Amfonelic Acid Research Articles

Accessing 1,8-Naphthyridone-3-carboxylic Acid Derivatives and Application to the Synthesis of Amfonelic Acid.

1,8-Naphthyridone-3-carboxyl is the core structure of several on-market antibacterial drugs. It has prompted significant interest from the synthetic community. Here, we report a practical synthesis of diversely functionalized 1,8-naphthyridone-3-carboxylic acid derivatives starting from readily available and inexpensive nicotinic acid derivatives. All key steps have been optimized. Furthermore, the usefulness of this protocol has been exemplified by the first synthesis of amfonelic acid.

Identification of potential biomarkers for soybean meal-induced enteritis in juvenile pearl gentian grouper, Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀

This study identifies the potential biomarkers of soybean meal-induced enteritis in juvenile pearl gentian grouper using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). There were 480 female juvenile grouper randomly assigned to two groups (n = 4), including the fish meal (FM) group (control) and 20% soybean meal (SBM20) group, which were fed by two iso‑nitrogenous (50% crude protein) and isolipidic (10% crude lipid) diets for 10 weeks. The diets and distal intestinal (DI) content samples of FM and SBM20 groups were collected for metabonomics analysis. The data generated from the UPLC-MS was analysed using principal components analysis (PCA) and partial least-squares discriminant analysis (PLS-DA). The PLS-DA model with satisfactory explanatory and predictive ability can discriminate the SBM20 from the FM group. The area under the curve (AUC) was calculated as the cumulative ability to distinguish between dietary patterns. Results showed that 20% SBM substitution level induced distal intestinal physiological injury and enteritis of juvenile grouper, which can be reflected by hematoxylin and eosin staining and transmission electron microscope analysis. In diets, a total of 171 metabolites in positive mode and 104 metabolites in negative mode in SBM20 group were significantly distinguished from the FM group. In DI contents, a total of 395 metabolites in positive mode and 219 metabolites in negative mode in SBM20 group were significantly distinguished from the FM group. Between diets and DI contents, there are only 9 co-contained differential metabolites in positive mode and 4 co-contained differential metabolites in negative mode. The 17 most influential metabolites in DI contents were identified as the potential biomarkers in positive and negative modes via the metabonomics UPLC-MS profiles. In DI contents, compared with the FM group, the intestines of 5-methylbenzimidazole, Glycitin, Byakangelicol, Genistin, Malonylglycitin, Genistein 4’-O-glucuronide, Glycitein, 3,4-dihydroxyphenylacetic acid, Daidzein, FMNH2, Soyasaponin I, olmelin, Genistein, Ginsenoside Ro, 4-Phenolsulfonic acid, and Baicalin in the SBM20 group were significantly increased (p < .01); however, the intensity of amfonelic acid in SBM20 group decreased significantly (p < .01) (AUC > 0.9). The present study identified a broad array of DI content metabolites that differed between FM and SBM dietary patterns that could provide some valuable reference for further management of fish intestine health issues.

MPTP-induced duodenal ulcers in rat. Prevention by reuptake blockers for serotonin and norepinephrine, but not dopamine.

Abnormal activity of dopamine, serotonin, and norepinephrine may contribute to the pathophysiology of duodenal ulcers. We therefore studied the effects of neuropharmacological manipulations on 1-methly-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-induced duodenal ulcers. Duodenal ulcers were produced in rats by 12 subcutaneous injections of a neurotoxin, MPTP, over 4 days. At an MPTP dose of 20 mg.kg. injection, duodenal ulcers developed in 91% (43 of 47) of animals with low mortality. When neuropharmacological agents were preadministered before MPTP, the following effects on duodenal ulcers incidence were obtained. MAO-B inhibitors (pargyline [55%], deprenyl [43%]) but not MAO-A inhibitors (clorgyline [91%]) significantly decreased the frequency of duodenal ulcers suggesting that, like MPTP-induced parkinsonism, formation of a toxic metabolite, probably 1-methyl-4-phenyl-pyridinium is involved. Reuptake blockers for serotonin (fluoxetine [18%], indalpine [25%]) also decreased the frequency of duodenal ulcers. Reuptake blockers for norepinephrine (desmethylimipramine [17%], tomoxepine [31%], but not amfonelic acid [82%]) decreased the frequency of duodenal ulcers. Reuptake blockers for dopamine (benztropine [73%], amfonelic acid [82%], GBR-12909 [80%]) did not protect against duodenal ulcers. However, GBR-12909 significantly decreased the severity of those duodenal ulcers that were produced. These data suggest that abnormally low levels of synaptic transmission in serotonergic and possibly noradrenergic neurons play an important role in the pathogenesis of duodenal ulcer while the role of dopamine may be limited to modulation of ulcer severity.

