

Eleven substituted 8-amino-3-benzyl-1,2,4-triazolo[4,3-a] pyrazines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures (MES) in rats. The compounds were prepared in four stages from the phenylacetonitriles. I. The intermediate (2,2,2-triethoxyethyl)benzenes III were condensed with 2-chloro-3-hydrazinopyrazine (IV) to provide the 3-benzyl-8-chloro-1,2,4-triazolo[4,3-a]pyrazines V. The latter were converted to the 8-amine targets VI with methylamine or ammonia. Several compounds exhibited potent activity against MES; the 3-(2-fluorobenzyl)-8-(methylamino) and 3-(2,6-difluorobenzyl)-8-(methylamino)congeners (4 and 12) exhibited the best anticonvulsant activity with oral ED50S of 3 mg/kg. The 1,2,4-triazolo[4,3-a]pyrazine ring system serves as a bioisostere of the purine ring for anticonvulsant activity; however, these agents exhibit less propensity to cause emesis.

Rats were made dependent upon alcohol by oral intubation and tested for either audiogenic Scizure susceptibility, the effects of GABA-ergic drugs on audiogenic Scizure susceptibility, or changes in GABA levels. Audiogenic Scizures occurred during a period of 12–36 hrs after ethanol withdrawal with a peak at 18–24 hrs. Intracisternal injection of GABA or GABA agonists antagonized Scizures as did treatment with GABA-T inhibitors. GABA levels in brain stem (but not whole brain) were decreased significantly by 18 hrs after withdrawal. This decrease was not seen if “dependent” rats received alcohol prior to sacrifice. A depletion of brain stem GABA with dl-C-allylglycine also resulted in audiogenic Scizure susceptibility. Results suggest that GABA may play a role in Scizure susceptibility during withdrawal from alcohol.

Intracisternal injections of the selective GABA-T inhibitor, ethanolamine-O-sulfate (EOS) resulted in the blockade of apomorphine-stimulated locomotor activity and stereotyped behavior which was compared to haloperidol. Unlike haloperidol, EOS did not elevate measures of dopamine synthesis. EOS also did not affect the reduction of dopamine synthesis produced by apomorphine at doses which completely blocked the behavioral effects of apomorphine. While other studies showed that no evidence could be obtained that EOS blocked dopamine receptors in vitro , prior EOS treatment antagonized accumulation of 3 H-spiroperidol in striatum in vivo . Since this effect was seen 24 hrs after EOS but not 1 hr after EOS, it appears that EOS treatment results in the accumulation of a substance which may produce effects similar to neuroleptic drugs. GABA would be one likely candidate for this action.

When the parameters of taste aversion conditioning and testing have been appropriately adjusted, benzodiazepines and barbiturates will markedly antagonize the expression of moderate taste aversions in rats. We call this the taste aversion conflict model of anxiety. In the present study, we investigate whether buspirone HCl (buspirone; p.o. and i.p.) is active in the taste aversion conflict model and whether buspirone will also increase unsuppressed saccharin (SACC) intake. We also investigated the effects of imipramine, desipramine, phenelzine sulfate, chlorpromazine, scopolamine and d-amphetamine sulfate in the taste aversion conflict model. To assess the possible effects of buspirone on the GABA-benzodiazepine supramolecular receptor complex, we compared buspirone with certain benzodiazepines, meprobamate and sodium phenobarbital on the antagonism of pentylenetetrazol-induced lethality in mice. Unlike benzodiazepines, meprobamate and phenobarbital, buspirone did not antagonize pentylenetetrazol-induced lethality. However, like those other anxiolytics, buspirone markedly antagonized the expression of conditioned taste aversion. All nonanxiolytic drugs tested had either no effect or very slight effects on the expression of conditioned taste aversion. These results suggest that the taste aversion conflict model is sensitive to novel anxiolytics and that it is selective for drugs clinically effective in the treatment of generalized anxiety disorders in man.

Thyrotropin releasing hormone (TRH) produced a rapid dose related elevation of muscle tonus accompanied by tremor and shivering-like movements in cats. This stimulant action of TRH also occurred in decerebrate cats and cats which had undergone spinal cord transection at the level of the first cervical vertebra. Recordings froir spinal cord ventral roots indicated that TRH induced a pronounced increase in spontaneous motor neuron action potentials. No such stimulation of muscle activity was produced by injections of thyrotropin (TSH), triiodothyronine (T3), deamidated TRH, or the constituent amino acids of TRH, pyroglutamic acid, histidine, and proline amide. Results suggest that TRH can act directly on the spinal cord to stimulate muscle activity via a nonendocrine mechanism.

