Amfonelic Acid Research Articles

Effect of repeated methamphetamine pretreatment on freezing behavior induced by conditioned fear stress

The present study examined the effect of methamphetamine (MA) pretreatment on conditioned fear stress in male Wistar-King rats. Rats received MA or the vehicle according to the repeated escalating dose schedule (1.25, 2.5, 3.75, and 5 mg/kg SC × 2/every other day for a week). After a 5-day drug abstinent period, the rats were exposed to conditioned fear stress (exposure to an environment paired previously with foot shock). Repeated but not single MA pretreatment significantly increased conditioned freezing behavior, suggesting that rats previously exposed to chronic MA are hypersensitive to subsequent stress than control rats. Repeated MA treatment did not decrease basal dopamine or serotonin concentrations in the brain. Furthermore, coadministration of MK-801 (noncompetitive NMDA antagonist), amfonelic acid (dopamine reuptake inhibitor), or fluoxetine (serotonin reuptake inhibitor) with MA did not alter the enhanced freezing behavior. Taken together, it seems that MA-induced hypersensitivity to stress is not due to the neurotoxic effect of MA. Coadministration of nemonapride (D 2/3/4 antagonist) with MA prevented the MA-induced increase in freezing. These results suggest that D 2/3/4 receptors play an important role for MA-induced enhancement of fear or anxiety.

Central nervous stimulants facilitate sexual behavior in male rats with medial prefrontal cortex lesions

Male rats with lesions of the cerebral cortex near the midline in the frontal region destroying most of the cingulate cortex and producing some dammage to adjacent frontal areas have very long mount and intromission latencies. Otherwise their sexual behavior is essentially normal. The dopamine releasers amfonelic acid, 0.5 mg/kg, and amphetamine, 1 mg/kg, reduced the mount and intromission latencies in males with such lesions. Caffeine, 30 mg/kg, had similar effects. None of the drugs modified sexual behavior in intact males. It has been suggested that medial prefrontal lesions reduce the animal's reactivity to environmental stimuli, and hence renders the activation of sexual behavior difficult. Present results show that stimulant drugs are capable of compensating for this reduced reactivity. The possible mechanisms behind this effect are discussed. The lesion had also a small but consistent effect on the intromission ratio, suggesting some motor impairment. The effect on intromission ratio was not reduced by the drugs, suggesting that the lesion's motor consequences are mediated by mechanisms different from those controlling behavioral reactivity. The noradrenaline precursor dl-threo-dihydroxyphenylserine, 10 mg/kg, in combination with carbidopa, 50 mg/kg, increased mount and intromission latencies in both intact and lesioned males. Thus, activation of noradrenergic neurotransmission had effects opposite to those found after activation of dopaminergic transmission. Noradrenergic stimulation cannot, therefore, be important for the effects of amphetamine or amfonelic acid.

Effects of various dopamine uptake inhibitors on striatal extracellular dopamine levels and behaviours in rats

In vivo central effects of some dopamine uptake inhibitors were evaluated in both brain microdialysis and behavioural studies in rats, and compared with their in vitro affinities to dopamine uptake sites. IC 50 values of GBR12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine), diclofensine, mazindol, amfonelic acid and nomifensine for inhibiting 1 nM [ 3H]GBR12935 (1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine) binding to rat striatal membrane were 7.0, 36, 81, 187 and 290 nM, respectively. In the brain microdialysis study, dopamine levels in the striatal dialysates were increased to 16.3- (GBR12909), 14.1- (nomifensine), 4.8- (diclofensine) and 1.9-fold (amfonelic acid) the respective basal levels 40–60 min after i.p. administration (0.1 mmol/kg) and thereafter decreased slowly but remained at the elevated levels for a further 3 h, while mazindol gradually increased dopamine levels though less pronouncedly than others (1.7-fold 200 min after administration). Remarkable and comparable stereotyped behaviours (licking and forepaw treading) were continuously observed at least for 3 h after administration of GBR12909, nomifensine and amfonelic acid, while stereotypies induced by diclofensine and mazindol were moderate and marginal, respectively. In vivo potencies of dopamine uptake inhibitors to increase the extracellular dopamine levels in the striatum tended to correlate with their in vitro affinities to dopamine uptake sites except in the case of nomifensine, and correlated significantly with their potencies to induce stereotyped behaviours except in the case of amfonelic acid. Based on these findings, pharmacological characteristics of these dopamine uptake inhibitors are discussed.

