Studies on the role of dopamine D1 receptors in the development and expression of MDMA-induced behavioral sensitization in rats

Rationale There is a large body of evidence indicating that the mesoaccumbens dopamine pathway is critically involved in the expression of behavioral sensitization to amphetamine and cocaine, but its role in the development of sensitization to psychostimulants is not that sound. Very few studies, however, have examined the role of dopamine transmission in 3,4-methylenedioxymethamphetamine (MDMA)-induced sensitization.Objectives The effects of the D1 receptor antagonist SCH 23390 on the development and expression of MDMA-induced behavioral sensitization were investigated in rats.Methods During the development phase of sensitization, SCH 23390 was administered 15 min before every administration of MDMA. After 12 days of withdrawal, a MDMA challenge dose was given and locomotor activity was measured. In separate experiments, 15 min before the challenge injection of MDMA, SCH 23390 was administered either systemically or directly into the core of the nucleus accumbens (NAc) of MDMA-pretreated rats.Results SCH 23390 did not prevent the development of MDMA-induced behavioral sensitization but completely blocked the expression when given before the challenge dose of MDMA. The same results were obtained when SCH 23390 was locally applied into the core of the NAc.Conclusions The present data suggest that D1 receptor stimulation is not critical for the development of long-term MDMA sensitization, in agreement with what has been reported for cocaine. By contrast, expression of sensitization depends on the activation of D1 receptors located in the NAc core.     

Behavioral sensitization to quinpirole is not associated with increased nucleus accumbens dopamine overflow

This study assessed the relationship between extracellular nucleus accumbens (NAc) dopamine (DA) concentrations and sensitized locomotor activation following repeated administration of the DA D2-like receptor agonist quinpirole. Locomotor activity measures and nucleus accumbens microdialysis samples were collected concurrently in response to the first (acute) and tenth (repeated) quinpirole injection (0.5 mg/kg s.c., every other day). Results indicate that acute quinpirole produced locomotor activation and that repeated quinpirole resulted in locomotor sensitization. Acute quinpirole significantly decreased the detection of extracellular concentrations of DA and the DA metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the NAc. Following repeated quinpirole, basal NAc DA levels were decreased, whereas basal DOPAC levels were increased. Nevertheless, quinpirole challenge elicited a significant decrease in DA, DOPAC and HVA following repeated treatment. In addition, although acute quinpirole did not affect NAc levels of the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA), quinpirole challenge produced a significant increase in 5-HIAA levels following repeated treatment. Taken together, these data indicate that functional DA autoreceptor subsensitivity is not a necessary condition for the expression of behavioral sensitization to quinpirole. Instead, it appears that behavioral sensitization to quinpirole occurs predominantly as a consequence of neuroadaptations that are post-synaptic to DA release.     

Hippocampal dopamine receptors modulate the motor activation and the increase in dopamine levels in the rat nucleus accumbens evoked by chemical stimulation of the ventral hippocampus.

A number of studies have shown that chemical stimulation (using N-methyl-D-aspartate (NMDA) infusions) or electrical stimulation of the ventral hippocampus (VH) elicits locomotor activation and sustained increases in nucleus accumbens (NAc) dopamine (DA) levels in rodents. How DA neurotransmission in NAc is involved in these effects has also been well established. However, the modulatory role of the DA receptors located in VH is not yet fully understood. The purpose of this study was to characterize the role played by VH D1 and D2 subtype receptors in both the locomotor activation and NAc DA increases induced by NMDA stimulation of the VH. This was assessed by studying how retrodialysis application of NMDA (50 mM, 10 min) affects motor activity and NAc DA levels during simultaneous retrodialysis administration of the D1/D5 receptor antagonist SCH 23390 (100 and 250 microM, 60 min) or the D2 receptor antagonist raclopride (100 and 250 microM, 60 min). SCH 23390 attenuated or completely abolished NMDA-evoked locomotor activation and the concurrent increase in NAc DA levels. On the other hand, raclopride was initially able to attenuate the effects of VH NMDA stimulation. However, in the last phase of the experiments, animals showed an important increase in clonic seizure activity with a simultaneous and dramatic increase in NAc DA levels. Our results show that the NMDA receptor-mediated effects in the VH require both D1 and, probably, D2 receptors and suggest that DA in VH strongly modulates the excitatory outputs from this brain area.     

