Biomedical subjects

J K Rowlett

Publications and source records attributed to J K Rowlett.

At least 55 records · Page 3Linked to original sources

PubMed1996

Assessment of benzodiazepine receptor heterogeneity in vivo: apparent pA2 and pKB analyses from behavioral studies.

The purpose of this review was to establish in vivo apparent pA2 and pKB values for antagonism of the discriminative stimulus effects of benzodiazepine ligands, and to compare these values to those obtained from other behavioral procedures. Articles were chosen from the Medline data base from January 1976 to August 1995. This literature consisted of studies with flumazenil (Ro 15-1788) as the antagonist, as well as other benzodiazepine ligands (beta-carbolines, CGS 9896, CGS 8216). The dose which occasioned 50% of the maximal response (ED50) was obtained from values estimated from the graphs presented in each article. These ED50 values were used to conduct apparent pKB and apparent pA2 analyses. Apparent pA2 values for antagonism of the discriminative stimulus effects of diazepam in rats were the following (antagonist, pA2, slope): flumazenil, 4.7, -1.5; beta-CCE, 4.0, -3.0; beta-CCtB, 5.0, -2.2. The apparent pA2 value for CGS 8216 antagonism of the discriminative stimulus effects of diazepam in rats was 5.74, -2.22 (reported in Shannon and Davis 1984). The mean apparent pA2 value for flumazenil antagonism of the discriminative stimulus effects of diazepam in rhesus monkeys was 6.55, with a mean slope of -1.42. Analysis of baboon data from Ator and Griffiths (1986) revealed apparent pKB values for flumazenil antagonism of the discriminative stimulus effects of lorazepam that were lower than the pKB values for either zopiclone or CL 218,872. Analyses of the pKB data also revealed the following: no effect of route of administration (rat, PO versus IP; baboon, PO versus IM), no effect of pretreatment time (grouped into two categories: 10-20 min and 40-70 min, in rats and non-human primates), and a species effect (pKB values for rats were reliably lower than either non-human primates or pigeons, rhesus monkeys were lower than baboons). The apparent pA2 and pKB values obtained in the present review were similar across behavioral assays, except that, in squirrel monkeys, flumazenil pKB values for antagonism of benzodiazepine-induced decreases in schedule-controlled behavior were lower than pKB values obtained from drug discrimination studies. This review provides apparent pA2 values for antagonism of the discriminative stimulus effects of benzodiazepine ligands and provides evidence from pKB analyses consistent with functional heterogeneity of benzodiazepine receptors in vivo.

Animals↗

PubMed1996

Cocaine-induced behavioral sensitization: effects of haloperidol and SCH 23390 treatments.

The objective of this study was to determine whether the development of behavioral sensitization to cocaine could be prevented by high doses of the dopamine receptor antagonists haloperidol and SCH 23390. In two experiments, male Wistar rats were injected daily for 4 days with either cocaine (15 mg/kg, IP) or vehicle in combination with haloperidol (1.0 mg/kg, IP), SCH 23390 (0.5 mg/kg, SC), or vehicle. After the daily injections, the rats were tested for locomotor activity in photocell arenas. At 24 h after the last preexposure test session, all rats were given a challenge injection of cocaine (15 mg/kg, IP) and tested for activity. Cocaine treatments produced a greater relative increase in locomotor activity with repeated exposure compared to vehicle treatments (i.e., sensitization). Moreover, the acute activating effects of cocaine over days were blocked by both haloperidol and SCH 23390. The coadministration of haloperidol, but not SCH 23390, blocked the development of behavioral sensitization to cocaine. That is, after the cocaine challenge injection, rats pretreated with SCH 23390 and cocaine did not differ from rats preexposed only to cocaine, whereas rats pretreated with haloperidol and cocaine did not differ from rats pretreated only with vehicle. Pretreatment with haloperidol or SCH 23390 without cocaine enhanced the locomotor-activating effects of the subsequent cocaine challenge injection. These findings suggest that cocaine-induced behavioral sensitization may develop as a result of repeated dopamine D1- or D2-type receptor stimulation, and that brief dopamine antagonist treatments enhance subsequent behavioral sensitivity to cocaine.

Animals↗

PubMed1996

Zipeprol: preclinical assessment of abuse potential.