Rats learned to avoid a saccharin solution if their initial consumption of it was followed by intraperitoneal (IP) administration of 25 mg/kg l-5-hydroxytryptophan (l-5-HTP); this taste aversion learning did not occur in rats pretreated with 50 mg/kg (IP) of the aromatic l-amino acid decarboxylase inhibitor RO 4-4602 (benserazide). RO 4-4602 antagonized the l-5-HTP-induced elevation of 5-hydroxytryptamine (5-HT) in the mesentery but significantly increased the l-5-HTP-induced elevation of 5-HT in the brain. These results indicate that l-5-HTP-induced taste aversion is correlated with peripheral, but not central, elevation of 5-HT.

Summary Intracisternal administration of 200 μg of 5,7-dihydroxytrptamine (5,7-DHT) caused a prolonged reduction of brain serotonin which was accompanied by a depletion of brain norepinephrine. The depletion of norepinephrine was found to be antagonized by agents that inhibit uptake of norepinephrine as well as by several monoamine oxidase inhibitors. Intracisternal injections of 5,7-DHT (75 or 100 μg) to 7-day-old neonatal rats reduced brain serotonin and norepinephrine and produced a significant reduction of adult body weight. As in adults, pretreatment of neonatal rats with pargyline or desipramine prevented 5,7-DHT induced depletion of norepinephrine without affecting depletion of serotonin. Behaviorally, treatment of adult rats with 5,7-DHT facilitated acquisition of an active avoidance task and enhanced muricidal behavior. 5,7-DHT treatment was also found to enhance the depressant effects of 5-hydroxytryptophan on a fixed-ratio barpress response, suggesting that 5,7-DHT treated rats are supersensitive to serotonin in the central nervous system.

Ethanolamine-O-sulfate (EOS) is an irreversible selective inhibitor of GABA-transaminase. Intracisternal injections of EOS (100–400 μg/brain) produced dose-related inhibition of food-motivated operant behavior, decreases in food consumption and body weight, inhibition of GABA-transaminase, and increases in brain GABA levels. The time course of the changes in brain GABA correlated with the alterations in food-related behaviors. EOS over the same dose range did not produce observable changes in behavior, changes in operant behavior not motivated by food, or produce a conditioned taste aversion. Although EOS crosses the blood-brain barrier poorly, repeated intraperitoneal injections of 250 and 500 mg/kg produced decreases in body weight and increases in brain GABA levels. Confirmation of a role for GABA was obtained in experiments using aminooxyacetic acid, another GABA transaminase inhibitor, and muscimol, a GABA receptor agonist. These results suggest that a prominent pharmacological effect of GABA receptor stimulation and elevation of whole brain GABA is anorexia indicating that this putative neurotransmitter has a function in regulating hunger (or satiety) in the rat.

Thyrotropin releasing hormone (TRH) antagonizes pentobarbital sedation and hypothermia; somatotropin release inhibiting factor amplifies them. Other hypothalamic polypeptide releasing factors, Substance P and a variety of amino acids are ineffective. Three congeners of TRH antagonize pentobarbital; one amplifies it. The potencies of congeners as pentobarbital antagonists are unrelated to their potencies as pituitary thyrotropin releasers.

1-(n-decyl)-3-Pyrazolidinone (BW357U) is a potent, selective inhibitor of gamma-aminobutyrate aminotransferase (GABA-T) in vitro and in vivo. After acute or chronic, oral or intraperitoneal administration of BW357U to rats, brain GABA levels were elevated in a dose-dependent manner. When inhibition of brain GABA-T exceeded 50%, whole brain GABA levels were elevated approximately threefold, and an anorectic effect was observed in the absence of other symptoms. This compound, because of its potency and selectivity, may be useful in studies relating to the function of GABA-containing neurons in appetite regulation.