Locomotor stimulant effects of nornicotine: role of dopamine

Nornicotine (NORNIC) is a tobacco alkaloid and behaviorally active nicotine metabolite in vivo. Previous behavioral research has shown that NORNIC has locomotor stimulant and reinforcing effects in rats similar to that of nicotine. Results from the current study showed that a bilateral lesion of the nucleus accumbens decreased the locomotor stimulant effect of NORNIC across repeated injections. Pretreatment with the dopamine (DA) D1 receptor antagonist SCH23390 did not block the locomotor stimulant effect of NORNIC or the initiation of sensitization following repeated NORNIC administration. The D2 receptor antagonist eticlopride, however, blocked both the stimulant effect and the initiation of sensitization following repeated NORNIC. Additionally, NORNIC was found to increase synthesis and metabolism of DA, with a greater effect in the mesolimbic pathway compared to the nigrostriatal pathway. Taken together, these results suggest that expression of NORNIC-induced locomotor activity is dependent upon ascending dopaminergic mesolimbic projections, providing additional evidence that NORNIC plays a contributory role in tobacco dependence.     

Inhibitory effects of MK-801 on contextual sensitization to climbing behavior and on development of tolerance to hypothermia induced by a single high dose of apomorphine

A single high dose of apomorphine (10 mg x kg(-1)) produced not only contextual sensitization to and conditioning of climbing behavior, but also context-independent tolerance to hypothermia. MK-801 (0.15 and 0.3 mg x kg(-1)) inhibited contextual sensitization to and conditioning of climbing behavior. Development of tolerance to hypothermia was also inhibited by MK-801. Dopamine D1 antagonist, SCH23390 (0.5 mg x kg(-1)), but not D2 antagonist, sulpiride, inhibited sensitization to and conditioning of climbing behavior. D2 antagonist, sulpiride (50 mg x kg(-1)), but not D1 antagonist, SCH23390, inhibited development of tolerance to hypothermia. These results suggest that MK-801 inhibited contextual sensitization to climbing behavior and development of tolerance to hypothermia through glutamatergic modulation of dopaminergic functions at dopamine receptors.     

Effects of blockade of NMDA receptors and NO synthase on the expression of associative and non-associative sensitization to effects of cocaine

After repeated administration of psychostimulant drugs, a sensitization rather than a tolerance to the behavioral effects can be observed. In our own previous studies, it was shown that both blockade of NMDA glutamate receptors and inhibition of NO synthase selectively inhibited the expression of associative but not non-associative sensitization to D-amphetamine. The present experiments were performed in order to study whether a similar selective inhibition of expression of associative sensitization to cocaine can be observed after blockade of NMDA receptors by MK-801 or inhibition of NO synthase by L-NAME. MK-801 as well as L-NAME inhibited the locomotor activity in acutely cocaine-treated rats. Both drugs did not prevent the sensitization either in the associative or the non-associative group. The results suggest that the acute locomotor effects of cocaine were inhibited by both drugs whereas both the non-associative and the associative sensitization to locomotor effects were not inhibited by blockade of NMDA receptors or inhibition of NO synthase. Accordingly, the expression of neither type of sensitization to cocaine was inhibited by any of these drugs.     

Development of behavioral sensitization to the cocaine-like fungicide triadimefon is prevented by AMPA, NMDa, DA D1 but not DA D2 receptor antagonists.