Zipeprol was evaluated in a number of in vitro and in vivo assays predictive of stimulant, depressant, or opioid abuse potential. Zipeprol had affinity for mu and kappa opioid binding sites as well as sigma binding sites. However, it failed to exert opioid-like agonist actions in rodents, and did not attenuate withdrawal signs in morphine- or pentobarbital-dependent rats. Zipeprol did not substitute for either amphetamine or pentobarbital in drug discrimination assays in rhesus monkeys. On the other hand, it suppressed morphine withdrawal signs in rhesus monkeys in two assays, and it acted as a quadazocine-sensitive reinforcer in monkeys trained to self-inject alfentanil. Zipeprol also acted as a reinforcer in monkeys trained to self-inject methohexital. In a dose range of 10-18 mg/kg, zipeprol induced convulsions in monkeys. Zipeprol appears to have abuse potential and a novel spectrum of action involving both opioid and non-opioid effects.

Animals↗

PubMed1995

Ascorbate potentiates amphetamine-induced conditioned place preference and forebrain dopamine release in rats.

In order to evaluate the effects of ascorbate, which is known to modulate dopamine neurotransmission, on the reinforcing effects of amphetamine, we coadministered ascorbate and amphetamine during the acquisition of conditioned place preference (CPP) in rats. Our results indicate that 100 mg/kg ascorbate potentiates the CPP induced by 0.5 mg/kg, but not 1.0 mg/kg, amphetamine. A higher dose of ascorbate (500 mg/kg) did not influence the CPP induced by either dose of amphetamine. In vitro release assays revealed that, whereas ascorbate alone (0.01-1.0 mM) did not influence striatal dopamine levels, this vitamin potentiated amphetamine-induced dopamine release in both the nucleus accumbens and neostriatum. Collectively, these results raise the possibility that ascorbate potentiates amphetamine-induced CPP by increasing the ability of this psychostimulant to release dopamine.

Amphetamine↗

PubMed1995

Repeated quinpirole treatment: locomotor activity, dopamine synthesis, and effects of selective dopamine antagonists.

Repeated treatment with the non-selective dopamine agonist apomorphine results in behavioral sensitization and enhanced dopamine synthesis in dopamine projection fields. To examine the role of D2-type dopamine receptors in modulating these effects, the present experiment assessed the effects of repeated treatment with the D2-type agonist quinpirole on locomotor activity and dopamine synthesis. In the first experiment, rats were treated with vehicle or one of two doses (0.3 or 3.0 mg/kg) of quinpirole for 8 days. Daily measures of locomotor activity revealed an initial suppression of activity produced by quinpirole which dissipated over the 8 days of treatment. A trend for an increase in activity for 3.0 mg/kg quinpirole compared to vehicle was obtained on day 8. Twenty-four hours after cessation of treatment, dopamine synthesis, measured as accumulation of 3,4-dihydroxyphenylalanine (DOPA) after treatment with the DOPA decarboxylase inhibitor NSD-1015, was enhanced in the striatum, but not nucleus accumbens-olfactory tubercle (NAOT) or ventral mesencephalon (VM). In Experiment 2, rats were treated for 8 days with vehicle, 3.0 mg/kg quinpirole or the D1 antagonist SCH 23390 (0.5 mg/kg) in a two (vehicle or quinpirole) x two (vehicle or SCH 23390) design. Quinpirole-alone treatment resulted in a reduction of the locomotor suppressant effects of the drug. SCH 23390-alone and quinpirole-SCH 23390 combined treatment resulted in decreased activity compared to the vehicle control group that did not change across days. DOPA accumulation was enhanced in the striatum and NAOT after quinpirole treatment; however, SCH 23390 had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Conditioned place preference using opiate and stimulant drugs: a meta-analysis.