Flumezapine and zotepine: 5-hydroxytryptamine antagonism not involved in the lack of synergism of these antipsychotic drugs with amfonelic acid in rats.

Two antipsychotic drugs, flumezapine and zotepine, resembled clozapine, not spiperone, in not acting synergistically with amfonelic acid to elevate striatal concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in rats. Since flumezapine, zotepine and clozapine antagonize 5-hydroxytryptamine (5-HT) receptors with potency similar to their potency in antagonizing dopamine receptors, the possibility that 5-HT receptor blockade prevented their synergism with amfonelic acid was considered. Methiothepin, a potent 5-HT antagonist and dopamine antagonist, mimicked spiperone in causing a marked increase in striatal DOPAC in amfonelic acid-treated rats, indicating that 5-HT antagonism is not involved in the lack of synergism of flumezapine and zotepine with amfonelic acid.

Differential effects of (+)-amphetamine, methylphenidate, and amfonelic aid on catecholamine synthesis in selected regions of the rat brain.

Differential effects of (+)-amphetamine, methylphenidate, and amfonelic aid on catecholamine synthesis in selected regions of the rat brain.

Effect of fluoxetine pretreatment on the neurochemical changes induced by amfonelic acid combined with spiperone in rats

Combined treatment with amfonelic acid plus spiperone caused large increases in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and a decrease in dopamine in rat striatum. 5-Hydroxytryptamine (5-HT) was decreased in striatum (but not in hypothalamus), and 5-hydroxyindoleacetic acid (5-HIAA) was increased in the striatum. Pretreatment with fluoxetine, an inhibitor of uptake into 5-HT neurons, antagonized the decrease in 5-HT and the increase in 5-HIAA and in the ratio 5-HIAA/5-HT but did not antagonize the changes in dopamine or its metabolites. The amfonelic acid-spiperone combination apparently causes increased release of dopamine in striatum, and the released dopamine is accumulated by 5-HT nerve terminals via the membrane uptake carrier. Inhibition of that carrier by fluoxetine prevents the release of 5-HT caused by the dopamine influx.

Amfonelic acid, a non-amphetamine stimulant, has marked effects on brain dopamine metabolism but not noradrenaline metabolism: association with differences in neuronal storage systems.

Amfonelic acid, a non-amphetamine stimulant, has marked effects on brain dopamine metabolism but not noradrenaline metabolism: association with differences in neuronal storage systems.

Comparative effects of pemoline, amfonelic acid and amphetamine on dopamine uptake and release in vitro and on brain 3,4-dihydroxyphenylacetic acid concentration in spiperone-treated rats

Comparative effects of pemoline, amfonelic acid and amphetamine on dopamine uptake and release <i>in vitro</i> and on brain 3,4-dihydroxyphenylacetic acid concentration in spiperone-treated rats

L-Tyrosine enhancement of the elevation of 3,4-dihydroxyphenylacetic acid concentration in rat brain by spiperone and amfonelic acid.

L-Tyrosine enhancement of the elevation of 3,4-dihydroxyphenylacetic acid concentration in rat brain by spiperone and amfonelic acid.

