Haloperidol-pretreated Rats Research Articles

Dopaminergic mechanisms underlying the expression of antipsychotic-induced dopamine supersensitivity in rats

Antipsychotic treatment can produce a dopamine-supersensitive state, potentiating the response to dopamine receptor stimulation. In both schizophrenia patients and rats, this is linked to tolerance to ongoing antipsychotic treatment. In rodents, dopamine supersensitivity is often confirmed by an exaggerated psychomotor response to d-amphetamine after discontinuation of antipsychotic exposure. Here we examined in rats the dopaminergic mechanisms mediating this enhanced behavioural response, as this could uncover pathophysiological processes underlying the expression of antipsychotic-evoked dopamine supersensitivity. Rats received 0.5 mg/kg/day haloperidol via osmotic minipump for 2 weeks, before treatment was discontinued. After cessation of antipsychotic treatment, rats showed a supersensitive psychomotor response to the D2 agonist quinpirole, but not to the D1 partial agonist SKF38393 or the dopamine reuptake blocker GBR12783. Furthermore, acute D1 receptor blockade (using SCH39166) decreased the exaggerated psychomotor response to d-amphetamine in haloperidol-pretreated rats, whereas acute D2 receptor blockade (using sulpiride) enhanced it. Thus, after discontinuation of antipsychotic treatment, D1- and D2-mediated transmission differentially modulate the expression of a supersensitive response to d-amphetamine. This supersensitive behavioural response was accompanied by enhanced GSK3β activity and suppressed ERK1/2 activity in the nucleus accumbens (but not caudate-putamen), suggesting increased mesolimbic D2 transmission. Finally, after discontinuing haloperidol treatment, neither increasing ventral midbrain dopamine impulse flow nor infusing d-amphetamine into the cerebral ventricles triggered the expression of already established dopamine supersensitivity, suggesting that peripheral effects are required. Thus, while dopamine receptor-mediated signalling regulates the expression of antipsychotic-evoked dopamine supersensitivity, a simple increase in central dopamine neurotransmission is insufficient to trigger this supersensitivity.

Repeated aripiprazole treatment causes dopamine D2 receptor up-regulation and dopamine supersensitivity in young rats

Aripiprazole is a second-generation antipsychotic that is increasingly being prescribed to children and adolescents. Despite this trend, little preclinical research has been done on the neural and behavioral actions of aripiprazole during early development. In the present study, young male and female Sprague-Dawley rats were pretreated with vehicle, haloperidol (1 mg/kg), or aripiprazole (10 mg/kg) once daily on postnatal days (PD) 10-20. After 1, 4, or 8 days (i.e. on PD 21, PD 24, or PD 28), amphetamine-induced locomotor activity and stereotypy, as well as dorsal striatal D2 receptor levels, were measured in separate groups of rats. Pretreating young rats with aripiprazole or haloperidol increased D2 binding sites in the dorsal striatum. Consistent with these results, dopamine supersensitivity was apparent when aripiprazole- and haloperidol-pretreated rats were given a test day injection of amphetamine (2 or 4 mg/kg). Increased D2 receptor levels and altered behavioral responding persisted for at least 8 days after conclusion of the pretreatment regimen. Contrary to what has been reported in adults, repeated aripiprazole treatment caused D2 receptor up-regulation and persistent alterations of amphetamine-induced behavior in young rats. These findings are consistent with human clinical studies showing that children and adolescents are more prone than adults to aripiprazole-induced side effects, including extrapyramidal symptoms.

Poor evidence for depolarization block but uncoupling of nigral from striatal dopamine metabolism after chronic haloperidol treatment in the rat