A meta-analysis was conducted on the data obtained from published articles that have used the conditioned place preference (CPP) paradigm to assess the rewarding effects of morphine, heroin, amphetamine and cocaine in rats. Using a histogram analysis of the data, significant dose-effect curves were evident with all of the drugs examined, except for cocaine. Analysis of the data also revealed that several methodological variables moderated the effect size for CPP, at least with some of the drugs examined. In particular, the following methodological variables significantly moderated CPP effect size: strain of rat used; housing condition (single or group cages); type of apparatus (2 or 3 compartments); preconditioning test (present or absent); route of drug administration; intervening saline trials (present or absent); conditioning trial duration; and drug compartment (nonpreferred, counterbalanced or white). No significant effect size differences were evident using sex, number of drug trials, or test duration as moderator variables in the analyses. These meta-analytic results may be useful to investigators for maximizing the effect size of drug-induced CPP.

Animals↗

PubMed1995

Unit-price analysis of opioid consumption by monkeys responding under a progressive-ratio schedule of drug injection.

Several reports have indicated that drug consumption in self-administration procedures is a function of the ratio of the instrumental requirement to the dose of drug, a quantity termed unit price. We evaluated three predictions from this unit-price model in a reanalysis of data on opioid self-administration in rhesus monkeys responding under a progressive-ratio schedule (Hoffmeister, 1979). We evaluated whether consumption was inversely related to unit price, and compared the goodness of fit of an equation devised by Hursh, Raslear, Shurtleff, Bauman, and Simmons (1988) to that of a linear model predicting consumption as a function of dose. We also tested whether consumption was constant when the same unit price was comprised of different combinations of dose and instrumental requirement. Consumption declined overall as unit price increased. The equation devised by Hursh et al. and the linear model based on dose fit the data equally well. Drug consumption was not uniform at a given unit price. The analyses suggest limits on the unit-price model as a characterization of drug consumption.

Animals↗

PubMed1994

Age-dependent differences in the rate of recovery of striatal dopamine D1 and D2 receptors after inactivation with EEDQ.

Recovery of striatal dopamine D1 and D2 binding sites in 10-, 16-, and 39-day-old rats was measured 1, 2, 4, and 8 days after irreversible antagonism with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Ontogenetic and EEDQ-induced changes in D1 and D2 binding sites were determined by Scatchard analyses using six concentrations of either [3H]SCH 23390 or [3H]spiperone. Twenty-four hours after EEDQ (7.5 mg/kg) treatment, a significant depletion of both dopamine D1 and D2 receptors was found for all age groups; however, the magnitude of the depletion was greater in 39-day-old rats than in the two preweanling age groups. Both 16- and 39-day-old rats showed significant recovery of dopamine D1 and D2 receptors by the eighth day after EEDQ treatment, but the 16-day-old rats showed a faster recovery of dopamine D1 receptors than did the 39-day-olds. Unexpectedly, 10-day-old rats did not show any evidence of receptor recovery, as the percent control values for these animals did not change across the 8-day recovery period. Pretreatment with the dopamine D1 receptor antagonist SCH 23390 and the dopamine D2 receptor antagonist sulpiride was sufficient to protect dopamine D1 and D2 receptors from EEDQ-induced inactivation. Protein values and receptor affinity (pKd values) were not affected by EEDQ treatment at any of the ages tested. Therefore, these results indicate that the rate of dopamine receptor repopulation varies across ontogeny, with 10-day-old rats exhibiting slower recovery than older rat pups or postweanling rats.

Aging↗

PubMed1994

Dissociation of buprenorphine-induced locomotor sensitization and conditioned place preference in rats.

The locomotor and rewarding effects of the opioid mixed agonist-antagonist buprenorphine were assessed in a conditioned place preference (CPP) experiment. Separate groups of rats were given one of three doses of buprenorphine (0.3, 1.0 or 3.0 mg/kg) or saline paired with the white compartment of a CPP apparatus. The following day, all rats received saline paired with the black compartment. After six conditioning trials, rats were given free access to all compartments of the CPP apparatus. Horizontal activity data obtained during conditioning revealed increased activity (i.e., behavioral sensitization) for the three doses on trial 6. Vertical activity data revealed significant increases on trial 6 for the 1.0 and 3.0 mg/kg doses only. Significant CPP was obtained with the 0.3 mg/kg and 1.0 mg/kg doses of buprenorphine, but not with the 3.0 mg/kg dose. These data indicate that buprenorphine elicits locomotor sensitization after repeated exposures that follows a linear dose-response relationship. In contrast, these data suggest that the rewarding effects of buprenorphine follow an inverted U-shaped dose-response curve.