Triadimefon (TDF) is a triazole fungicide that blocks the reuptake of dopamine (DA) and leads to increased locomotor activity levels in mice and rats, effects similar to those of indirect DA agonists such as cocaine. We recently found in mice that intermittent TDF administration led to robust locomotor sensitization, a phenomenon reflecting neuronal plasticity, following challenge with the same TDF dose after a 2-week withdrawal period. The current study sought to determine whether antagonists to DA D1-like receptors (SCH 23390; SCH), DA D2-like receptors (remoxipride; Rem), ionotropic glutamate n-methyl-d-aspartate (NMDA) receptors (CPP), or ionotropic glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (NBQX) could prevent the development of TDF behavioral sensitization, therefore indicating their mechanistic involvement in TDF sensitization. Mice were treated with either vehicle, SCH (0.015 mg/kg), remoxipride (Rem, 0.3 mg/kg), CPP (2.5 mg/kg) or NBQX (10.0 mg/kg), followed 30 min later by vehicle or 75 mg/kg TDF (TDF), twice a week for 7 weeks, with locomotor activity measured post-dosing once a week. After a 2-week withdrawal period, mice were challenged with 75 mg/kg TDF or vehicle, to test for the presence of behavioral sensitization. Pretreatment with SCH, CPP, or NBQX, but not Rem, blocked the development of behavioral sensitization to TDF specifically for vertical activity. Antagonists that blocked TDF vertical sensitization also attenuated the increase in extracellular DA turnover (homovanillic acid [HVA]/DA) normally associated with this behavioral response. Therefore, DA D1, NMDA and AMPA receptors appear to be necessary for the development of behavioral sensitization to TDF. As such, TDF may be considered an environmental risk factor for behavioral dysfunctions linked to glutamatergic and dopaminergic systems.     

Evidence for dissociable mechanisms of amphetamine-and stress-induced behavioral sensitization: effects of MK-801 and haloperidol pretreatment

The present study examined the ability of pretreatment with MK-801 or haloperidol to block the induction of behavioral sensitization to amphetamine challenge by repeated immobilization stress in male Sprague-Dawley rats. Fifteen minutes before each of ten 30-min restraint sessions, rats were administered saline, MK-801 (0.01, 0.10 or 0.25 mg/kg IP) or haloperidol (0.10 or 0.25 mg/kg IP). Control rats received the same injection regimen without restraint. An additional experiment examined the ability of MK-801 to block the induction of sensitization by repeatedd-amphetamine. In this experiment, rats were administered saline or MK-801 (0.25 mg/kg IP) 15 min before each of ten amphetamine injections (1.0 mg/kg IP, administered under the same regimen as immobilization stress). Four days after the final immobilization or amphetamine injection, rats were tested for locomotor response to novelty, saline andd-amphetamine (1.5 mg/kg IP). Exposure to repeated immobilization stress significantly enhanced the locomotor response to amphetamine challenge but not to saline challenge whether rats were pretreated with saline, MK-801 or haloperidol. Secondary analysis of dose effects in each pretreatment group revealed that at 0.25 mg/kg, repeated MK-801 in itself induced sensitization to the response to amphetamine in control rats and potentiated stress-induced sensitization in restrained rats. In contrast, the sensitization induced by repeated amphetamine was attenuated by MK-801 pretreatment. Neither dose of haloperidol affected the locomotor response to saline or amphetamine in control or stressed rats. These results indicate that the effects of MK-801 on the induction of sensitization are complex and suggest that amphetamine-and stress-induced behavioral sensitization may arise through different mechanisms.     

The role of D1 and D2 dopamine receptors in the acquisition and expression of cocaine-induced conditioned increases in locomotor behavior