The effects of magnesium pemoline, tricyanoaminopropene, and d-amphetamine on the acquisition of a discriminated avoidance response were compared in 30-, 50-, and 100-day-old naive rats. The rats were placed in an automated shuttlebox immediately after drug treatment. The number of avoidance responses in a series of 100 trials was measured. Ten days after the initial acquisition session, the rats were retrained on the same task. The 30-day group was inferior to the 50- and 100-day groups in the training session, but no differences occurred in retraining. The drug-treated groups showed improved performance in the initial training session but were not different from the controls in the retraining session. No Drug by Age interaction was significant.

Thyrotropin releasing hormone (TRH) reduced the narcosis and hypothermia produced by ethanol in mice. This action of TRH does not appear related to release of thyroid hormone or to the effects of a metabolite of TRH. The ability of TRH to reduce the actions of ethanol after intracisternal injection suggests that the mechanism of the ethanol antagonism is central in origin. The antagonism of ethanol by TRH does not appear to be related to an amphetamine-like stimulant action.

Intracisternal injections of ethanolamine-O-sulfate (EOS), an irreversible selective inhibitor of GABA-transaminase (GABA-T), resulted in relatively long lasting dose dependent decreases in food consumption and body weight of rats. The anorexic effects of EOS generally corresponded in both time course and magnitude to the elevation of GABA levels and associated decreases in GABA-T activity. Chronic treatment with very high intraperitoneal doses of EOS which were able to cross the blood-brain barrier elevated GABA levels and resulted in weight loss. Muscimol, a GABA receptor agonist also produced anorexia. These findings are consistent with the view that GABA may be involved in mediation of satiety in the rat.

The significance of central noradrenergic, dopaminergic and serotonergic neural systems for the locomotor stimulant effects of methylphenidate was investigated in the rat. In order to study the role of brain catecholamines, rats were pretreated with reserpine (2.5 mg/kg) followed 24 hrs later by treatment with alpha-methyltyrosine (25 mg/kg) or U-14,624 (75 mg/kg), a dopamine-beta-hydroxylase inhibitor. In these experiments, methylphenidate stimulated motor activity was antagonized by alpha-methyltyrosine and enhanced after treatment with U-14,624, suggesting that release of newly synthesized dopamine is important to a locomotor stimulant action of methylphenidate. Evidence implicating brain serotonin in the actions of methylphenidate was obtained in rats pretreated with pargyline or p-chlorophenylalanine (PCPA). Administration of pargyline 1 hr prior to methylphenidate was found to reduce the locomotor activity induced by methylphenidate and this was antagonized by pretreatment with low doses of PCPA. Higher doses of PCPA caused a significant elevation of methylphenidate induced activity which could be reduced by 5-hydroxytryptophan. Destruction of serotonergic neurons with 5,7-dihydroxytryptamine also potentiated methylphenidate induced locomotion. These latter findings suggest that serotonergic fibers have an inhibitory function in brain. These results are discussed in relation to the possible mechanism by which methylphenidate may act in hyperkinesis.

Intracisternal administration of two doses of 6-hydroxydopamine, one with pargyline pretreatment and one without, caused an initial disruption of consummatory behavior. In spite of measures to enhance recovery from these acute effects, 6-hydroxydopamine treated rats were found to maintain body weight at a lower level than control rats. Similar to controls, treated animals were found to drink water in the absence of food and to enhance water consumption in response to the administration of a hypertonic saline solution. However, unlike control rats, animals treated with 6-hydroxydopamine failed to increase food intake following insulin administration. Desoxycorticosterone acetate (DOCA) treatment enhanced saline preference in 6-hydroxydopamine treated rats, but the maximum volume of saline consumed was markedly less than the intake of control rats following DOCA treatment. While control rats drank a large volume of either a sucrose or a saline solution when substituted for water, 6-hydroxydopamine treated animals showed little increase in their intake of these solutions. Preferential deplition of norepinephine in brain did not alter consumption of a sucrose solution; however, depletion of dopamine produced a significant reduction in sucrose intake. These latter findings suggest that this deficit observed in the 6-hydroxydopamine treated rat involves interruption of dopaminergic pathways.

The effects of several doses of magnesium pemoline, caffeine, and picrotoxin on the acquisition of a food-reinforced light-dark discrimination task in the T-maze were compared. Both magnesium pemoline and caffeine facilitated the acquisition of the task at appropriate doses. The picrotoxin-treated animals were incapacitated except at the lowest dose administered.