Combined Norepinephrine/Serotonergic Reuptake Inhibition: Effects on Maternal Behavior, Aggression, and Oxytocin in the Rat

Background: Few systematic studies exist on the effects of chronic reuptake of monoamine neurotransmitter systems during pregnancy on the regulation of maternal behavior (MB), although many drugs act primarily through one or more of these systems. Previous studies examining fluoxetine and amfonelic acid treatment during gestation on subsequent MB in rodents indicated significant alterations in postpartum maternal care, aggression, and oxytocin levels. In this study, we extended our studies to include chronic gestational treatment with desipramine or amitriptyline to examine differential effects of reuptake inhibition of norepinephrine and combined noradrenergic and serotonergic systems on MB, aggression, and oxytocin system changes. Methods: Pregnant Sprague-Dawley rats were treated throughout gestation with saline or one of three doses of either desipramine, which has a high affinity for the norepinephrine monoamine transporter, or amitriptyline, an agent with high affinity for both the norepinephrine and serotonin monoamine transporters. MB and postpartum aggression were assessed on postpartum days 1 and 6 respectively. Oxytocin levels were measured in relevant brain regions on postpartum day 7. Predictions were that amitriptyline would decrease MB and increase aggression relative to desipramine, particularly at higher doses. Amygdaloidal oxytocin was expected to decrease with increased aggression. Results: Amitriptyline and desipramine differentially reduced MB, and at higher doses reduced aggressive behavior. Hippocampal oxytocin levels were lower after treatment with either drug but were not correlated with specific behavioral effects. These results, in combination with previous findings following gestational treatment with other selective neurotransmitter reuptake inhibitors, highlight the diverse effects of multiple monoamine systems thought to be involved in maternal care.

Increased striatal dopamine synthesis is associated with decreased tissue levels of tyrosine

Tyrosine levels do not generally affect indices of dopamine (DA) synthesis or efflux under basal conditions, but can do so when DA synthesis is increased. One possibility is that a high rate of DA synthesis depletes the normally adequate pool of endogenous tyrosine. To study this, we administered drugs known to preferentially increase striatal DA synthesis and examined DOPA levels in striatal microdialysate during perfusion with NSD-1015. In additional groups, we also measured DA, tyrosine and large neutral amino acids in striatal microdialysate, as well as in tissue from striatum and medial prefrontal cortex (MPFC). γ-butyrolactone (GBL) (750 mg/kg i.p.) increased DOPA levels in striatal microdialysate, increased tissue DA levels in the MPFC and striatum, but lowered tissue tyrosine levels only in striatum. In striatal microdialysate, GBL markedly lowered DA levels; tyrosine levels were only marginally lower. Haloperidol (HAL) (1.0 mg/kg s.c.) ± amfonelic acid (AFA) (5 mg/kg i.p.) increased striatal DOPA accumulation, increased striatal DA efflux, lowered striatal tissue tyrosine levels, but did not affect microdialysate tyrosine levels. There were no consistent changes in levels of other large neutral amino acids. We conclude that increased tyrosine hydroxylation can significantly deplete the endogenous pool of tyrosine. Under such conditions, near normal extracellular tyrosine levels are maintained despite lower tissue levels. The data are consistent with a net transfer of tyrosine from non-DAergic cells to DA terminals in support of DA synthesis.

The effects of dopaminergic/serotonergic reuptake inhibition on maternal behavior, maternal aggression, and oxytocin in the rat

Studies using dopaminergic and serotonergic agonists or antagonists implicate involvement of these systems in various aspects of early maternal behavior and postpartum aggression towards an intruder in rats, both of which are associated with the presence of oxytocin in specific brain regions. It is unclear however, if or how long-term uptake inhibition of either neurotransmitter system alone or in combination, affects oxytocin system dynamics or maternal behavior/aggression. Pregnant women frequently take drugs (antidepressants, cocaine) that induce long-term reuptake inhibition of dopamine and/or serotonin, thus it is important to understand these effects on behavior and biochemistry. Rat dams were treated throughout gestation with amfonelic acid, fluoxetine, or a combination of both, to investigate effects of reuptake inhibition of dopamine and serotonin systems respectively, on maternal behavior, aggression and oxytocin. The more appetitive aspects of maternal behavior (nesting, licking, touching) and activity were increased by the low dose of amfonelic acid, high dose of fluoxetine, or the high dose combination more than other treatments. Aggression was decreased by amfonelic acid and somewhat increased by fluoxetine. Dopamine uptake inhibition appears to have a strong effect on hippocampal oxytocin levels, while receptor dynamics may be more strongly affected by serotonin uptake inhibition.