Animals↗

PubMed1993

Neurochemical correlates of behavioral sensitization following repeated apomorphine treatment: assessment of the role of D1 dopamine receptor stimulation.

Previous research has revealed a role of repeated D1 dopamine receptor stimulation in the development of behavioral sensitization to the D1/D2 agonist apomorphine. The present experiments assessed the role of repeated D1 receptor stimulation in neurochemical changes accompanying locomotor sensitization to apomorphine. To assess direct effects of D1 stimulation on dopamine synthesis, rats were injected with the D1 agonist SKF 38393 (8 mg/kg), followed by an injection with the 3,4-dihydroxyphenylalanine (DOPA) decarboxylase inhibitor, NSD-1015. DOPA accumulation, assessed in striatal, nucleus accumbens-olfactory tubercle (NAOT), and ventral mesencephalon (VM) tissue samples, was not affected by acute SKF 38393. In the second experiment, rats were treated with 10 daily injections of vehicle, apomorphine (5 mg/kg) or the D1 agonist SKF 38393 (8 or 16 mg/kg). Daily measures of locomotor activity demonstrated a progressive increase in the apomorphine-treated rats, but not the SKF 38393-treated rats, across the 10 days. On day 11, all rats were injected with NSD-1015 for measurement of DOPA accumulation. Dopamine synthesis was enhanced in the striatum after repeated apomorphine treatment. In contrast, repeated SKF 38393 treatment resulted in either a small decrease or no change in DOPA accumulation in the different brain regions (striatum, NAOT, VM). In the third experiment, tissue levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and [3H]SCH 23390 binding to D1 receptors were measured in rats treated with 10 daily injections of vehicle, apomorphine (5 mg/kg), or SKF 38393 (16 mg/kg). In the striatum and NAOT, none of the repeated drug treatments had an effect on DOPAC or dopamine levels.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1993

Effects of daily SKF 38393, quinpirole, and SCH 23390 treatments on locomotor activity and subsequent sensitivity to apomorphine.

In three experiments, male Wistar rats (250-350 g) were injected (SC) daily with the D1-type dopamine receptor agonist, SKF 38393 (0.0, 4.0, 8.0, or 16.0 mg/kg), the D2-type dopamine receptor agonist, quinpirole (0.0, 0.3, or 3.0 mg/kg), and/or the D1-type dopamine receptor antagonist, SCH 23390 (0.0 or 0.5 mg/kg) for 8-10 days. After each daily injection, the rats were tested for locomotor activity in photocell arenas for 20 min. Following this subchronic pretreatment, all rats were challenged with the mixed dopamine receptor agonist apomorphine (1.0 mg/kg, SC) and tested for locomotor activity. SKF 38393 treatments produced a dose-dependent decrease in locomotor activity which did not significantly change across days. Quinpirole also depressed locomotor activity when first injected, but this quinpirole-induced inhibition of activity progressively decreased across days. When subsequently challenged with apomorphine, rats in both the SKF 38393 and the quinpirole pretreatment groups displayed greater locomotor activity than rats pretreated with only vehicle. Although SCH 23390 pretreatments did not affect subsequent sensitivity to apomorphine, SCH 23390 completely blocked the effect of quinpirole. These results suggest that although repeated D1 receptor stimulation may be sufficient to induce behavioral sensitization to apomorphine, D2 receptor stimulation also contributes to the effect.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1993

The effect of environmental enrichment on amphetamine-stimulated locomotor activity, dopamine synthesis and dopamine release.

