Dopamine receptor sensitive effect of dizocilpine on feeding behaviour

The effect of intracerebroventricular administration of dizocilpine on feeding behaviour and adrenal corticrotropic hormone (ACTH)-induced anorexia in elevated plus maze was examined. Dizocilpine (10, 20 and 40 nmol/rat, i.c.v.) showed a dose-dependent increase in food intake in 16 h food deprived rats. Dopamine receptor antagonists such as SCH 23390 (0.25 and 0.5 mg/kg, i.p.), pimozide (0.5 and 1 mg/kg, i.p.) and haloperidol (0.25 and 0.5 mg/kg, i.p.) dose-dependently blocked dizocilpine (40 nmol)-induced potentiation of food intake. Brain dopamine depletion by pretreatment with reserpine (5 mg/kg, i.p.) and alpha-methyl-p-tyrosine (200 mg/kg, i.p.) decreased food intake in rats. Similarly, pretreatment with reserpine and alpha-methyl-p-tyrosine (AMPT) reversed the hyperphagic effect of dizocilpine (20 and 40 nmol). Intracerebroventricular administration of ACTH (5 μg/rat) produced significant diminution of feeding duration and increased tasting latency and feeding latency in elevated plus maze which was reversed by dizocilpine (40 nmol). SCH 23390 (0.25 mg/kg), pimozide (0.5 mg/kg) and haloperidol (0.25 mg/kg) reversed the effect of dizocilpine on ACTH-induced behaviours in elevated plus maze. The present observations support and extend the hypothesis that endogenous excitatory aminoacids (EAAs) play a role in the control of food intake. Further, dizocilpine-induced hyperphagia and dizocilpine-induced reversal of ACTH effect on feeding behaviour in elevated plus maze involve DAergic mediation.     

A behavioural study of the changes in the central nervous system of mice after subchronic treatment with the selective dopamine autoreceptor agonist 3-PPP (dl-3-[3-hydroxyphenyl]-N-n-propylpiperidine)

Summary In naive mice the selective dopamine (DA) autoreceptor agonist 3-PPP (dl-3-[3-hydroxyphenyl]-N-n-propylpiperidine) produced a dose-dependent depression of locomotor activity. The duration of action of the depression was short, with no significant depression being noted one or more hours after a dose of 23.47 mg/kg (expressed as the base). Mice, administered the drug twice daily (23.47 mg/kg, in the morning and the evening, i.p.) for 5 days, were, 15 to 25 hours after the last dose, marginally less sensitive to the locomotor depressant effects of a challenge with the same drug. There was no change in the sensitivity of postsynaptic DA and-adrenergic receptors, as assessed by the locomotor stimulant effects of apomorphine and apomorphine plus clonidine, respectively, in reserpine and-methyltyrosine pretreated animals. However, 3-PPP-pretreated mice were more sensitive to the activating effects ofd-amphetamine, and this increased sensitivity was blocked by pretreatment with reserpine. In naive mice, a low, DA autoreceptor selective dose of haloperidol (25g/kg) potentiated the locomotor stimulant effects ofd-amphetamine. One explanation for the data obtained is that subchronic pretreatment with 3-PPP produced DA autoreceptor subsensitivity with no concomitant change in postsynaptic DA or-adrenergic receptor sensitivity. The increased sensitivity tod-amphetamine in the 3-PPP pretreated mice may be due to a reduction in the feedback control exerted by the DA released by thed-amphetamine due to the DA autoreceptors having become subsensitive.     