Presynaptic control of striatal dopamine neurotransmission in adult vesicular monoamine transporter 2 (VMAT2) mutant mice.

The vesicular monoamine transporter 2 (VMAT2) plays a pivotal role in regulating the size of vesicular and cytosolic dopamine (DA) storage pools within the CNS, and can thus influence extracellular DA neurotransmission. Transgenic mice have been generated with a dramatically reduced (by approximately 95%) expression of the VMAT2 gene which, unlike complete knockout lines, survive into adulthood. We compared the pre-synaptic regulation of both impulse-dependent (exocytotic) and carrier-mediated (via reversal of the DA transporter, DAT) DA release in the dorsolateral caudate putamen (CPu) of striatal slices derived from adult homozygous VMAT2 mutant and wild-type mice using fast cyclic voltammetry. Impulse-dependent DA release, evoked by a single electrical pulse, was lower in homozygous (116 nm) than wild-type mice (351 nm) indicating smaller vesicular DA stores, an observation supported by the evanescent effect of amfonelic acid (300 nm) in homozygous mice. Amphetamine (2 microm) increased extracellular DA via DAT reversal in both wild-type (by 459 nm) and VMAT2 mutant (by 168 nm, p < 0.01 vs. wild-type) mice. In both cases, the effect was blocked by the DAT inhibitor GBR12935 (1 microm). Simultaneously, amphetamine decreased impulse-dependent DA release, albeit less in homozygous (by 55%) than in wild-type (by 78%) mice. In wild-types, this decrement was largely reversed by GBR12935 but not by the D2/D3 autoreceptor antagonist (-)sulpiride (1 microm). Conversely, in homozygous VMAT2 mutant mice, it was attenuated by (-)sulpiride but not GBR12935. The D2/D3 receptor agonist quinpirole inhibited impulse-dependent DA release with a lower EC50 value in homozygous mice (12 nm) compared with wild-types (34 nm), indicating the compensatory presence of functionally supersensitive release-regulating autoreceptors. However, analysis of DA reuptake kinetics obtained in the absence and presence of DAT blockade (by cocaine and amfonelic acid) revealed only minor differences in DAT functionality. These results demonstrate that impaired vesicular DA storage constrains extracellular DA levels in the dorsolateral CPu whether induced by either impulse-dependent or carrier-mediated mechanisms and that the relative importance of the DAT and terminal autoreceptors as control mechanisms in the actions of amphetamine are reversed in VMAT2 mutant mice.

Effects of norepinephrine and serotonin transporter inhibitors on hyperactivity induced by neonatal 6-hydroxydopamine lesioning in rats.

Consistent with their clinical effects in attention deficit-hyperactivity disorder (ADHD), the stimulants methylphenidate and amphetamine reduce motor hyperactivity in juvenile male rats with neonatal 6-hydroxydopamine (6-OHDA) lesions of the forebrain dopamine (DA) system. Since stimulants act on several aminergic neurotransmission systems, we investigated underlying mechanisms involved by comparing behavioral actions of d-methylphenidate, selective inhibitors of the neuronal transport of DA [GBR-12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride), amfonelic acid], serotonin [5-hydroxytryptamine (5-HT), citalopram, fluvoxamine], and norepinephrine (NE; desipramine, nisoxetine) in 6-OHDA lesioned rats. Selective dopamine lesions were made using 6-OHDA (100 microg, intracisternal) on postnatal day (PD) 5 after desipramine pretreatment (25 mg/kg, s.c.) to protect noradrenergic neurons. Rats were given test agents or vehicle, intraperitoneally, before recording motor activity for 90 min at PD 25 in a novel environment. d-Methylphenidate stimulated motor activity in sham controls and antagonized hyperactivity in lesioned rats. Selective DA transport inhibitors GBR-12909 and amfonelic acid greatly stimulated motor activity in sham control subjects, too, but did not antagonize hyperactivity in lesioned rats. In contrast, all selective 5-HT and NE transporter antagonists tested greatly reduced motor hyperactivity in 6-OHDA lesioned rats but did not alter motor activity in sham controls. The findings indicate that behavioral effects of stimulants in young rats with neonatal 6-OHDA lesions may be mediated by release of NE or 5-HT and support interest in using drugs that increase activity of norepinephrine or serotonin to treat ADHD.