Certain motoric effects of cocaine increase in intensity with repetitive administration. Conditioned drug effects are among primary determinants of such sensitization. The purpose of these experiments was to evaluate the role of D1 and D2 dopamine (DA) receptor mechanisms in the acquisition and expression of cocaine conditioning. On Day 1, rats were injected with cocaine (40mg/kg) either before (PAIRED) or after (UNPAIRED) exposure to a locomotor activity chamber. On Day 2, all animals were injected with a low dose of cocaine (10mg/kg) prior to placement in the locomotor chambers. Conditioning on Day 2 was evidenced by significantly higher activity levels in the PAIRED group relative to the UNPAIRED or saline-treated groups. Pretreatment with D1 (SCH 23390) or D2 (raclopride, sulpiride, haloperidol) DA antagonists on Day 1 prevented the development of conditioning as assessed on Day 2, indicating that both receptor subtypes are involved in acquisition. However, pretreatment with raclopride or SCH 23390 on Day 2, prior to cocaine injections, did not eliminate the differences in behavior between the conditioned and non-conditioned groups. Neither D1 (SKF 82958, SKF 38393) nor D2 (quinpirole) agonists administered alone were effective in establishing conditioning, while a combination of SKF 82958 and quinpirole was effective, suggesting that conditioning in this experimental paradigm requires the concurrent activation of both receptor subtypes. In the final study it was found that conditioned cocaine effects could be revealed only in the presence of quinpirole or apomorphine on Day 2. The D1 agonists (SKF 38393 and SKF 82958) were ineffective. This would suggest either that only quinpirole and apomorphine are effective in amplifying the conditioned effects of cocaine on Day 2 or that the cues produced by these drugs are more similar to those produced by cocaine than those produced by D1 agonists.     

Haloperidol conditioned catalepsy in rats: a possible role for D1-like receptors

Decreases in brain dopamine (DA) lead to catalepsy, quantified by the time a rat remains with its forepaws resting on a suspended horizontal bar. Low doses of the DA D2 receptor-preferring antagonist haloperidol repeatedly injected in a particular environment lead to gradual day-to-day increases in catalepsy (catalepsy sensitization) and subsequent testing following an injection of saline reveal conditioned catalepsy. We tested the hypothesis that D1-like and D2 receptors play different roles in catalepsy sensitization and in acquisition and expression of conditioned catalepsy. Rats were repeatedly treated with the DA D1-like receptor antagonist SCH 23990 (0.05, 0.1 and 0.25 mg/kg i.p.), the D2 receptor-preferring antagonist haloperidol (0.1, 0.25 and 0.5 mg/kg i.p.) or a combination of the two drugs and tested for catalepsy each day in the same environment. Following 10 drug treatment days, rats were injected with saline and tested for conditioned catalepsy in the previously drug-paired environment. Haloperidol did not elicit cataleptic responses in the initial session; however, rats developed sensitization with repeated testing. Significant catalepsy sensitization was not observed in rats repeatedly tested with SCH 23390. When rats were injected and tested with saline following haloperidol sensitization they exhibited conditioned catalepsy in the test environment; conditioned catalepsy was not seen following SCH 23390. Rats treated with 0.05 mg/kg SCH 23390+0.25 mg/kg haloperidol showed catalepsy sensitization but failed to show conditioned catalepsy. Conversely, SCH 23390 (0.05 mg/kg) given on the test day after sensitization to haloperidol (0.25 mg/kg) failed to block conditioned catalepsy. Repeated antagonism of D2 receptors leads to catalepsy sensitization with repeated testing in a specific environment. Conditioned catalepsy requires intact D1-like receptor function during sensitization sessions but not during test sessions. In conclusion, repeated antagonism of D2, but not D1-like receptors leads to catalepsy sensitization with repeated testing in a specific environment. Conditioned catalepsy requires functional D1-like receptors during sensitization sessions but not during test sessions.     

Effects of dopamine D1 and D2 receptor blockade on MK-801-induced hyperlocomotion in rats