Role of D1 and D2 dopamine receptors in mediating locomotor activity elicited from the nucleus accumbens of rats

The present study examined the role of D1 and D2 receptors in mediating locomotor activity induced by dopamine (DA) agonists after injection into the nucleus accumbens (Acb). The D1 receptor agonist SKF38393 (as the racemic mixture) induced a dose-related increase in activity when injected bilaterally (1-10 micrograms/side). At a dose of 1 microgram/side, only the R-enantiomer was active. The SKF38393 (10 micrograms/side)-induced activity was antagonized by the D1 receptor antagonist SCH23390 (0.5 mg/kg i.p.), by the D2 receptor antagonist spiperone (0.1 mg/kg, i.p.), but not by the 5-HT2 antagonist ketanserin (1 mg/kg, i.p.). Another D1 agonist, CY208 243, also induced a moderate increase in activity when injected into the Acb (2 and 8 micrograms/side), but this was of much less intensity and of shorter duration than that produced by SKF38393. The D2 receptor agonist quinpirole slightly increased activity when administered into the Acb (0.3-3 micrograms/side), with the magnitude and duration of the response, however, being much less than that produced by SKF38393. The locomotor stimulant effects of SKF38393 (5 micrograms/side), CY208 243 (2 micrograms/side) and quinpirole (1 microgram/side) were blocked by the depletion of catecholamines with reserpine (5 mg/kg s.c., 24 h pretreatment) and alpha-methyl-p-tyrosine (200 mg/kg, i.p.). However, when SKF38393 and quinpirole were injected concurrently into the Acb at doses of 5 and 1 microgram/side respectively, a marked locomotor stimulation occurred in catecholamine-depleted rats. Furthermore, SKF38393 (1 microgram/side) or CY208 243 (2 micrograms/side), injected concurrently with quinpirole (0.3 microgram/side), into the Acb of rats with intact DA stores produced an at least additive effect on locomotor activity. These results suggest that both D1 and D2 receptor stimulation in the Acb is required for the expression of locomotor effects. Furthermore, D1 and D2 receptors in this nucleus appear to interact positively with each other, and may mediate the additive locomotor stimulatory effects induced by concurrent systemic administration of selective D1 and D2 agonists.     

Involvement of dopamine (DA)/serotonin (5-HT)/sigma (sigma) receptor modulation in mediating the antidepressant action of ropinirole hydrochloride, a D2/D3 dopamine receptor agonist

Multiple lines of investigation have explored the role of dopaminergic systems in mental depression. Chronic treatment with antidepressant drugs has been reported to alter dopaminergic neurotransmission, most notably a sensitization of behavioural responses to agonists acting at D2/D3 dopamine receptors within the nucleus accumbens. Recent clinical evidences have shown that ropinirole, a D2/D3 dopamine receptor agonist, augments the action of various standard antidepressant drugs in treatment-resistant depression. The present study was undertaken to elucidate the possible mechanism of antidepressant action of ropinirole employing various behavioral paradigms of despair supported by the measurements of neurochemical changes in the tissue contents of dopamine (DA) and serotonin (5-HT) in the whole brain using high-performance-liquid chromatography (HPLC) with electrochemical detectors (ECD). In the mouse forced swim test (FST) or tail-suspension test (TST), ropinirole (1-10 mg/kg, i.p.) produced S-shaped dose-response curve in the percentage decrease in immobility period. Compared with vehicle, ropinirole (10 mg/kg., i.p.) had a significant anti-immobility effect without affecting locomotor activity. The reduction in the immobility period elicited by ropinirole (10 mg/kg, i.p.) in the FST was reversed by dopaminergic and sigma receptor antagonist, haloperidol (0.5 mg/kg, i.p.), and specific D2 dopamine receptor antagonist sulpiride (5 mg/kg i.p.), but not by SCH 23390 (0.5 mg/kg i.p), a D1 dopamine receptor antagonist. Rimcazole (5 mg/kg i.p.) (a sigma receptor antagonist), progesterone (10 mg/kg i.p.) (a sigma receptor antagonistic neurosteroid), BD 1047 (1 mg/kg i.p.) (a novel sigma receptor antagonist with preferential affinity for sigma-1 sites) also reversed the anti-immobility effect of ropinirole (10 mg/kg i.p.). The neurochemical studies of whole brain revealed that ropinirole at 10 mg/kg i.p. did not affect the tissue levels of dopamine but significantly increased serotonin levels. The study indicated that ropinirole possessed anti-immobility activity in FST by altering dopaminergic, serotonergic or sigma receptor function.     

