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PubMed1986

The effects of d-amphetamine, alpha-flupenthixol, and mesolimbic dopamine depletion on a test of attentional switching in the rat.

A test of attentional switching was devised for the rat in which it obtained sucrose reinforcement by an appropriate nose-poke response that discriminated which of two visual events terminated first, in a specially designed chamber. The effect of mesolimbic dopamine depletion (to 20% of control values) produced by infusions of 6-hydroxydopamine (6-OHDA) into the nucleus accumbens (N. Acc) on stable discrimination was measured alone and in the presence of a range of doses of d-amphetamine (0.4-2.3 mg/kg IP). The 6-OHDA lesion of the N. Acc impaired postoperative performance transiently by reducing choice accuracy and slowing response latency. By post-operative days 12-16, however, performance recovered to control levels and was not differentially affected by a manipulation of task difficulty. d-Amphetamine produced dose-dependent performance impairments, which were antagonised by the 6-OHDA treatment. In a second group of N. Acc lesioned rats, the neuroleptic alpha-flupenthixol (0.1-1.0 mg/kg) led to fewer trials being completed and longer latencies than in the sham-operated control group. The results are discussed in terms of the possible attentional mechanisms underlying the d-amphetamine-induced disruption of performance mediated by the N. Acc and of the implications for psychopathology resulting from possible dysfunction of this region.

Animals↗

PubMed1979

The action of DL-2,4-diaminobutyric acid on the cataleptogenic effects of pilocarpine and alpha-flupenthixol in rats.

The existence of a strionigral GABA-ergic pathway having an inhibitory effect on the nigrostriatal dopaminergic system has been proposed. The work reported in this paper was undertaken to investigate whether modification of the GABA-eric system by the GABA neuronal uptake inhibitor DL-2,4-diaminobutyric acid (DABA) would affect cholinergic (pilocarpine) and/or neuroleptic alpha-flupenthixol (alpha-FPT) induced catalepsy. DABA pretreatment was shown to enhance significantly both alpha-FPT and pilocarpine induced catalepsy. DABA alone had no cataleptic activity. The results are interpreted as supporting the existence of an inhibitory strionigral GABA-ergic pathway.

Aminobutyrates↗

PubMed1980

Further evidence that 3H-cis(Z)flupenthixol binds to the adenylate cyclase-associated dopamine receptor (D-1) in rat corpus striatum.

The proposal that 3H-cis(Z)flupenthixol (3H-FPT) preferentially binds to striatal dopamine receptors associated with adenylate cyclase activity (D-1), distinct from dopamine receptors to which 3H-haloperidol (3H-hal) binds (D-2), has been investigated further. The dopamine agonists bromocriptine and ergotamine were 60-times more potent as displacers of 3H-hal than 3H-FPT binding. Other dopamine agonists (ergometrine, dopamine, apomorphine, 2-amino-6,7-dihydroxy-tetralin (ADTN), and ergocornine) also shared this profile, although a smaller ratio was found for these compounds. Substituted benzamides (clebopride greater than sultopride greater than sulpiride greater than metoclorpramide greater than tiapride) displace 3H-hal but have only a very slight displacing effect towards 3H-FPT, and did not inhibit dopamine-stimulated adenylate cyclase activity. The same pattern is shared by oxiperomide and molindone. Together, these results support the idea that 3H-FPT labels another class of dopamine receptors than does 3H-hal, and that the former class most likely is associated with adenylate cyclase.

Adenylyl Cyclases↗

PubMed1983

Dissociable effects of d-amphetamine, chlordiazepoxide and alpha-flupenthixol on choice and rate measures of reinforcement in the rat.

The role of reinforcers in influencing choice was studied by use of a schedule that included a random intermixing of reinforced and explicitly non-reinforced components. The just-reinforced response had a high likelihood of being repeated (win-stay), although there was no differential reinforcement for doing so, whereas responses just followed by explicit non-reinforcement had a very low probability of repetition (lose-stay). Non-parametric indices based on the theory of signal detection were used to derive a choice measure of reinforcement which was independent of alterations in average response rate. Treatments with d-amphetamine (0.2-4.5 mg/kg), chlordiazepoxide (0.25-16 mg/kg) and alpha-flupenthixol (0.03-0.6 mg/kg) showed that changes in the choice measure could be dissociated from changes in the response rate. These findings were supported by extinction and satiation tests.