In two separate experiments, rats were raised in either an enriched condition (EC) or impoverished condition (IC) from 21 to 60 days of age. Experiment 1 assessed amphetamine-stimulated locomotor activity and in vivo dopamine (DA) synthesis and metabolism in the nucleus accumbens (NA) and striatum (Str). In Experiment 2, amphetamine-stimulated DA release in the NA and Str was assessed in vitro. The results showed that EC rats have lower basal levels of locomotor activity than IC rats. However, in the presence of amphetamine, EC rats showed a greater increase in locomotion over IC when compared to their own controls. Concomitant with this behavioral difference, EC rats also showed an enhanced neurochemical response to amphetamine in vivo. That is, relative to IC rats, amphetamine produced a greater synthesis of DA in the Str of EC rats, as well as a greater metabolism of DA in the NA of EC rats. In the in vitro DA release experiment, EC rats had a lower concentration of tissue DA than IC. However, in contrast to the in vivo experiment, there were no significant differences between EC and IC rats in amphetamine-stimulated release of DA in vitro in either the Str or NA. The failure of amphetamine to produce differential neurochemical effects in EC and IC rats in vitro may be because this experiment eliminated either pharmacokinetic effects or neurochemical differences in brain regions outside the NA and Str.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Depletion of dopamine binding sites and changes in dopamine and dihydroxyphenylacetic acid levels in 17- and 90-day-old rat striatum after irreversible receptor antagonism.

Irreversible antagonism of dopamine (DA) receptors by the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) results in a depression of DA agonist mediated behaviors in adult, but not preweanling rats. DA D1 and D2 receptors, dihydroxyphenylacetic acid (DOPAC) and DA levels were assessed in 17- and 90-day-old rats in order to identify a neurochemical mechanism for this difference. EEDQ caused a depletion in D1 and D2 receptors in both young and adult rats, with the depletion in adults being relatively greater. In both age groups, EEDQ caused an unexpected decrease in DA levels which returned to normal levels by 30 days post-injection. In addition, DOPAC levels of adult rats, but not rat pups, were elevated after EEDQ treatment. The depletion of endogenous DA levels must be considered when interpreting the effects of EEDQ. Age-dependent differences in DA metabolism may be important for understanding the ontogenetic differences in EEDQ's behavioral effects.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Serotonin, but not dopamine, metabolites are increased in selected brain regions of subordinate male rats in a colony environment.

Subordinate male laboratory rats maintained in mixed-sex groups in a Visible Burrow System habitat show a complex pattern of stress-related changes including enhanced defensive behavior, early mortality and increased voluntary ethanol consumption. Analysis of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels indicated that 5-HT levels do not differ between colony subordinates, colony dominants, and singly-housed control animals. However, 5-HIAA levels were higher in subordinates than either dominants or control animals in the preoptic area, amygdala, hippocampus, and spinal cord, and, were higher than dominants only, in entorhinal cortex. Subordinates' regional 5-HIAA/5-HT ratios were reliably higher than those of dominant or control animals in midbrain and spinal cord and reliably higher than dominants only, in hypothalamus. Dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels and DA/DOPAC ratios were affected neither in hypothalamus nor midbrain. These findings suggest that a consistent increase of 5-HIAA levels in selected brain regions of subordinate rats may represent a biological substrate for a well-characterized pattern of alterations in defensive behaviors for these animals.

Animals↗

PubMed1991

Effects of selective D1 and D2 dopamine antagonists on the development of behavioral sensitization to apomorphine.

The objective of the present study was to determine whether the development of behavioral sensitization to apomorphine could be blocked by either D1 or D2 selective dopamine antagonists. In three experiments, male rats received 10-21 daily injections of a selective D1 (SCH 23390; 0 or 0.5 mg/kg IP) or D2 (sulpiride; 0, 30, or 100 mg/kg IP) antagonist followed by an apomorphine (0 or 1.0 mg/kg SC) injection. In two experiments, the rats were tested for locomotor activity in photocell arenas after the daily injections. In all experiments, the rats were tested for sensitization to apomorphine following the training phase. The results indicated that apomorphine produced a progressively greater increase in locomotor activity with each injection, and this apomorphine-induced increase in activity was completely blocked by both sulpiride and SCH 23390 treatments. However, although both sulpiride and SCH 23390 blocked apomorphine-induced activity, only SCH 23390 injections prevented the development of sensitization to apomorphine. That is, rats pretreated with sulpiride and apomorphine displayed significant sensitization when subsequently tested with a challenge dose of apomorphine alone. These findings suggest that the development of behavioral sensitization to apomorphine is related specifically to the stimulation of dopamine D1 receptors.

Analysis of Variance↗

PubMed1991

Neurochemical and behavioral effects of acute and chronic treatment with apomorphine in rats.