Interaction of haloperidol and γ-butyrolactone with (+)-amphetamine-induced changes in monoamine synthesis and metabolism in rat brain

Summary The interaction of (+)-amphetamine with haloperidol and-butyrolactone on synthesis of monoamines in rat brain regions was investigated using anin vivo method, in which the accumulation of dopa and 5-hydroxytryptophan (5-HTP) was measured after inhibition of the aromatic amino acid decarboxylase by means of 3-hydroxybenzylhydrazine. The accumulation of 3-methoxytyramine (3-MT) after inhibition of the monoamine oxidase with pargyline was taken as an indicator of thein vivo release of dopamine (DA) into the extraneuronal space.(+)-Amphetamine at doses of 1-3 mg/kg caused an increase of dopa formation in the DA-rich areas c. striatum and mesolimbic forebrain but had no effect on dopa formation in neocortex and 5-HTP formation in all brain regions investigated. At a dose of 10 mg/kg (+)-amphetamine decreased dopa as well as 5-HTP formation in all brain regions studied.3-MT accumulation in whole rat brain was stimulated by (+)-amphetamine as well as haloperidol and inhibited by-butyrolactone.Combined treatment with haloperidol and (+)-amphetamine not only potentiated the stimulation of dopa formation but also the increase of 3-MT accumulation. Pretreatment with-butyrolactone antagonized the stimulation of 3-MT formation induced by (+)-amphetamine at a dose of 10 mg/kg. This dose of (+)-amphetamine markedly counteracted the-butyroiactoneinduced increase in dopa formation especially in the DA-rich areas.The data support the view that impulse flow in DA neurons facilitates the effect of (+)-amphetamine on DA release and DA synthesis. Inhibition of catecholamine synthesis after high doses of (+)-amphetamine may be due to an increase in cytoplasmatic DA concentration causing end-product inhibition of tyrosine hydroxylase.A preliminary report has been given recently (Kehr, 1976 b).Data of this communication are part of W.S.'s thesis for an M.D.     

D(3) dopamine receptors are down-regulated in amphetamine sensitized rats and their putative antagonists modulate the locomotor sensitization to amphetamine

D(3) dopamine receptor agonists inhibit locomotor activity in rodents and modulate the reinforcing effect of psychostimulants; however, their functional role during behavioral sensitization remains unclear. In the present study, we intend to investigate if D(3) dopamine receptors alter during the amphetamine sensitization and test if manipulation of D(3) receptors would affect the development of locomotor sensitization to amphetamine. We have found that D(3) dopamine receptors are down-regulated in the limbic forebrain in chronic amphetamine-treated (5 mg/kg x 7 days) animals. The levels of both D(3) receptor protein (B(max) value) and mRNA decreased significantly in the behaviorally sensitized rats compared to the saline-treated controls. When animals were co-administered a putative D(3) receptor antagonist (U99194A or GR103691; 20 microg x 7 days; intracerebroventricle) and amphetamine (5 mg/kg x 7 days, i.p.), the locomotor sensitization to amphetamine was significantly inhibited. However, when the putative D(3) receptor antagonist U99194A was administered during the amphetamine withdrawal period at day 10, it did not affect the development of locomotor sensitization. Furthermore, pretreatment with the preferential D(3) agonist 7-hydroxydipropylaminotetralin partially blocked the inhibitory effect of U99194A on locomotor sensitization. These data prove the participation of D(3) dopamine receptors in the development of amphetamine sensitization and, in addition, suggest a potential application for D(3) antagonists in the prevention of amphetamine addiction.     