Blocking glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptor complex with MK-801 (0.15–0.5 mg/kg, IP) was found to induce a robust, dose-dependent increase in locomotor activity. This behavioural activation was similar in intensity to that observed afterd-amphetamine (1 mg/kg, SC). The locomotor stimulation induced by MK-801 at 0.3 mg/kg was significantly inhibited by the D₂ dopamine receptor antagonist raclopride (0.1–0.3 mg/kg, SC) and by the D₁ receptor antagonist SCH 23390 (0.04 mg/kg, SC). The locomotor activity induced by a higher dose of MK-801 (0.5 mg/kg) was reduced by higher doses of raclopride or SCH 23390 administered alone (0.3 and 0.08 mg/kg, respectively), and was inhibited by simultaneous administration of ineffective doses. Raclopride significantly reducedd-amphetamine-induced locomotor activity at a dose (0.2 mg/kg) that also blocked the effects of a low dose of MK-801. In contrast, SCH 23390 blocked the effects ofd-amphetamine at a dose (i.e. 0.01 mg/kg) lower than that needed to block MK-801. These results suggest that the dopaminergic system may in part mediate the locomotor effects induced by the NMDA antagonist, MK-801, in rats. However, the locomotor activity induced by MK-801 appears to be less sensitive to dopaminergic receptor blockade than that induced byd-amphetamine, suggesting that the underlying mechanisms, although similar, are not identical.     

D1/D2 dopamine and N-methyl-d-aspartate (NMDA) receptor participation in experimental catalepsy in rats

Mixed D₁/D₂ dopamine (DA) antagonists, perphenazine (5 mg/kg) and haloperidol (2 mg/kg) induced catalepsy in rats. SCH 23390 (1 mg/kg), a D₁ DA antagonist, also produced catalepsy. Co-administration of perphenazine (0.5 mg/kg) and SCH 23390 (0.1 mg/kg), at low doses, produced a marked increase in cataleptic response. B-HT 920, a D₂ agonist, reversed the cataleptogenic effects of perphenazine, haloperidol and SCH 23390. SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy. SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy. Combined administration of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) enhanced the protective effect of B-HT 920 in SCH 23390-treated animals but not in animals treated with haloperidol or perphenazine. MK-801 (0.025–0.5 mg/kg), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reduced the cataleptogenic effects of perphenazine, haloperidol as well as SCH 23390. The anticataleptic action of MK-801 was enhanced by scopolamine (0.1 mg/kg) but not by bromocriptine (1 mg/kg) or clonidine (0.05 mg/kg) in perphenazine-treated rats. Unlike B-HT 920 (0.1 mg/kg), SKF 38393 (5 mg/kg) potentiated the anticataleptic effect of MK-801 (0.01 mg/kg) against SCH 23390-induced catalepsy. The above data suggests D₁/D₂ interdependence in catalepsy and a modulatory role of D₁ and D₂ DA receptor stimulation on the anticataleptic effect of MK-801.     

Inhibitory effects of ginseng total saponins on behavioral sensitization and dopamine release induced by cocaine

Many studies have suggested that the behavioral and reinforcing effects of cocaine can be mediated by the central dopaminergic systems. It has been shown that repeated injections of cocaine produce an increase in locomotor activity, the expression of the immediate-early gene, c-fos, and the release of dopamine (DA) in the nucleus accumbens (NAc), which is one of the main dopaminergic terminal areas. Several studies have shown that behavioral activation and changes in extracellular dopamine levels in the central nervous system induced by psychomotor stimulants are prevented by ginseng total saponins (GTS). In order to investigate the effects of GTS on the repeated cocaine-induced behavioral and neurochemical alterations, we examined the influence of GTS on the cocaine-induced behavioral sensitization and on c-Fos expression in the brain using immunohistochemistry in rats repeatedly treated with cocaine. We also examined the effect of GTS on cocaine-induced dopamine release in the NAc of freely moving rats repeatedly treated with cocaine using an in vivo microdialysis technique. Pretreatment with GTS (100, 200, 400 mg/kg, i.p.) 30 min before the daily injections of cocaine (15 mg/kg, i.p.) significantly inhibited the repeated cocaine-induced increase in locomotor activity as well as the c-Fos expression in the core and shell in a dose-dependent manner. Also, pretreatment with GTS significantly decreased the repeated cocaine-induced increase in dopamine release in the NAc. Our data demonstrate that the inhibitory effects of GTS on the repeated cocaine-induced behavioral sensitization were closely associated with the reduction of dopamine release and the postsynaptic neuronal activity. The results of the present study suggest that GTS may be effective for inhibiting the behavioral effects of cocaine by possibly modulating the central dopaminergic system. These results also suggest that GTS may prove to be a useful therapeutic agent for cocaine addiction.     