Fluoxetine at anorectic doses does not have properties of a dopamine uptake inhibitor.

Although fluoxetine is a highly selective inhibitor of serotonin uptake in vitro and in vivo, some investigators have suggested that dopamine uptake inhibition may contribute to anorectic actions of fluoxetine. The present experiments were done to determine fluoxetine's effects in some animal protocols in which dopamine uptake inhibitors have characteristic actions. Mazindol prevented the depletion of striatal dopamine and its metabolites by amphetamine in iprindole-pretreated rats, but fluoxetine had no effect. Mazindol prevented the depletion of striatal dopamine and its metabolites by 6-hydroxydopamine injected intracerebroventricularly into rats, but fluoxetine had no effect. Mazindol enhanced the elevation of 3,4-dihydroxyphenylacetic acid concentration in rat brain after spiperone injection, but fluoxetine did not cause that effect. Fluoxetine did not mimic amfonelic acid in antagonizing the retention of alpha-methyl-m-tyramine invant striatum after the injection of alpha-methyl-m-tyrosine. These results show that fluoxetine, at doses that are effective in blocking the serotonin uptake carrier and causing anorexia, does not block the dopamine uptake carrier.

The effects of amfonelic acid, a dopamine uptake inhibitor, on methamphetamine-induced dopaminergic terminal degeneration and astrocytic response in rat striatum

Administration of methamphetamine (MA) induces degeneration of dopaminergic nerve terminals and astrogliosis, such as hypertrophy and an increase in apparent number, in the neostriatum. In this experiment adult rats were treated with MA (10 mg/kg, i.p.) 4 times in one day at 2 h intervals. Amfonelic acid (AFA), a dopamine reuptake inhibitor, was administered (20 mg/kg, i.p.) at the same time the last MA dose was given. Three days later, dopaminergic terminals and astrocytes were examined immunohistochemically and the contents of striatal dopamine and its metabolites were analyzed by HPLC. The results showed that MA-induced the typical depletion of dopaminergic terminals, reduction of dopamine content and astrogliosis in the neostriatum. AFA treatment completely prevented the effects of MA on the dopaminergic system, both morphologically and biochemically. However, the reaction of astrocytes remained in the region where the most severe depletion dopaminergic terminals was seen in MA treated animals (ventral-lateral portion of neostriatum). The results support the concept that the dopamine transporter is involved in MA-induced dopaminergic nerve terminal degeneration. The results also indicate that blocking the dopamine transporter cannot completely prevent the reaction of astrocytes in the neostriatum, which indicates that the astrocytic reaction can be induced by factors other than degeneration of dopaminergic terminals in this region. Based on these and other data, it is hypothesized that MA may cause degeneration of corticostriatal glutamate pathways and this effect may be responsible for the astrogliosis in MA-AFA treated animals.

Prenatal exposure to cocaine: Effects on aggression in sprague‐dawley rats

Social/aggressive behavior in adult rat offspring (beginning at postnatal Day 180) prenatally exposed to saline, cocaine, or amfonelic acid (AFA) was examined. Pregnant rats received injections of 15 mg/kg of cocaine, or 0.9% saline twice daily, s.c., or on 2 consecutive days at 4-day intervals, or 1.5 mg/kg amfonelic acid daily throughout gestational Days 1-20. Frequency, duration, and latency of 11 social/aggressive behaviors were recorded for two 15-min sessions during which a smaller male intruder replaced an ovariectomized female in the resident's home cage. Subjects received a s.c. saline injection before Session 1 and 2.0 mg/kg of gepirone, a 5HT1a partial agonist, prior to Session 2. Prenatal cocaine treatment resulted in alterations of aggressive behavior. Aggressive behavior was reduced by gepirone in all groups but to a lesser extent in the AFA group.