Stimulant-conditioned locomotion is not affected by blockade of D1 and/or D2 dopamine receptors during conditioning

A series of experiments were conducted to investigate the role of dopamine (DA) D1 and D2 receptor subtypes in stimulant-conditioned locomotion in rats. Expt. 1 demonstrated that locomotion could be induced by a testing situation when that situation was previously paired with (+)-amphetamine (1.5 mg/kg, s.c.) or a D2 receptor selective agonist (PHNO, 15 or 30 micrograms/kg, s.c.), but not when the drug treatments were given 3 h after exposure to the situation. The selective D2 receptor antagonist, haloperidol (50 micrograms/kg, i.p.), and the D1 receptor antagonist, SCH 23390 (20 micrograms/kg, s.c.), blocked amphetamine-induced locomotion during the pairing process, but failed to block amphetamine-conditioned locomotion as assessed during a drug-free test in Expt. 2. This was true when the antagonists were given separately or together. The results of Expts. 3 and 4 showed that doses of the D1 (20 micrograms/kg, s.c.) and D2 antagonist (250 micrograms/kg, i.p.) that blocked the unconditioned locomotor effects of PHNO failed to block its conditioned locomotion. It is concluded that neither D1 nor D2 DA receptors are essential for the development of stimulant-conditioned locomotion.     

Bromocriptine-induced locomotor stimulation in mice is modulated by dopamine D-1 receptors

Summary Mice were pretreated with reserpine plus-methyl-p-tyrosine (10 mg/ kg plus 200 mg/kg). One hour later they were administered the selective dopamine D-2 agonist bromocriptine or vehicle. Three hours after the bromocriptine, mice were challenged with the selective D-1 agonist SKF 38393, and locomotor activity was measured each 5 min for three hours. Neither bromocriptine nor SKF 38393 produced significant stimulation. The combination, however, produced a dose-dependent and coordinated increase in activity. If the bromocriptine was given only one hour before the SKF 38393 challenge (i.e., three hours after the reserpine plus-methyl-p-tyrosine), no interaction was seen. In naive mice, when SKF 38393 and bromocriptine were administered together, the locomotor response to bromocriptine was quantitatively and qualitatively altered. The initial depressant response to bromocriptine was shortened, producing a more rapid onset of the stimulant response. In one experiment, the maximal activity induced by bromocriptine was increased by SKF 38393. The ability of SKF 38393 to alter the locomotor stimulant effect of bromocriptine in naive mice was blocked by their pretreatment with the selective D-1 antagonist, SCH 23390. The data indicate that the locomotor stimulant effects of bromocriptine are modulated by D1 receptors.     

Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost-variable-payoff fixed-ratio cocaine self-administration in rats

In rats, acute administration of SB-277011A, a highly selective dopamine (DA) D(3) receptor antagonist, blocks cocaine-enhanced brain stimulation reward, cocaine-seeking behaviour and reinstatement of cocaine-seeking behaviour. Here, we investigated whether SB-277011A attenuates cocaine reinforcement as assessed by cocaine self-administration under variable-cost-variable-payoff fixed-ratio (FR) and progressive-ratio (PR) reinforcement schedules. Acute i.p. administration of SB-277011A (3-24 mg/kg) did not significantly alter cocaine (0.75 mg/kg/infusion) self-administration reinforced under FR1 (one lever press for one cocaine infusion) conditions. However, acute administration of SB-277011A (24 mg/kg, i.p.) progressively attenuated cocaine self-administration when: (a) the unit dose of self-administered cocaine was lowered from 0.75 to 0.125-0.5 mg/kg, and (b) the work demand for cocaine reinforcement was increased from FR1 to FR10. Under PR (increasing number of lever presses for each successive cocaine infusion) cocaine reinforcement, acute administration of SB-277011A (6-24 mg/kg i.p.) lowered the PR break point for cocaine self-administration in a dose-dependent manner. The reduction in the cocaine (0.25-1.0 mg/kg) dose-response break-point curve produced by 24 mg/kg SB-277011A is consistent with a reduction in cocaine's reinforcing efficacy. When substituted for cocaine, SB-277011A alone did not sustain self-administration behaviour. In contrast with the mixed DA D(2)/D(3) receptor antagonist haloperidol (1 mg/kg), SB-277011A (3, 12 or 24 mg/kg) failed to impede locomotor activity, failed to impair rearing behaviour, failed to produce catalepsy and failed to impair rotarod performance. These results show that SB-277011A significantly inhibits acute cocaine-induced reinforcement except at high cocaine doses and low work requirement for cocaine. If these results extrapolate to humans, SB-277011A or similar selective DA D(3) receptor antagonists may be useful in the treatment of cocaine addiction.     