Chronic haloperidol treatment induces depolarization block in midbrain dopamine neuronal systems. We studied the effect of this treatment on nigrostriatal dopamine catabolism using microwave fixation in situ of the brain to prevent post-mortem changes. Male Sprague-Dawley rats were given haloperidol (0.4 mg/kg/day, i.p.) or vehicle for 21 days. On day 22, some rats in each group received a haloperidol challenge (0.4 mg/kg, i.p.), and the remaining rats were given the vehicle. Dopamine metabolite levels 60 min after the challenge were assayed by combined gas chromatography-mass fragmentography. Haloperidol pretreatment significantly modified haloperidol challenge effect on regional dopamine metabolite contents. The challenge elevated all striatal metabolites studied similarly in the chronic vehicle- or chronic haloperidol-pretreated rats. In contrast, it did not significantly affect nigral dopamine metabolites except it elevated 3,4-dihydroxyphenylacetic acid in the haloperidol-pretreated rats. A linear correlation between the nigral and striatal contents of 3-methoxytyramine (R = 0.72, p = 0.03), and a trend for correlation (R = 0.65, p = 0.06) between the respective 3,4-dihydroxyphenylacetic acid contents were found after the haloperidol challenge in the vehicle-pretreated rats only. These results suggest that chronic haloperidol treatment uncouples somatodendritic dopamine turnover and release from those in the axon terminals of nigrostriatal dopamine neurons.

Differential behavioural effect of quinpirole in neuroleptic-pretreated rats — role of α 1-adrenoceptor

This paper presents the effect of 14-day intraperitoneal (i.p.) neuroleptic treatment on the behavioural response of Wistar rats to (−)-quinpirole hydrochloride (3 mg/kg, i.p.) administered 24 h after the last neuroleptic dose. Chlorpromazine hydrochloride (10 mg/kg), haloperidol (2 mg/kg) or (±)-sulpiride (100 mg/kg) increased the effect of quinpirole; however, there were qualitative and quantitative differences between the neuroleptics. Chlorpromazine and haloperidol, but not sulpiride, pretreatment enhanced quinpirole-induced locomotor hyperactivity. Prazosin (0.5 mg/kg, i.p.) given to chlorpromazine-treated rats 1 h before quinpirole attenuated the quinpirole-induced hyperlocomotion. In chlorpromazine-pretreated rats, quinpirole elicited defensive aggressive behaviour with vocalization, copulatory attempts, intense rearing and head-down sniffing. When prazosin was given before quinpirole, head-down sniffing and object-directed oral activity were mainly observed. In haloperidol-pretreated rats, quinpirole induced intense head-down sniffing, rearing, grooming and object-directed oral activity. In sulpiride-pretreated rats, quinpirole induced intense head-down sniffing, grooming and object-directed oral activity. The results of the study suggest that differences in the behavioural expression of dopamine D 2 receptor supersensitivity induced by neuroleptics may be, at least in part, caused by concurrent stimulation of α 1-adrenoceptors.

Effects of amphetamine and phencyclidine on brain monoamines and neuropeptides in haloperidol pretreated rats

Effects of amphetamine and phencyclidine on brain monoamines and neuropeptides in haloperidol pretreated rats

Hypothermic effect of harmala alkaloid in rats: Involvement of serotonergic mechanism

The effect of total alkaloid extracted from Peganum harmala seeds collected in Egypt on body temperature was studied in rats. Intraperitoneal administration of the Peganum harmala extract produced significant and dose-dependent hypothermia. Similarly, harmine and harmaline, major constituents of the harmala alkaloid, lowered the body temperature. Pretreatment with p-chlorophenylalanine (100 mg/kg/day for 3 days), a 5-HT synthesis inhibitor, significantly attenuated the hypothermic effect of the total alkaloid and harmine, while it tended to block the hypothermic action of harmaline. Methysergide (2 mg/kg), a 5-HT antagonist, significantly attenuated the hypothermia induced by harmala alkaloids. Pindolol (0.05–2 mg/kg), a 5-HT1A receptor and β-adrenoceptor antagonist, partly blocked the hypothermic effect of the harmala alkaloids in a dose-dependent manner, whereas propranolol (10 mg/kg), a β-adrenoceptor antagonist, failed to alter it, suggesting that β-adrenoceptor is not involved in the hypothermia caused by the alkaloids. Pretreatment with a dopamine receptor antagonist haloperidol (5 mg/kg, SC and 2 mg/kg, IP 24 and 2 h before the experiment, respectively) significantly attenuated the hypothermic effect of harmala alkaloids. Moreover, in haloperidol pretreated rats, methysergide (2 mg/kg, IP) and pindolol (0.05 and 2 mg/kg) completely attenuated the hypothermic effect of the alkaloids. These data suggest that harmala alkaloids produce hypothermic effect mainly through endogenous 5-HT stimulation of 5-HT1A receptor.