Dopamine agonists and stress produce different patterns of Fos-like immunoreactivity in the lateral habenula

In rats treated systemically with either amphetamine, amfonelic acid or apomorphine, large numbers of cells displaying Fos-like immunoreactivity (FLI) could be seen in the lateral zone of the lateral habenula. The induction of FLI by amphetamine could be blocked either by pretreatment with haloperidol or by 6-hydroxydopamine lesions of ascending dopamine fibers at the level of the lateral hypothalamus. In contrast, a variety of stressors selectively induced FLI in the most medial portion of the lateral habenula. These findings support the concept of a functional differentiation of the medial and lateral regions of the lateral habenula and provide further evidence for involvement of the habenula in the circuitry of the basal ganglia.

Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers.

Narcolepsy is currently treated with anti-depressants to control REM-related symptoms such as cataplexy and with amphetamine-like stimulants for the management of sleepiness. Both stimulant and antidepressant drugs presynaptically enhance monoaminergic transmission but both classes of compounds lack pharmacological specificity. In order to determine which monoamine is selectively involved in the therapeutic effect of these compounds, we examined the effects of selective monoamine uptake inhibitors and release enhancers on cataplexy using a canine model of the human disorder. A total of 14 compounds acting on the adrenergic (desipramine, nisoxetine, nortriptyline, tomoxetine, viloxazine), serotoninergic (fenfluramine, fluoxetine, indalpine, paroxetine, zimelidine) and dopaminergic (amfonelic acid, amineptine, bupropion, GBR 12909) systems were tested. Some additional compounds interesting clinically but with less pharmacological selectivity, i.e., cocaine, dextroamphetamine, methylphenidate, nomifensine and pemoline, were also included in the study. All compounds affecting noradrenergic transmission completely suppressed canine cataplexy at low doses in all dogs tested, whereas compounds which predominantly modified serotoninergic and dopaminergic transmission were either inactive or partially active at high doses. Our results demonstrate the preferential involvement of adrenergic systems in the control of cataplexy and, presumably, REM sleep atonia. Our findings also demonstrate that canine narcolepsy is a useful tool in assessing the pharmacological specificity of antidepressant drugs.

Changes in dopamine, serotonin and their metabolites in discrete brain areas of rat offspring after in utero exposure to cocaine or related drugs.

The concentrations of dopamine (DA), serotonin (5HT) and their metabolites were quantified in 5 brain areas of rats exposed to saline, cocaine (15 mg/kg b.i.d.), amitriptyline (10 mg/kg), or amfonelic acid (AFA, 1.5 mg/kg) throughout gestation. Male pups from 3 similarly treated dams were fostered to 2 surrogate dams. The process of breeding and rearing was repeated 4 times with new dams to build the groups to 4-12, since only one pup per litter was used for any one measurement. AFA was used to mimic the dopamine (DA) uptake blockade and stimulant properties of cocaine and amitriptyline was used to mimic the other pharmacological effects of cocaine. At postnatal days (PND) 30, 60, and 180, one pup per litter was removed for HPLC analysis of monoamines. A second pup received 0.3 mg/kg haloperidol, catalepsy assessed after 1 hr, and the brain used for analysis. The cataleptic response to haloperidol was unaffected by any prenatal treatment. The striatum from PND 30 cocaine rats had decreased levels of DA without a decrease in DA metabolites. At PND 60 in cocaine exposed rats, DA and DOPAC concentrations were increased, and 5HT levels were decreased in the striatum. The amitriptyline-exposed group exhibited decreased 5HT and 5-HIAA levels in the striatum. The hypothalamus of the cocaine group had lower levels of 5-HIAA, and other brain areas had a trend for lower levels of 5HT and 5-HIAA. At PND 180, DOPAC was increased in the striatum and prefrontal cortex of the cocaine group. Haloperidol-induced altered monoamine metabolism was unaffected by any prenatal treatment at any age. These data suggest that age-related changes in the DA and 5HT neurotransmission systems occur in rats exposed prenatally to cocaine. However, the ability of the dopaminergic system to respond to a challenge by a DA receptor blocker is unaltered by these in utero treatments.