Changes in dopamine efflux associated with extinction, CS-induced and d-amphetamine-induced reinstatement of drug-seeking behavior by rats

The present experiment employed chronoamperometry with stearate–graphite paste electrodes to monitor dopamine efflux in the nucleus accumbens during extinction and subsequent reinstatement of bar-pressing for a conditioned stimulus (CS) following presentation of a CS or following a systemic injection of d-amphetamine. Rats self-administered d-amphetamine (0.25 mg/kg per infusion) for 3 h a day on 6 consecutive days. Each infusion was paired with a flashing light CS. On the 7th day, rats self-administered d-amphetamine for 1 h, followed by 10 h of extinction. Presentation of the CS 2 days following extinction induced small and transient increases in responding for the CS, with no significant associated increases in DA efflux. Lower rates of responding were observed in rats that had received random presentations of the CS during d-amphetamine self-administration, and in an experimentally-naïve control group. A subsequent systemic injection of d-amphetamine increased dopamine efflux in the nucleus accumbens in all groups and was most effective in reinstating bar-pressing in the CS-d-amphetamine paired group. This is consistent with the hypothesis that exposure to psychostimulant drugs, and a drug-paired CS, can reinstate drug-seeking behavior. Together, these findings suggest that enhanced DA efflux may contribute to the reinstatement of drug-seeking behavior induced by the single administration of a psychostimulant drug, but not transient reinstatement induced by presentation of a drug-paired CS alone following extinction.     

Evidence for roles of κ-opioid and NMDA receptors in the mechanism of action of ibogaine

Ibogaine, a putatively anti-addictive alkaloid, binds to κ-opioid and NMDA receptors. In the present study we investigated the roles of κ-opioid and NMDA actions in mediating ibogaine's (40 mg/kg, i.p.) behavioral and neurochemical effects in rats. A combination of a κ-opioid antagonist (norbinaltorphimine, 10 mg/kg, s.c.) and a NMDA agonist (NMDA, 20 mg/kg, i.p.) partially prevented ibogaine-induced inhibition of intravenous morphine self-administration and ibogaine-induced antagonism of morphine-induced locomotor stimulation. The combination, as well as norbinaltorphimine and NMDA alone, blocked the acute effects of ibogaine on dopamine release and metabolism in the striatum. The data suggest that both κ-opioid agonist and NMDA antagonist actions of ibogaine contribute to its putative anti-addictive effects.     

The demonstration of a change in responsiveness of mice to physostigmine and atropine after withdrawal from long-term haloperidol pretreatment

Summary Mice, administered haloperidol 3 mg/kg/day, in their drinking water for 21 days, were tested for their responsiveness to cholinergic and anticholinergic drugs 4 days after withdrawal from haloperidol (or vehicle). Haloperidol-treated animals administered methylhyoscine (1 mg/kg i.p.) and various doses of physostigmine (5 to 1215g/kg) displayed significantly less depression of locomotor activity than vehicle-treated animals. Atropine, 5 mg/kg, whilst ineffective in producing locomotor stimulation in vehicle-treated animals, produced marked stimulation in haloperidol-treated animals. Methylatropine (5 mg/kg) did not produce significant stimulation in either group. Dopamine receptor supersensitivity was present in these animals as haloperidol-treated mice, pretreated with-methyl-tyrosine and reserpine, displayed a significantly greater locomotor response to apomorphine than did vehicle-treated animals. The data support the hypothesis that long-term administration of haloperidol produces an apparent hyposensitivity of central muscarinic receptors.     