Regulation of dopamine quantal size in midbrain and hippocampal neurons

Since the pioneering work of Bernard Katz and his colleagues decades ago, neurotransmitter quantal size (defined as the number of neurotransmitter molecules released by a single synaptic vesicle during exocytosis) is often modeled as invariant. This assumption had tremendous implications for basic research on synaptic plasticity. For instance, it focused attention on the postsynaptic rather than the presynaptic component in studies of learning and memory (the field of long-term potentiation comes to mind as the best example). Furthermore, this assumption somehow ‘spilled over’ onto studies of monoamine neurotransmitters, which apparently use diffusion and slow action to exert their modulatory effects, in contrast to the fast acting neurotransmitters studied by Katz. Consequently, research on dopamine-related diseases (e.g. psychotic and movement disorders) did not pay as much attention to presynaptic mechanisms that regulate dopamine release, as to postsynaptic receptor action. Part of the problem, of course, has been the lack of technology to directly measure quanta from presynaptic sites and the obligatory reliance on measurements of miniature postsynaptic potentials (minis) for reaching conclusions about presynaptic quantal events. Due to the introduction of the carbon fiber amperometric microelectrode in tissue electrophysiology, initially by Francois Gonon (University of Bordeaux) and then by Mark Wightman (University of North Carolina), we were able to directly measure dopamine quanta from neurites of cultured midbrain dopamine neurons by amperometry. This was the first approach to provide direct measurement of the number of molecules and kinetics of presynaptic quantal release from CNS neuronal terminals. The interventions altering dopamine quantal size are so far the following. (1) Alteration of neurotransmitter synthesis—an increase of cytosolic dopamine availability (e.g. by exposure to l-DOPA) increases quantal size and a decrease of cytosolic dopamine by D2 autoreceptor activation (by quinpirole) decreases quantal size. (2) Modulation of vesicle transmitter transporter activity—overexpression of the neuronal vesicular monoamine transporter VMAT2 increases dopamine quantal size. The reduction or elimination of VMAT2 protein in mice significantly hampers or eliminates monoamine release. (3) Reuptake blockade—cocaine and amfonelic acid are dopamine reuptake blockers which reduce quantal size independently of D2-related effects. (4) Changes in transvesicular pH gradient—neuronal stimulation apparently leads to vesicular acidification via the activation of chloride channels on the vesicular membrane and increased quantal size. (5) Fusion pore kinetics—a vesicle undergoing exocytosis may discharge only part of its neurotransmitter content before recycling. Plasticity of the fusion pore shape may, therefore, be a crucial determinant of quantal size. Other possible sources of variability in quantal size are altered transmitter degranulation and changes in synaptic vesicle volume. We suggest that plasticity in dopamine quantal seems likely to be involved in both normal synaptic modification and disease states.

A comparison of the patterns of striatal Fos-like immunoreactivity induced by various dopamine agonists in rats

In contrast to the highly patchy patterns of Fos-like immunoreactivity seen in the rostral striatum after administration of a number of dopamine agonists, the monoamine uptake blocker cocaine has been reported to produce a relatively homogenous pattern of gene expression. In the current study we extended these observations by using a quantitative technique to demonstrate that while amphetamine and apomorphine produce patchy striatal Fos expression, the selective dopamine uptake inhibitors amfonelic acid, nomifensine and GBR-12909 all, like cocaine, produce near random patterns of gene expression. These findings suggest that the production of relatively ‘non-patchy’ patterns of immediate early gene expression may be a general property of dopamine transport inhibitors unrelated to any unique pharmacological properties of cocaine.