Simultaneous real-time correlation of drug effects on dopamine efflux and uptake in rat striatal slices.

An increasing body of evidence suggests that striatal dopamine (DA) terminal areas in the rat (the caudate-putamen (CPu) and nucleus accumbens (NAc)) differ in their DA transport sites [ l ] and possibly DA storage pools [2]. We therefore compared the effects of various drugs acting at each site on the efflux and uptake of DA in CPu and NAc. We used fast cyclic voltammetry (FCV) [3] to electrochemically monitor DA efflux and uptake half-life on a sub-second time scale in these two brain areas. The DA uptake blockers GBR 12935 (GBR: 0.2 pM) and bupropion (Bup: 1 pM), the psychomotor stimulant amfonelic acid (AFA: 0.1 pM) and a putative DA mobiliser (the M2 metabolite of nomifensine (M2: 0.5 pM) [4]) were used in order to probe these suggested differences. Their effects on DA efflux and uptake half-life were measured simultaneously at each site. All experiments were conducted in 350 pm brain slices from male Wistar rats (100-1509) superfused with artificial CSF at 32°C. NAc slices were taken at approximately +10.5 mm vs the interaural line [5] and recordings made in the core of the nucleus. CPu slices were taken from approximately +9.2 mm and recordings made from the dorsolateral region. DA efflux was evoked using alternate single pulse ( lp ) and 5 pulse (5p) trains (0.1 ms, 50 Hz, 10 mA, every 10 min) via a bipolar tungsten electrode. FCV was used to monitor DA efflux and subsequent reuptake at a carbon fibre microelectrode sampling at 2 Hz. Drugs were administered after the third 5p stimulation train and were allowed to equilibrate for two hours. DA efflux and uptake half-life after this period was expressed as a percentage of the mean of the pre-drug period. The data on l p stimulations is not reported here. Figure 1 shows the effects of the drugs on DA efflux and uptake half-life in the CPu. It can be seen that M2, GBR and AFA produced significant increases in efflux in the CPu. Only GBR and AFA had a significant effect on uptake half-life.

Locomotor stereotypy is produced by methylphenidate and amfonelic acid and reduced by haloperidol but not clozapine or thioridazine

In addition to its well-known behavioral effects in rats, amphetamine also produces patterned locomotion (referred to below as locomotor stereotypy) in an open field. Locomotor stereotypy may be mediated by different mechanisms than those mediating the better-known behavioral effects of amphetamine. To determine whether the ability to produce locomotor stereotypy is an exclusive property of amphetamine or is a property of many amphetamine-like stimulants, several doses of methylphenidate and amfonelic acid were tested. The ability of both atypical and typical neuroleptics to block amphetamine-induced locomotor stereotypy was also tested. Both amfonelic acid and methylphenidate produced some degree of locomotor stereotypy. In addition, amphetamine-induced locomotor stereotypy was reduced by haloperidol but not by clozapine or thioridazine. These data suggest that locomotor stereotypy is more closely related to focused stereotypy than to hyperlocomotion.

Regulation of Dopamine Receptors by Bupropion: Comparison with Antidepressants and CNS Stimulants

Acute treatment of rats with the antidepressant bupropion increased [3H]spiperone binding to D2 receptors in vivo. This dose- and time-dependent effect was greatest in striatum and minimal in cerebellum and pituitary. A parallel behavioral stimulation occurred in the same rats. Among 21 antidepressants and CNS stimulants tested, only those that activate dopamine (DA) transmission had similar effects: nomifensine, amineptine, methylphenidate, D-amphetamine, amfonelic acid, cocaine, benztropine and GBR 12909. Decreasing DA transmission with reserpine plus alpha-methyl-p-tyrosine prevented the action of bupropion. Finally, bupropion was inactive in vitro and ex-vivo. Therefore, we propose that bupropion and other DA-enhancing agents modify the characteristics of [3H]spiperone binding through the intervention of a dynamic regulation of the D2 receptors by the neurotransmitter itself.

Interaction of amfonelic acid with antipsychotic drugs on dopaminergic neurons.