Injections of the selective adenosine A2A antagonist MSX-3 into the nucleus accumbens core attenuate the locomotor suppression induced by haloperidol in rats

There is considerable evidence of interactions between adenosine A2A receptors and dopamine D2 receptors in striatal areas, and antagonists of the A2A receptor have been shown to reverse the motor effects of DA antagonists in animal models. The D2 antagonist haloperidol produces parkinsonism in humans, and also induces motor effects in rats, such as suppression of locomotion. The present experiments were conducted to study the ability of the adenosine A2A antagonist MSX-3 to reverse the locomotor effects of acute or subchronic administration of haloperidol in rats. Systemic (i.p.) injections of MSX-3 (2.5-10.0 mg/kg) were capable of attenuating the suppression of locomotion induced by either acute or repeated (i.e., 14 day) administration of 0.5 mg/kg haloperidol. Bilateral infusions of MSX-3 directly into the nucleus accumbens core (2.5 microg or 5.0 microg in 0.5 microl per side) produced a dose-related increase in locomotor activity in rats treated with 0.5 mg/kg haloperidol either acutely or repeatedly. There were no overall significant effects of MSX-3 infused directly into the dorsomedial nucleus accumbens shell or the ventrolateral neostriatum. These results indicate that antagonism of adenosine A2A receptors can attenuate the locomotor suppression produced by DA antagonism, and that this effect may be at least partially mediated by A2A receptors in the nucleus accumbens core. These studies suggest that adenosine and dopamine systems interact to modulate the locomotor and behavioral activation functions of nucleus accumbens core.     

Enhanced apomorphine sensitivity and increased binding of dopamine D2 receptors in nucleus accumbens in prepubertal rats after neonatal blockade of the dopamine D3 receptors by (+)-S14297

The role of dopamine (DA) D3 receptors is controversial in early developmental stages of specially locomotor activity. Past studies have only tested behavioral changes induced by neonatal administration of nonselective dopamine antagonist such as haloperidol or sulpiride in adult rats. We investigated the role of neonatal blockade of DA D3 receptors at (postnatal day, P1 to P12) using the DA D3 receptor antagonist (+)-S14297 on paradigms related to DA behaviors including locomotor activity in novel environment and after administration of the DA nonspecific agonists d-amphetamine, and apomorphine. Additionally, autoradiographic studies were performed to correlate behavioral alterations with DA D1-like, D2-like, and D3 receptors. All studies were performed at two critical ages, prepubertal (P35) and postpubertal (P60). The quantitative autoradiogaphic study revealed increases in the expression of DA D2-like receptor expression in the nucleus accumbens (NAcc) in prepubertal animals that received the DA D3 antagonist (+)-S14297 at neonatal age. In addition, novel environment and apomorphine administration (0.5 mg/kg, s.c.), induced increases of locomotor activity in prepubertal animals that received the DA D3 antagonist (+)-S14297. Autoradiographic and behavioral results suggest that blockade of DA D3 receptors after birth may mediate different neurodevelopmental aspects of the dopaminergic pathway before and after puberty.     