Effects of Dopamine Agonists on Appetitive and Consummatory Male Sexual Behavior in Japanese Quail

The effects of pharmacological manipulations of dopaminergic transmission on appetitive and consummatory aspects of male sexual behavior were investigated in castrated male Japanese quail treated with exogenous testosterone. Appetitive male sexual behavior was assessed by measuring a learned social proximity response and consummatory behavior was assessed by measuring copulatory behavior per se. The nonselective dopamine receptor agonist, apomorphine, inhibited in a dose-dependent manner both components of male sexual behavior. Two indirect dopamine agonists were also tested. Nomifensine, a dopamine re-uptake inhibitor, decreased appetitive sexual behavior but increased the frequency of mount attempts, a measure of consummatory sexual behavior. Amfonelic acid, a compound that enhances dopaminergic tone by a complex mechanism, increased aspects of both appetitive and consummatory behaviors. These data suggest that, in quail, as in rodents, increases in dopaminergic tone facilitate both appetitive and consummatory aspects of male sexual behavior. Apomorphine may be inhibitory in quail because it acts primarily on D2-like receptors, unlike in rats, where it stimulates sexual behavior and acts primarily on D1-like receptors at low doses but interacts with D2-like receptors at higher doses. This is supported by the observation that stereotyped pecking, a behavior stimulated selectively in quail by D2 agonists, was increased by apomorphine but not by the two indirect agonists. The observed partial dissociation between the effects of these dopaminergic agonists on appetitive and consummatory sexual behaviors suggests that these two components of male sexual behavior may be controlled by the action of dopamine through different neuronal systems.

A direct dopaminergic control of aromatase activity in the quail preoptic area

In the quail preoptic area (POA) anatomical and pharmacological data suggest that catecholamines may be implicated in the control of testosterone (T) aromatization into estrogens. The biochemical mechanism(s) mediating this control of the enzyme activity is (are) however unexplored. The present studies were carried out to investigate whether the catecholamines, dopamine (DA) and norepinephrine (NE) are able to directly affect aromatase activity (AA) measured during in vitro incubations of POA homogenates. AA was quantified in the POA-hypothalamus of adult male Japanese quail by measuring the tritiated water production from [1β- 3H]-androstenedione. Enzyme activity was linear as a function of the incubation time and of the protein content of homogenates. It exhibited a typical Michaelis-Menten kinetics, with an apparent K m of 2.8 nM and a V max of 266.6 fmol h −1 mg wet weight −1. AA was then measured at a substrate concentration of 25 nM in the presence of catecholamines and some of their receptor agonists or antagonists, at two concentrations, 10 −3 and 10 −6 M. Norepinephrine and prazosin (α1-adrenergic antagonist) had no or very limited effects on AA at both concentrations. In contrast, DA and some D1 and/or D2 receptor agonists (apomorphine[ D1 D2 ], SKF-38393 [D1] and RU-24213 [D2]) depressed AA by 40 to 70% at the 10 −3 M concentration. One D2 receptor antagonist also produced a major inhibition of AA (sulpiride) while other antagonists either had no significant effect or only produced moderate decreases in enzyme activity (SCH-23390 [D1], spiperone [D2], pimozide [D2]) as did two DA indirect agonists, amfonelic acid and nomifensine. The inhibitory effect of the agonists was not antagonized by the less active antagonists, SCH-23390 [D1] or spiperone [D2]. Taken together these results suggest that the inhibitory effects do not involve specific binding of DA or its agonists/antagonists to dopaminergic receptors mediating changes in cAMP concentration. This conclusion is also supported by the observation that addition of dibutyryl cAMP did not change brain AA. It appears more likely that DA and dopaminergic drugs inhibit AA by a direct effect on the enzyme, as suggested by the competitive nature of DA and SKF-38393 inhibition of AA ( K i's of 59 and 84 μM, respectively). The functional significance of this effect should still be demonstrated but this mechanism may represent an important physiological pathway through which neurotransmitters could rapidly affect steroid-dependent processes such as the neural synthesis of estrogens. This would provide a mean by which environmental stimuli could affect reproductive behavior and physiology.