The effects of GBR 12909, a dopamine re-uptake inhibitor, on monoaminergic neurotransmission in rat striatum, limbic forebrain, cortical hemispheres and substantia nigra.

In order to investigate the physiological importance of the membrane pump in eliminating released dopamine (DA) we have studied the effects of the putative selective dopamine re-uptake inhibitor, GBR 12909, on synthesis and metabolism of monoamines in the rat striatum, limbic forebrain, cortical hemispheres and substantia nigra (SN). The effects of the drug on the firing rate of catecholamine containing neurons in the SN and locus coeruleus (LC) were also investigated. For comparison we have investigated the effects of desipramine and maprotiline. As a measure of the synthesis of noradrenaline (NA), DA and 5-hydroxytryptamine (5-HT) we determined the 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) accumulation after inhibition of aromatic L-amino acid decarboxylase by 3-hydroxy-benzylhydrazine (NSD 1015). As indirect measurements of DA and NA release in vivo, we have assessed pargyline-induced 3-methoxytyramine (3-MT) and normetanephrine (NM) accumulation and disappearance rates of DA and NA after inhibition of their synthesis by alpha-methyl-p-tyrosine (alpha-MT). Administration of GBR 12909 (2.5, 5, 10, 20 or 40 mg/kg) decreased the NSD 1015-induced DOPA accumulation in the striatum and in the limbic forebrain. In contrast, only minor effects of the drug were seen on the DOPA accumulation in the cortical hemisphere and on the cerebral 5-HTP accumulation. GBR 12909 increased the 3-MT accumulation in the striatum, limbic forebrain and the cortical hemispheres, an effect that was even more pronounced in haloperidol-pretreated animals. However, GBR 12909 did not alter the 3-MT accumulation in the SN either when given alone or when given to haloperidol-pretreated rats. In haloperidol-pretreated rats GBR 12909 markedly enhanced the DA disappearance in the striatum and in the limbic forebrain, but not in the SN. Furthermore, GBR 12909 did not significantly affect the firing rate of dopaminergic neurons in the SN or that of noradrenergic neurons in the LC. Taken together, our results support the notion that GBR 12909 is a specific DA uptake inhibitor without a transmitter releasing action. In addition, our findings indicate that DA re-uptake is of physiological importance in the elimination of DA from the synaptic cleft in the striatum, limbic forebrain and cortical hemispheres, but not in the SN. Furthermore, a large part of the DA taken up by the dopaminergic terminals in the striatum and in the limbic forebrain seems to be re-incorporated into the storage vesicles.

Effect of chronic D-1 and/or D-2 dopamine antagonist treatment on SKF 38393-induced non-stereotyped grooming

The effects of chronic D-1 and/or D-2 dopamine (DA) receptor blockade on a putative D-1 DA receptor-mediated behavioral function was studied in rats treated for 21 days with the selective D-1 antagonist SCH 23390, the predominantly D-2 antagonist haloperidol, or the combination of both drugs at the same daily doses. Four days after the last drug dose, the non-stereotyped grooming response to the selective D-1 agonist SKF 38393 increased in SCH 23390-pretreated rats decreased in haloperidol-pretreated rats compared to controls, but remained unchanged in animals receiving both drugs. Underlying DA receptor changes and the resulting imbalance between D-1 and D-2 receptor presumably contribute to these effects, suggesting that the upregulation of one DA receptor subtype may modify the expression of behaviors associated with the other subtype.

Ascorbate antagonizes the behavioral effects of amphetamine by a central mechanism.

The behavioral response to amphetamine was monitored in rats that received simultaneous intraventricular infusions of saline or ascorbate. Both groups of animals displayed comparable responses, although ascorbate significantly delayed the onset of amphetamine-induced locomotion and rearing. In rats pretreated with a threshold dose of haloperidol (0.025 mg/kg), virtually all aspects of the amphetamine response were attenuated, and this effect was enhanced by ascorbate. In haloperidol-pretreated rats, ascorbate significantly lowered sniffing and forepaw shuffling throughout the amphetamine response. These results suggest that ascorbate antagonizes dopaminergic transmission by a central mechanism.