Animals↗

PubMed1981

3H-Flupenthixol binding in post-mortem brains of schizophrenics: evidence for a selective increase in dopamine D2 receptors.

The binding of 3H-cis flupenthixol (3H-FPT) to dopamine receptors in membrane preparations from control subjects and schizophrenics was studied. Using a fixed concentration of 3H-FPT, no differences were observed between controls and all schizophrenics, although 3H-FPT binding was increased in schizophrenics who apparently were drug-free at the time of death. Scatchard analysis of 3H-FPT binding revealed that in drug-treated schizophrenics both the number of binding sites (BM) and the dissociation constant (KD) were increased, whilst in drug-free schizophrenics only the BM was increased. Using domperidone to differentiate 3H-FPT binding to D1 and D2 dopamine sites, it was found that only D2 sites were increased in drug-free schizophrenics. The results are discussed with reference to previous studies on dopamine receptors in schizophrenia, and the effects of neuroleptic treatment. It is suggested that a selective increase in D2 receptors may be associated with the disease process in schizophrenia.

Binding, Competitive↗

PubMed1988

Milk concentrations of flupenthixol, nortriptyline and zuclopenthixol and between-breast differences in two patients.

Flupenthixol (FP), nortriptyline (NT) and zuclopenthixol, (ZCP) were determined in breast milk and plasma from 2 puerperal, lactating women with psychiatric disorders. The milk concentrations were equal to, higher and lower than those in plasma for FP, NT and ZCP, respectively. Variation in milk triglyceride concentration, but not milk pH, could partly explain between-breast differences in the milk concentrations. The study demonstrates the need for appropriate and representative milk sampling procedures. The estimated daily infant exposure averaged 0.5, 2.3 and 0.3% of the corresponding maternal weight related doses of FP, NT and ZCP. FP was also detectable in infant plasma. These drugs are not known to be harmful in small doses to breast-fed infants. However, concern about the effect of dopamine blocking agents on neurobehavioral mechanisms in animals warrants caution. If neuroleptics are required for a long period this risk must be weighed against the benefits of breast-feeding, also considering the psychological effects of the latter.

Adult↗

PubMed1992

Opposite effects of prefrontal cortex and nucleus accumbens infusions of flupenthixol on stimulant-induced locomotion and brain stimulation reward.

Ventral tegmental area (VTA) stimulation produced conditioned place preferences for stimulation-paired environments the magnitudes of which were dose-dependently reduced by systemic application of the dopamine antagonist, haloperidol (0.0, 0.15, 0.3 mg/kg). Bilateral microinjections of cis-flupenthixol (FLU) into the nucleus accumbens (0.0, 1.0, 5.0 or 10.0 micrograms) also resulted in reductions in the size of stimulation-induced place preferences as well as reductions in the magnitude of the hyperlocomotor response to 1.5 mg/kg (s.c.) D-amphetamine. Comparable microinjections of FLU into the medial prefrontal cortex (PFC) produced diametrically opposite effects: the size of VTA stimulation-induced place preferences was either unaffected (1.0 and 5.0 microgram groups) or slightly increased (10 micrograms group) and amphetamine-stimulated hyperlocomotion was dose-dependently potentiated. These behavioral findings suggest a dopamine-mediated modulatory role for the PFC over reward relevant elements within the nucleus accumbens.

Animals↗

PubMed1992

N-methyl-D-aspartate unilaterally injected into the dorsal striatum of rats produces contralateral circling: antagonism by 2-amino-7-phosphonoheptanoic acid and cis-flupenthixol.