The effects of two inhibitors of dopamine (DA) reuptake, amfonelic acid and GBR 12909, on the clozapine- and haloperidol-induced increases in DA synthesis, release, and metabolism were investigated in the rat. In the striatum, as well as in the nucleus accumbens, the haloperidol-induced increase in tissue concentrations of dihydroxyphenylacetic acid (DOPAC) or the accumulation of dihydroxyphenylalanine (DOPA) was potentiated or unaltered, respectively, in rats treated with amfonelic acid. In contrast, amfonelic acid attenuated the stimulatory effects of clozapine on DOPAC concentrations and DOPA accumulation in both brain regions. GBR 12909 also differentially affected the haloperidol- and clozapine-induced increases in DOPAC concentrations. However, the clozapine-induced increase in DOPA accumulation in the median eminence was not significantly altered by treatment with amfonelic acid. The haloperidol-induced increase in the extracellular concentrations of DA and DOPAC in the striatum also was potentiated by amfonelic acid, whereas the increase elicited by clozapine was suppressed. The increase in extracellular DA produced by the administration of morphine or the coadministration of ritanserin, a 5-HT2 antagonist, and haloperidol also was potentiated by amfonelic acid. The ability of amfonelic acid to distinguish between the actions of clozapine and haloperidol on nigrostriatal and mesocorticolimbic DA neurons does not appear to be related to differences in the effects of the drugs on DA autoreceptors or 5-HT2 receptors. Moreover, the mechanism through which clozapine activates tuberoinfundibular DA neurons may differ from that which is involved in the activation of nigrostriatal or mesocorticolimbic DA neurons.

Prenatal exposure to cocaine I: Effects on gestation, development, and activity in Sprague-Dawley rats

Spermpositive Sprague-Dawley rats received one of four treatments for 20 days beginning within 24 hours of conception. One group received subcutaneous injections of 15 mg/kg cocaine twice daily (Cocaine-D); a second group received 15 mg/kg cocaine twice daily for two consecutive days at 5-day intervals (Cocaine-I); a third group received normal saline twice daily (Saline); and a fourth group received 1.5 mg/kg amfonelic acid (AFA), a dopamine reuptake inhibitor, once daily. Cocaine-D, Cocaine-I, and AFA dams were fed ad lib. An attempt was made to pair-feed the Saline dams with the Cocaine-D dams; however, the Saline dams did not eat as much as the Cocaine-D dams which resulted in dams in all groups essentially eating ad lib. The Cocaine-D pups showed a slightly delayed righting behavior and neophobia at 30 days of age, as evidenced by hypoactivity during the first 15 min of a 6-h activity test. The Cocaine-I pups were hypoactive during the 3-h dark phase of the 6-h activity test when tested at 30 days of age. These effects did not occur in the offspring exposed to AFA, a potent dopamine uptake inhibitor and CNS stimulant which indicate that one or more other sites for cocaine action may combine for its effects on the developing fetus.

Prenatal exposure to cocaine II: Effects on open-field activity and cognitive behavior in Sprague-Dawley rats

Pregnant rats received subcutaneous injections of 15 mg/kg of cocaine twice daily (Cocaine-D), twice daily for two consecutive days at 5-day intervals (Cocaine-I), 0.9% saline (Saline) twice daily, or 1.5 mg/kg amfonelic acid (AFA) daily from gestational days 1–20. Offspring were tested for: rates of spontaneous alternation at postnatal days (PND) 32, 35, 40, and 45; acquisition and retention performance on a water maze task beginning at PND 30 and 60; entrance into and activity in an open-field apparatus at PND 60 and 180. The Cocaine-D offspring were less likely than Control offspring to enter the open field when tested at PND 60. The Cocaine-I offspring were hyperactive in the open-field apparatus when tested at PND 60. The drug treated offspring did not differ from the Saline control animals on all other measures. The failure of the Cocaine-D animals to enter the open field is consistent with neophobic behavior that we have observed before in rats exposed in utero to cocaine.