Regular stripe-like activation and suppression of metabolic activity in the cerebellar cortex following apomorphine administration to haloperidol-pretreated rats

Alteration of the pattern of metabolic activity in the cerebellar cortex, as produced by apomorphine in rats given chronic pretreatment with haloperidol was studied by means of the [ 14 C]deoxyglucose method. Apomorphine induced a regular stripe-like activation and suppression of metabolic activity in the caudal paravermal area of the cerebellar hemisphere and in the caudal vermis of the cerebellar cortex. This stripe-like pattern, oriented perpendicularly to the cerebellar fissure, suggests the functional organization of the cerebellar cortex in a direction which is parallel to the longitudinal axis of folia.

Regular stripe-like activation and suppression of metabolic activity in the cerebellar cortex following apomorphine administration to haloperidol-pretreated rats

Alteration of the pattern of metabolic activity in the cerebellar cortex, as produced by apomorphine in rats given chronic pretreatment with haloperidol was studied by means of the [ 14C]deoxyglucose method. Apomorphine induced a regular stripe-like activation and suppression of metabolic activity in the caudal paravermal area of the cerebellar hemisphere and in the caudal vermis of the cerebellar cortex. This stripe-like pattern, oriented perpendicularly to the cerebellar fissure, suggests the functional organization of the cerebellar cortex in a direction which is parallel to the longitudinal axis of folia.

Supersensitivity on methamphetamine effects of rats after chronic pretreatment of haloperidol

The present investigation examined methamphetamine-induced stereotypy and hypermotility after withdrawal from chronic haloperidol. Haloperidol was administered intraperitoneally to male rats of Wistar strain (150-160gr) daily (a dose of 0.5mg or 2.5mg) or every two days (a dose of lmg/kg or 5mg/kg) for 14 days. All “measurements were taken during the 60 min period following methamphetamine (3mg/kg or 10mg/kg i.p.) on every rat 4 days or 8 days after withdrawal from chronic haloperidol or saline injections. Stereotyped licking and biting (especially the former activity) were shown in every haloperidol-pretreated group given methamphetamine (3mg/kg), but not in saline-pretreated rats given methamphetamine with a same dose. Stereotyped biting activity was manifested in many cases of haloperidol-pretreated rats given methamphetamine (10mg/kg), while the licking activity was shown in saline-pretreated rats given methamphetamine at the same dose. Methamphetamine (3mg/kg) induced hypermotility; especially, horizontal movement and stereotyped locomotion were potentiated partially in haloperidol (2.5mg/kg) -pretreated rats only. These results suggested that the supersensitivity after withdrawal from chronic haloperidol treatment was manifested clearly by an enhanced stereotypy in response to doses of methamphetamine, but not markedly by locomotor activity.

Pharmacologic analysis of the postictal immobility syndrome in the rat

Postictal immobility (PI) following chemically (picrotoxin, metrazol) and electrically-induced (maximal electroshock, MES) convulsions has behavioral features close to neuroleptic-type catalepsy. EEG, monitored postictally, showed that catalepsy is accompanied by a variety of EEG patterns. Cataleptic behavior extended beyond the period of “postictal EEG depression”. During PI rats had vivid righting and corneal reflexes. Like haloperidol-pretreated rats they were able to maintain uncomfortable postures on the vertical grid or horizontal bar; although signs of rigidity were noticed, the rats would fail to remain self-supporting when placed across metal bookends (“bridge” test). All rats reacted to the tail-pinch immediately when the seizure would halt. However, 10–15 min later when PI was minimal or not detectable, animals became totally unresponsive to pressure applied to the tail (“delayed analgesia”). Examination of VEP recovery after MES showed that the secondary slow negativity and sensory afterdischarge were well developed irrespective of the score of the tail-pinch test. Pharmacological profile of PI suggests that the endogenous opiate system might contribute to this syndrome. Similar to morphine-induced catalepsy/catatonia: (1) PI is insensitive to atropine and scopolamine; (2) neither haloperidol nor alpha-methyl-p-tyrosine was able to potentiate it; (3) PI is reduced by apomorphine, naloxone, and physostigmine. Also, drugs acting via GABA system (γ-vinyl GABA, diazepam, sodium valproate) reduce PI intensity. It is hypothesized that PI system (1) is controlled by GABA carrying fibers and (2) uses neuropeptide with neuroleptic properties.