To evaluate the possible contribution of dorsal striatal glutamate receptors to motor behavior, circling responses were observed in rats following unilateral intrastriatal microinjections of the agonist, N-methyl-D-aspartate (NMDA) or the antagonist, 2-amino-7-phosphonoheptanoic acid (APH). The role of dopamine (DA) in NMDA-produced circling also was evaluated. In experiment 1, an NMDA dose of 5.0 micrograms (in 0.5 microliter), but not 0.5 or 0.05 microgram produced significant contraversive circling. In experiment 2, an APH dose of 10.0 micrograms but not 1.0 or 0.1 microgram produced significant ipsiversive circling. In experiment 3, microinjection of the ineffective 0.1 microgram dose of APH or a dose (20 micrograms) of the DA antagonist, cis-flupenthixol, that did not produce circling when administered alone, significantly reduced the circling response produced by the 5.0 micrograms dose of NMDA. As NMDA produced circling in the same direction as that seen following similar unilateral injections of locomotion-stimulating DA agonists, the present results suggest that glutamate, acting via NMDA receptors in the dorsal striatum, may exert an excitatory influence on motor systems. The observation that a DA receptor blocker antagonized the NMDA response further suggests that the observed motor excitatory effect of glutamate at NMDA receptors requires concurrent stimulation of DA receptors in the same region of the striatum.

2-Amino-5-phosphonovalerate↗

PubMed1980

Characteristics of 3H-cis-flupenthixol binding to calf brain membranes.

The binding of 3H-cis flupenthixol (3H-FPT) to calf brain membranes was investigated in vitro. Highest levels of 3H-FPT binding were observed in striatum and nucleus accumbens, whilst no significant binding was observed in pituitary. The potencies of neuroleptics, dopaminergic ergot alkaloids and dopamine (DA) agonists in inhibiting 3H-FPT binding to calf striatal membranes were compared with their potencies in inhibiting 3H-spiperone (3H-SPIP) binding and DA-stimulated adenylate cyclase (AC). A high correlation was observed between drug potencies in inhibiting 3H-FPT binding and DA stimulated AC. However, potencies of the drugs inhibiting 3H-SPIP binding were only weakly correlated with their potencies in inhibiting either 3H-FPT binding or DA stimulated AC. A detailed analysis of the inhibition of 3H-FPT binding by butyrophenones revealed two classes of 3H-FPT binding sites. It is suggested that 3H-FPT binds predominantly to a class of dopaminergic sites associated with DA-stimulated AC.

Adenylyl Cyclases↗

PubMed1981

Kainic acid lesions dissociate [3H] spiperone and [3H]cis-flupenthixol binding sites in rat striatum.

The effects of striatal kainic acid lesions on [3H] cis-flupenthixol ([3H]FPT) and [3H]spiperone (3H-SPIP) binding to dopamine (DA) receptors in control and lesioned striata were examined. Significant reductions in both binding parameters were observed, [3H] FPT binding was depleted to a greater extent than [3H] SPIP binding. Reductions in both [3H] FPT and [3H] SPIP binding were significantly correlated with reductions in glutamic acid decarboxylase activity. After complete loss of GAD activity, 30-40% of [3H] SPIP binding sites remained in the lesioned striata, whereas all [3H] FPT binding sites were destroyed. The results are discussed in relation to the presence of distinct types of DA receptors in rat striatum, and ligand binding to these receptors.

Animals↗

PubMed1982

Irreversible blockade of striatal dopamine receptors in vivo by a derivative of alpha-flupenthixol.

Flupenthixyl chloride (FPT-Cl), a derivative of the dopamine (DA) receptor antagonist and neuroleptic alpha-flupenthixol possessing a chloroethyl side chain, has been prepared and evaluated for use in vivo in affinity labeling of DA receptors. Binding of [3H]spiperone to rat striatal DA receptors was markedly altered up to 12 h after intraventricular injection of FPT-Cl as compared with controls, while Scatchard plots of [3H]spiperone binding obtained on rat striatal homogenates 24 and 48 h after injection of FPT-Cl had values of Bmax significantly lower than in controls. The results suggest that the administration of FPT-Cl leads to irreversible and possibly covalent blockade of a portion of the spiperone binding sites in rat striatum. A second population of receptors appears to be blocked reversibly and presumably noncovalently by FPT-Cl, and these spiperone binding sites are partially reactivated in vivo after 48 h.