Differential modulation of dopamine D2 receptors by chronic haloperidol, nitrendipine, and pimozide

Chronic administration of the neuroleptic haloperidol, the calcium channel antagonist nitrendipine, and the calcium channel antagonist neuroleptic pimozide produce differential effects on rat striatal 3H-spiperone binding. Following 7 days of 10 mg/kg i.p. administration, haloperidol significantly increases (p less than 0.01) dopamine D2 receptor binding to 123% +/- 6% of control values, whereas pimozide treatment significantly reduces (p less than 0.001) striatal 3H-spiperone binding to 46% +/- 6% of control values. Chronic administration of the calcium channel antagonist nitrendipine does not alter 3H-spiperone binding relative to control values. Saturation analysis reveals an increase in Bmax following chronic haloperidol and a decrease in Bmax following chronic pimozide treatment. No alterations in muscarinic cholinergic sites, dopamine uptake sites, or calcium channel antagonist sites result following chronic drug administration. These results are the first demonstration of a decrease in dopamine D2 binding sites after chronic neuroleptic treatment.     

Opposite effects of low versus high dose haloperidol treatments on spontaneous and apomorphine induced motor behavior: evidence that at a very low dose haloperidol acts as an indirect dopamine agonist

Anti-psychotic drugs are antagonists at the dopamine D2 receptors and repeated administration can lead to the development of dopamine receptor supersensitivity. In two experiments, separate groups of rats were administered 10 daily low or high doses of the typical anti-psychotic drug haloperidol (0.03 or 1.0 mg/kg). The high dose decreased locomotion whereas, the low dose increased locomotion. After 5 days of withdrawal, all groups received 2.0 mg/kg apomorphine on 5 successive days. The apomorphine treatments given to the vehicle group generated a progressive locomotion sensitization effect and this effect was potentiated by pre-exposure to 0.03 mg/kg haloperidol. Initially, the prior high dose of haloperidol exaggerated the apomorphine locomotor stimulant effect but with repeated apomorphine treatments desensitization developed. Following a 5-day withdrawal period an apomorphine challenge test was conducted and apomorphine sensitization was absent in the haloperidol high dose pre-exposure group but potentiated in the low dose pre-exposure group. In the second replication experiment a conditioning test instead of a sensitization challenge test was conducted 5 days after completion of the 5-day apomorphine treatment protocol. The repeated apomorphine treatments induced conditioned hyper- locomotion and this conditioned effect was prevented by the prior high dose haloperidol pre-exposure but enhanced by the prior low dose haloperidol pre-exposure. Two new key findings are (a) that a low dose haloperidol regimen can function as a dopamine agonist and these effects persist after withdrawal and (b) that repeated apomorphine treatments can desensitize D2 receptors previously sensitized by a high dose haloperidol treatment regimen.     

The NMDA antagonist dizocilpine (MK-801) reverses haloperidol-induced movement initiation deficits

The present study shows that systemic dopamine receptor blockade impaired movement initiation of rats, trained in a simple reaction time task for rapid initiation of locomotion in response to a combined optic/acoustic cue. Reaction time, movement time and the accelerative force were recorded for each initiation of locomotion. Results indicate a dose-related increase of reaction time following systemic administration of haloperidol (0.1, 0.15, 0.3 mg/kg i.p.). Measures derived from resulting force-time patterns showed a haloperidol-induced decrease (0.15 mg/kg i.p.) of the mean rate of force development, indicating a decreased initial acceleration. These effects were reversed by systemic co-administration of dizocilpine (MK-801) (0.08 mg/kg i.p.), a selective non-competitive N-methyl-D-aspartate (NMDA) antagonist. The haloperidol-induced movement initiation deficits in this task are in part comparable to akinesia seen in Parkinson's disease and their reversal by dizocilpine has implications for the treatment of this disease.     