Activity of two primary human metabolites of nomifensine on stimulated efflux and uptake of dopamine in the striatum: In vitro voltammetric data in slices of rat brain

Several antidepressant drugs have active metabolites. This study sought to establish whether two of the main human metabolites of nomifensine (M2: 8-amino-2-inethyl-4-(3-methoxy-4-hydroxyphenyl)-1, 2,3,4-tetrahydroisoquinoline and M3: 8-amino-2-methyl-4-(3-hydroxy-4-methoxyphenyl)-1, 2,3,4-tetrahydroisoquinoline) had actions on the release and uptake of dopamine (DA). Experiments were conducted in superfused striatal slices of the rat. The efflux of DA was evoked by single constant-current pulses (0.1 msec, 10mA) and trains (20 pulses, 50 Hz), applied alternately every 10 min and monitored using fast cyclic voltammetry at carbon fibre microelectrodes. Nomifensine (5 × 10 −7 M) significantly increased the efflux of DA on both single pulse (302% of pre-drug) and train stimuli (529%) and increased the uptake half-life (178% of pre-drug). The M2 metabolite had similar potency on the efflux of DA (260%: pulse, 570%: train) but without any effect on uptake of DA. Nomifensine and M2 increased efflux of DA more on trains than on single pulses. The M3 metabolite (5 × 10 −7 M) increased efflux of DA only moderately. The selective blocker of the uptake of DA, GBR 12909 (3 × 10(−7) M), increased efflux of DA on single pulse (430%) and train stimuli (645%) and blocked uptake of DA ( t 1 2 : 292% ). Amfonelic acid, the psychomotor stimulant (10 −7 M) blocked uptake of DA ( t 1 2 : 234% ) and elevated efflux of DA to a greater extent on trains (1007%) than on single pulses (495%). It is concluded that the means by which M2 increased the efflux of DA is independent of blockade of uptake. The greater effect on trains than single pulses is consistent with mobilisation of the storage pool of DA, since it also occurred with amfonelic acid but not with the pure uptake blocker, GBR 12909.

A pharmacological comparison of [ 3H]GBR12935 binding to rodent striatal and kidney homogenates: Binding to dopamine transporters?

Binding of [ 3H]GBR12935 to homogenates of mouse and rat striatum and kidney was studied [ 3H]GBR12935 bound to both tissue preparations with high affinity (mouse striatum K d = 2.4±0.4 nM, n = 4; mouse kidney K d = 3.8±0.9 nM, n = 4), in a saturable (striatal B max = 1.5±0.4 pmol/mg protein; kidney B max = 4.9±0.5 pmol/mg protein) and reversible manner. Saturation experiments revealed the presence of a single class of high affinity binding sites in both tissues of both species. Mouse kidney appeared to possess a greater density of [ 3H]GBR12935 binding sites than the striatum while the reverse situation prevailed for the rat. Although two dopamine uptake inhibitors, namely GBR12909 and benztropine, displaced [ 3H]GBR12935 binding from striatal and kidney homogenates with a similar affinity in both tissues of these species, unlabelled mazindol, (±)cocaine, nomifensine and amfonelic acid were significantly ( P < 0.001–0.02) more potent inhibitors of [ 3H]GBR12935 binding in the striatum than in the kidney. While the pharmacological profile of [ 3H]GBR12935 binding in the rodent striatum compared well with that of the dopamine transporter reported previously, the pharmacology in the kidney was considerably different to that in the striatum. GBR12909 (1–30 mg/kg, i.p.), a close analog of GBR12935, induced significant antidiuretic and antinatriuretic effects in spontaneously hypertensive rats. These data suggest that while [ 3H]GBR12935 labels the dopamine uptake sites in the brain, it does not appear to label similar sites in the kidney. The mechanism of action of GBR12909 on sodium and water excretion remains to be determined.

Differential effects of amfonelic acid on the haloperidol- and clozapine-induced increase in extracellular DOPAC in the nucleus accumbens and the striatum.