Animals↗

PubMed1982

alpha-Flupenthixol increases slow-wave in rats: effect of dopamine receptor blockade.

alpha-Flupenthixol (0.2 mg/kg, i.p.), a dopamine receptor blocker, significantly increased slow-wave sleep and decreased wakefulness in rats when administered either at the onset of a 12-hr light period or a 12-hr dark period. The same dose of the drug strongly antagonized the dopamine-mediated stereotype produced by an injection of apomorphine (1 mg/kg, i.p.) for at least 9-hr, indicating that dopamine receptors were blocked throughout most of the recording session. The results suggest a relationship between the blockade of dopamine receptors and the increase of slow-wave sleep time.

Animals↗

PubMed1989

[D-TRP11]-neurotensin, unlike alpha-flupenthixol, may not block amphetamine-induced hyperactivity in rats.

Recent reports have suggested that neurotensin (NT) and some of its analogues resemble neuroleptics, for example alpha-flupenthixol (FLU), in their ability to suppress locomotor activity. The results obtained support this conclusion, but only if total photocell counts (the "traditional" index) are considered. An improved method of measuring activity--where subjects have to interrupt photocell beams in sequence before a ("conditional") count is registered--suggested, in direct contrast to the total counts index, that the stable analogue of neurotensin [D-Trp11]-neurotensin (DTNT) increased activity slightly (Sahgal and Keith, 1986). The present report is on the effects of DTNT (0-8 microgram/rat, i.c.v.) and FLU (0-1 mg/kg, i.p.) on hyperactivity induced by D-amphetamine (1.5 mg/kg, i.p.). The usual total counts index of activity suggested that FLU and DTNT blocked the increase. On the other hand, conditional count data suggested that only FLU was effective. Both measures indicated that FLU and amphetamine, administered separately, suppressed and enhanced activity, respectively. In contrast, DTNT at these doses had no significant effect on the conditional counts but markedly suppressed total counts. Subsequent observation of DTNT-treated rats placed in small open fields, suggested that the peptide induced marked circling (ambulatory) behaviour, at the cost of other behavioural categories, especially rearing and grooming. It is argued that (a) DTNT may not resemble neuroleptics in its effects on motor behaviour and (b) conditional activity counts, and also measures relating to brief interruptions of photocell beams, can provide useful additional information concerning motor activity.

Amphetamine↗

PubMed1993

Neuropeptide Y: intraaccumbens injections produce a place preference that is blocked by cis-flupenthixol.

Neuropeptide Y (NPY) has been localized in the nucleus accumbens (NAcc), where it may influence dopamine (DA) neurotransmission. Extensive data implicate NAcc DA in reward-related learning, raising the possibility that NPY microinjected into the NAcc may induce rewarding effects mediated by DA. This hypothesis was tested using the conditioned place preference (CPP) paradigm. Each experiment consisted of three distinct phase: preconditioning (three 15-min exposures to an apparatus with two compartments connected by a tunnel); conditioning (four 30-min pairing of one compartment with drug and four similar pairings of the other compartment with vehicle); and test (three 15-min exposures to the apparatus). A significant increase in the time spent in the drug-paired compartment from preconditioning to test was taken as evidence of a CPP. Two experiments showed that systemic (2.0 mg/kg, IP) or intraaccumbens amphetamine (10.0 micrograms in 0.5 microliters on each side) produced a CPP. The third experiment showed that intraaccumbens NPY (0.1 micrograms in 0.5 microliter on each side) produced a CPP. This CPP was blocked by pretreatment with a dose of the DA receptor blocker cis-flupenthixol (20.0 micrograms in 0.5 microliter on each side in the NAcc) that, alone, produced no CPP effect. These results strongly suggest that NPY applied to the NAcc is rewarding. In addition, these rewarding properties of NPY may be mediated by DA neurotransmission.

Amphetamine↗

PubMed1991

Stereospecific effect of flupenthixol on neuroreceptor gene expression.