In three experiments, rats were injected once daily with 5.0 mg/kg apomorphine or vehicle and tested for locomotor activity for 10-14 days. In each experiment, apomorphine produced behavioral sensitization, characterized by a progressively greater increase in locomotor activity with each succeeding injection. On day 11 of testing, in an experiment designed to assess the synthesis of dopamine (DA), rats were injected with 5.0 mg/kg apomorphine or vehicle, followed by 100 mg/kg NSD-1015, an inhibitor of the enzyme l-aromatic amino acid decarboxylase. After administration of NSD-1015, concentrations of dihydroxyphenylalanine (DOPA) were determined in striatal and mesolimbic tissues by high performance liquid chromatography (HPLC) with electrochemical detection. The results revealed a significant decrease in accumulation of DOPA in both striatal and mesolimbic tissue after acute treatment with apomorphine. More important, chronic treatment with apomorphine produced a significant increase in accumulation of DOPA in both areas. In subsequent experiments, rats on day 14 of testing were sacrificed for determination of levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) or specific binding of [3H]spiperone in the striatum and mesolimbic region. Although levels of DOPAC were significantly reduced in the regions of the brain after an acute injection of apomorphine, chronic treatment with apomorphine did not significantly affect levels of DA, DOPAC or specific binding of [3H]spiperone. These findings suggest that the development of behavioral sensitization to apomorphine may be related to an alteration in the synthesis of DA.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Catalepsy produced by striatal microinjections of the D1 dopamine receptor antagonist SCH 23390 in neonatal rats.

Systemic injection of the D1 dopamine receptor antagonist SCH 23390 produces catalepsy that is of lesser magnitude in neonatal than in adult rats. The present experiments were conducted in order to determine if SCH 23390 would produce catalepsy in neonatal rats following intrastriatal injection and if the ontogenetic pattern of catalepsy induced by intrastriatal SCH 23390 would be similar to the pattern observed with systemic injections. Rat pups (11 or 28 days of age) were microinjected unilaterally with SCH 23390 (0.2, 1, 5 or 10 micrograms) and tested for catalepsy using the forepaw-on-horizontal-bar test. The results demonstrated that robust catalepsy occurred at both ages following intrastriatal injection and that catalepsy induced by 5 micrograms SCH 23390 was of lesser magnitude in 11-day-olds than in 28-day-olds. A separate study assessed the distribution of [3H]SCH 23390 (5 micrograms) following intrastriatal injection in 28-day-olds. Results of the distribution study indicated that [3H]SCH 23390 was localized primarily within the striatum. Taken together, these results suggest that the striatal mechanisms for catalepsy produced by D1 receptor blockade are present, but not fully mature, in preweanling rat pups.

Age Factors↗

PubMed1991

Chronic ascorbate potentiates the effects of chronic haloperidol on behavioral supersensitivity but not D2 dopamine receptor binding.

Ample behavioral evidence suggests that ascorbate parallels the action of haloperidol, a widely used neuroleptic. To determine the extent to which this parallel extends to chronic treatment, 21 days of exposure to ascorbate (100 or 500 mg/kg) alone or combined with haloperidol (0.5 mg/kg) were assessed on stereotyped behavior and neostriatal D2 dopamine receptor binding in rats. Our results indicate that when challenged with the dopamine agonist, apomorphine (0.5 mg/kg), animals chronically treated with haloperidol or high-dose ascorbate alone display a supersensitive sniffing response relative to controls, while animals chronically treated with the combination of haloperidol and high-dose ascorbate display a further potentiation of sniffing relative to the haloperidol groups. In addition, [3H]spiperone saturation studies showed, as expected, an up-regulation of striatal D2 dopamine receptors in rats treated with haloperidol as reflected by a change in receptor density (Bmax) but not affinity (KD). Ascorbate treatment, however, had no effect on D2 receptor density or the distribution of [3H]apomorphine in whole brain. Even though chronic treatment with the haloperidol-high-dose-ascorbate combination produced an up-regulation of striatal D2 dopamine receptors, this treatment did not cause a further up-regulation relative to haloperidol alone nor did it have any effect on [3H]apomorphine distribution. Taken together, these findings indicate that although chronic ascorbate produces behavioral supersensitivity to apomorphine through central mechanisms, they appear to differ from those induced by chronic haloperidol.

Amphetamines↗