This study compares the effects of the nonamphetamine stimulant amfonelic acid on the increase in extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) induced by haloperidol and clozapine in the nucleus accumbens and the striatum of anaesthetized rats. DOPAC was simultaneously recorded in both regions using differential pulse voltammetry with electrically pretreated carbon fibre electrodes. Amfonelic acid (2.5 mg/kg s.c.) did not alter basal striatal DOPAC but produced a significant reduction in extracellular DOPAC in the nucleus accumbens. Haloperidol (1 mg/kg s.c.) increased extracellular DOPAC in both regions. When amfonelic acid was injected 5 min before haloperidol, the increase in DOPAC was potentiated in both the nucleus accumbens and the striatum but with a greater effect in the striatum. Clozapine (30 mg/kg i.p.) increased extracellular DOPAC in both regions, an effect partially attenuated by amfonelic acid in both regions but to a greater extent in the striatum. When ritanserin (5 mg/kg i.p.), a serotonergic antagonist (5-HT-2), was co-administered with haloperidol, the potentiation by amfonelic acid of the increase in extracellular DOPAC induced by haloperidol was attenuated in both the nucleus accumbens and the striatum. The present results confirm that amfonelic acid can be used to discriminate neurochemically between haloperidol and clozapine in vivo. The effects of amfonelic acid on the neuroleptic-induced changes in extracellular DOPAC were greater in the striatum than the nucleus accumbens. These results further demonstrate that both neuroleptics increase dopamine metabolism in the two brain regions but by different mechanisms, supporting the view that the regulation of dopamine metabolism differs in the two regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of ritanserin on the interaction of amfonelic acid and neuroleptic-induced striatal dopamine metabolism

In the present study we evaluated the interaction of amfonelic acid (AFA) with the typical neuroleptic haloperidol and the atypical antipsychotic clozapine on rat striatal dopamine metabolism in the absence or presence of the 5HT 2 receptor antagonist ritanserin. In the absence of ritanserin, AFA significantly enhanced haloperidol stimulated 3,4- dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) accumulation by 36% and 37% respectively above that produced by haloperidol alone. This effect is believed to be due to AFA's ability to facilitate dopamine release produced by the potent haloperidol-induced increase in nigrostriatal impulse flow. In contrast, AFA did not potentiate the ability of clozapine to stimulate DOPAC or HVA. This lack of potentiation could be explained by clozapine's known potent 5HT 2 receptor blocking activity attenuating its stimulatory effects on impulse flow. To test this, we combined ritanserin with haloperidol and again studied the interaction with AFA on dopamine metabolism. In the presence of ritanserin, AFA failed to potentiate the effects of haloperidol on DOPAC or HVA accumulation; an effect similar to that seen with clozapine. This result extends the idea that 5HT 2 receptor blockade modulates nigrostriatal dopaminergic neurotransmission.

Long-term consequences of prenatal exposure to cocaine or related drugs: Effects on rat brain monoaminergic receptors

Reports from both this laboratory and others indicate that prenatal exposure of rats to cocaine can produce alterations in development, activity and responses to environmental stimuli. In order to determine a biochemical basis for these effects, radioligand receptorbinding assays for different monoaminergic receptors were performed on rat brain tissues obtained from offspring of dams treated SC with saline, cocaine (15 mg/kg b.i.d.), amitriptyline (10 mg/kg) or amfonelic acid (AFA, 1.5 mg/kg). Male rat pups were fostered by surrogate dams and one rat per litter taken at 30, 60 or 180 days postnatal for determination of striatal and prefrontal cortical D 2 receptors, prefrontal cortical 5HT 2 receptors, cortical alpha 1-, alpha 2-, beta 1- and beta 2-adrenoceptors. Across all drug treatments and times, the only significant change was at 30 days of age when beta,-adrenoceptors were increased 68% in the cocaine exposed pups—a time when these rats show hyperactivity—and at 180 days postnatal when a 20% decrease in DA 2 receptor B max was observed. Also, cortical membrane Mg 2+-dependent Na +,K +-ATPase activities and basal ATPase activities were unaltered by any of the treatments at any of the times. These results suggest that few changes have occurred in monoaminergic receptor sensitivity as a result of the exposure to these drugs during gestation. The behavioral changes that are known to occur following prenatal exposure to cocaine may be due to presynaptic alterations in neurotransmitter function rather than changes in postsynaptic receptors.