An experimental method to test the hypothesis that antipsychotic (neuroleptic) agents influence gene expression in the mouse brain has been developed using the cis and trans stereoisomers of flupenthixol. The cis form of the drug is known to be clinically effective against some of the psychotic symptoms of schizophrenia as opposed to the trans isomer which is relatively inactive. A 2- to 3-fold increase in the abundance of dopamine 2 receptor mRNA was observed in the cis treated mice after a period of ten weeks. No change was observed in the expression of the dopamine D2 receptor gene upon treatment with the trans isomer. No change in the amount of 5-HT1A, 5-HT1C, alpha 1 adrenergic, beta 1 and beta 2 adrenergic neuroreceptor mRNA was found in the mice treated with active drug. The results show a long-term adaptation to D2 antagonism at the level of gene expression which occurs over a similar time scale to that of the clinical response to neuroleptic treatment of schizophrenia.

Actins↗

PubMed1997

DAMGO and DPDPE facilitation of brain stimulation reward thresholds is blocked by the dopamine antagonist cis-flupenthixol.

The role of dopamine neurotransmission in opioid reward was investigated using a rate-independent measure for determining brain stimulation reward (BSR) thresholds. Intra-accumbens infusions of the mu- and delta-specific peptides, D-Ala2, N-Me-Phe4, Gly-ol5-Enkephalin and D-Pen2, D-Pen5-Enkephalin caused significant lowering of BSR thresholds. The dopamine D1/D2 antagonist, cis-flupenthixol, blocked these effects at a dose that did not significantly alter thresholds when given alone. These data suggest both mu- and delta-opioid potentiation of BSR is dopamine dependent.

Animals↗

PubMedDate not supplied

The dopamine antagonist, alpha-flupenthixol, interferes with naloxone-induced place aversion learning, but not with acute opiate dependence in rats.

Pretreatment with the dopamine antagonist alpha-flupenthixol (alpha-flu) interfered with the establishment of a naloxone-induced place aversion in two experiments. In Experiment 1, the potential of pretreatment with alpha-flu to interfere with the establishment of a naloxone-induced place aversion was evaluated in rats administered morphine (Group MN) or saline (Group SN) 24 h prior to the naloxone conditioning trial. Naloxone-precipitated withdrawal from morphine administered 24 h prior to the trial produced a stronger place aversion than produced by naloxone alone. The neuroleptic, alpha-flu, attenuated the naloxone-induced place aversion, but did not selectively interfere with the place aversion produced by acute opiate dependence. Experiment 2 replicated demonstration of interference with naloxone-place aversion learning by neuroleptic pretreatment with the inclusion of saline controls. These results suggest that dopamine modulates either the aversive motivational properties of naloxone or learning, even in opiate naïve rats.

Animals↗

PubMed2000

Effects of intra-accumbens infusions of amphetamine or cis-flupenthixol on sustained attention performance in rats.

Attentional abilities, as reflected by performance in sustained, selective, or divided attention tasks, have been extensively demonstrated to depend on the integrity of cortical cholinergic inputs and their basal forebrain afferent circuits. As nucleus accumbens (NAC) efferent projections have been hypothesized to modulate the excitability of basal forebrain corticopetal projections, the effects of drug-induced modulation of NAC dopaminergic transmission on sustained attention performance in rats were assessed. Unexpectedly, bilateral infusions of amphetamine (AMPH; 0, 3.0, 10.0, 30.0 microg/microl/hemisphere) into the shell region of the NAC did not affect sustained attention performance. In contrast, microinjections of the non-selective dopamine (DA) receptor antagonist cis-flupenthixol (FLU; 0, 3.0, 10.0, 25.0 microg/microl/hemisphere) into the NAC of a separate group of animals impaired the detection of both signals and non-signals, as reflected by decreases in the relative numbers of hits and correct rejections. As the effects of neither AMPH nor FLU followed the predictions made on the basis of current hypotheses about the modulation of basal forebrain neuronal activity by NAC DA, the present results challenge such hypotheses and indicate that the conditions which implicate NAC DA in attentional performance remain unsettled.

Amphetamine↗