Clozapine, haloperidol, and the D4 antagonist PNU-101387G: in vivo effects on mesocortical, mesolimbic, and nigrostriatal dopamine and serotonin release

Summary. With in vivo microvoltammetry, the dopamine (DA) receptor antagonists, clozapine (D₄/D₂), haloperidol (D₂) and the selective D₄ antagonist, PNU-101387G, were evaluated for their effects on DA and serotonin (5-HT) release within A₁₀ neuronal terminal fields [mesocortical, prefrontal cortex (PFC), mesolimbic, nucleus accumbens, (NAcc)] and within A₉ neuronal terminal fields [nigrostriatal, caudate putamen (CPU)], in chloral hydrate anesthetized rats. Clozapine, which also has 5-HT₂ receptor antagonist properties, significantly (p < 0.001) increased DA release within A₁₀ terminal fields, PFC and NAcc; DA release was not increased by clozapine within A₉ terminals, CPU. Serotonin release was significantly (p < 0.001) increased by clozapine within A₁₀ and A₉ terminal fields. Haloperidol significantly (p < 0.001) increased DA release within PFC, dramatically and significantly (p < 0.001) increased DA release within CPU, but not within NAcc; haloperidol had a small but statistically significant (p < 0.05) increase on 5-HT release within PFC [only at the highest dose studied (2.5 mg/kg)] and within CPU [only at the lowest dose studied 1.0 mg/kg) (p < 0.05)]. The selective D₄ antagonist, PNU-101387G dramatically and significantly (p < 0.001) increased DA release within PFC, modestly, but significantly (p < 0.001) increased DA release within CPU, did not alter DA release within NAcc at the lowest dose studied (1.0 mg/kg) and significantly (p < 0.05) decreased DA release within NAcc at the highest dose studied (1.0 mg/kg). The selective D₄ antagonist did not affect 5-HT release within either A₁₀ or A₉ terminal fields. The present data are discussed in terms of the neurochemistry, antipsychotic activity, and side effect profiles of clozapine and haloperidol, in order to provide comparative profiles for a selective D₄ antagonist, PNU-101387G. Received January 13, 1998; accepted April 27, 1998     

Involvement of the nucleus accumbens–ventral pallidal pathway in postictal behavior induced by a hippocampal afterdischarge in rats

The hypothesis that postictal motor behaviors induced by a hippocampal afterdischarge (AD) are mediated by a pathway through the nucleus accumbens (NAC) and ventral pallidum (VP) was evaluated in freely moving rats. Tetanic stimulation of the hippocampal CA1 evoked an AD of 15–30 s and an increase in number of wet-dog shakes, face washes, rearings and locomotor activity. Bilateral injection of haloperidol (5 μg/side) or the selective dopamine D₂ receptor antagonist, (±)-sulpiride (200 ng/side) before the hippocampal AD, into the NAC selectively reduced rearings and locomotor activity, but not the number of wet-dog shakes and face washes. Injection of R(+)-SCH-23390 (1 μg/side), a D₁ receptor antagonist, or rimcazole (0.4 mg/side), a σ opioid receptor antagonist, into the NAC did not significantly alter postictal behaviors. Bilateral injection of muscimol (1 ng/side), a γ-aminobutyric acid (GABA_A) receptor agonist, into the VP before the AD significantly blocked all postical behaviors. It is concluded that postictal locomotor activity induced by a hippocampal AD is mediated by activation of dopamine D₂ receptors in the NAC and a pathway through the VP.     

Acute prefrontal rTMS increases striatal dopamine to a similar degree as d-amphetamine

Prefrontal repetitive transcranial magnetic stimulation (rTMS) has been shown to increase striatal dopaminergic activity. Here we investigated dopaminergic neurotransmission using single photon emission computed tomography (SPECT) and [¹²³I]IBZM to indirectly assess the change in endogenous striatal dopamine concentration upon rTMS as compared with d-amphetamine challenge. SPECT imaging was performed twice each in five patients during rTMS, and in two patients who received 0.3 mg/kg d-amphetamine. Administration of rTMS led to a mean relative decrease in striatal IBZM binding by 9.6 ± 6.2%, and d-amphetamine challenge (n = 4) induced a mean relative reduction by 8 ± 2.95% (difference not statistically significant). Acute rTMS challenge showed similar striatal dopaminergic effects to those associated with the administration of d-amphetamine, a substance known to increase synaptic dopamine.