A rat model of distractibility: effects of drugs modifying dopaminergic, noradrenergic and GABAergic neurotransmission.

A procedure for analyzing effects of drugs on distractibility is proposed. Rats are trained to traverse a straight runway with a sucrose solution as reinforcement. Once the response has been acquired, an additional runway ending in an empty box is connected. The time spent investigating this additional runway is the measure of distractibility. Amphetamine, 1 mg/kg i.p., increased distractibility. In rats that were never reinforced, amphetamine at a dose of 1 mg/kg reduced the time spent in the additional runway. This shows that the effects of amphetamine in the reinforced animals cannot be interpreted as enhanced exploration. Furthermore, the benzodiazepines diazepam (2 and 4 mg/kg, i.p.) and chlordiazepoxide (2.5, 5 and 10 mg/kg, i.p.), known to enhance exploration of novel environments, did not affect the time spent in the additional runway in sucrose-reinforced animals. It was concluded that the procedure indeed is a model of distractibility. The dopamine antagonist cis(Z)-flupenthixol, at a dose of 0.25 mg/kg, i.p., blocked the effects of amphetamine, 1 mg/kg. Flupenthixol itself, in doses of 0.25 and 0.5 mg/kg, did not affect the time spent in the additional runway. This suggests that enhanced dopaminergic activity indeed is responsible for the effects. This proposal is further supported by experiments showing that the noradrenaline precursor dihydroxyphenylserine (10 mg/kg + carbidopa, 50 mg/kg, both i.p.) and the noradrenergic neurotoxin DSP4 (50 mg/kg, i.p.) had no effect on distractibility. Moreover, amfonelic acid, a dopamine releaser with slight or no effect on noradrenergic neurotransmission, had effects very similar to those of amphetamine when given in doses of 0.25 and 0.5 mg/kg, i.p. A lower dose, 0.125 mg/ kg, was ineffective. Taken together, these data suggest that enhanced dopaminergic neurotransmission increases distractibility in the rat. However, both amphetamine and amfonelic acid may stimulate serotonin release. Until serotonergic drugs have been tested, a contribution of this transmitter cannot be ruled out. The distraction procedure may constitute an animal model of some kinds of disordered information processing.

Interactions between dopamine and GABA in the control of ambulatory activity.

Ambulatory activity of male rats was quantified in an open field. The subjects were treated with DL-amphetamine and amfonelic acid alone or combined with the GABA transaminase inhibitors gamma-acetylen GABA (GAG) and sodium valproate as well as with the GABAA agonist THIP and the GABAB agonist baclofen. Subeffective doses of the GABAergic drugs did not modify the effects of moderate doses of the dopaminergic stimulants whereas effective doses continued to reduce ambulatory activity just as in the absence of dopaminergic activation. When DL-amphetamine or amfonelic acid were administered in doses that strongly enhanced ambulatory activity, doses of the GABAergic drugs that were inhibitory in the absence of dopaminergic stimulation were no longer effective. The mixed D1/D2 dopamine antagonist pimozide, the D1 antagonist SCH 23390 and the D2 antagonist sulpiride were then combined with subeffective doses of the GABA agonists. GAG, sodium valproate and baclofen were potentiated by pimozide and SCH 23390 but not by sulpiride. THIP was ineffective. These data show that GABAergic drugs had a reduced effect after stimulation of dopaminergic neurotransmission. On the other hand, when dopamine D1 receptors were blocked, nonselective GABA agonists and the GABAB agonist baclofen were potentiated. This was not the case for the GABAA agonist THIP, suggesting that the GABAA receptor is of slight importance for the interactions between GABA and dopamine in the control of ambulatory activity. No potentiation of GABAergic agonists was obtained after treatment with a dopamine D2 antagonist.