Selective antagonism of dopamine D1 and D2 receptors does not block the development of behavioral sensitization to cocaine

The objective of this study was to determine whether the development of behavioral sensitization to cocaine could be prevented by either D₁ or D₂ selective dopamine receptor antagonists. Male Wistar rats were treated daily for 7 days with either cocaine (15 mg/kg, IP) or vehicle in combination with the D₁ dopamine antagonist SCH 23390 (0.3 mg/kg, SC), the D₂ dopamine antagonist sulpiride (100 mg/kg, IP), or vehicle. After the daily injections, the rats were tested for locomotor activity in photocell arenas. Twenty-four hours after the last pre-exposure 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 (i.e. sensitization). Moreover, this increase in cocaine-induced locomotor activity was attenuated by both SCH 23390 and sulpiride. In contrast, neither sulpiride nor SCH 23390 blocked the development of behavioral sensitization to cocaine. That is, rats pretreated with sulpiride or SCH 23390 and cocaine did not differ from rats pre-exposed only to cocaine when given a cocaine challenge injection. These results suggest that behavioral sensitization to cocaine may develop through either D₁ or D₂ dopamine receptor stimulation or possibly through stimulation of some non-dopaminergic receptor.Portions of this paper were presented at the 1992 Society for Neuroscience meetings, Anaheim, Cal., USA     

Effects of irreversible dopamine receptor inactivation on locomotor activity and grooming in the 17- and 90-day-old rat

Ontogenetic differences in the behavioral recovery of R(-)-propylnorapomorphine (NPA) treated rats were assessed following irreversible DA receptor antagonism by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). In the first two experiments, 17-and 90-day-old rats were given EEDQ (7.5 or 15.0 mg/kg, IP) or vehicle after half the rats were initially treated with the selective DA D-1 and D-2 antagonists SCH 23390 and sulpiride. (The sulpiride/SCH 23390 treatment protects DA receptors from EEDQ-induced inactivation.) NPA's (0.1 or 1.0 mg/kg) effects on locomotor activity and grooming were assessed 1, 2, 4 and 8 days after the EEDQ pretreatment. In a third experiment, the effects of habituating the 17- and 90-day-old rats to the testing chamber were assessed 1, 2 and 4 days after EEDQ pretreatment. In this experiment, some groups received successive treatments of saline or NPA prior to behavioral testing. To assess the possible effects of drug-sensitization other groups received saline on days 1 and 2 and NPA on day 4. In 90-day-old rats, EEDQ eliminated, for up to 4 days, the ability of NPA to enhance locomotor activity and depress grooming. Prior treatment with DA antagonist drugs was sufficient to protect DA receptors from EEDQ-induced inactivation, since these groups exhibited normal behavioral responses after challenge with NPA. In contrast, EEDQ did not eliminate, and may have enhanced, NPA's effects on the locomotor activity and grooming of 17-day-old rat pups. Habituating the rats to the testing chamber decreased the locomotor activity of the mature rats, but not the 17-day-old rat pups. Drug sensitization did affect locomotor activity, but could not account for the behavioral recovery exhibited by the mature rats and pups. These results indicate that the behavioral effects of EEDQ differ dramatically in young rats compared to adults. The neurochemical bases for these ontogenetic differences remain unknown.     

The effect of antidepressant drugs on the locomotor hyperactivity induced by MK-801, a non-competitive NMDA receptor antagonist.

It was found earlier that imipramine, amitriptyline and citalopram enhanced the locomotor hyperactivity induced by MK-801, a non-competitive NMDA receptor antagonist, in rats. Now, three other antidepressants: (+)-oxaprotiline, an inhibitor of the uptake of noradrenaline, (-)-oxaprotiline, an enantiomer devoid of any effect on the uptake of noradrenaline and fluoxetine, an inhibitor of the uptake of 5-hydroxytryptamine, have been examined in male Wistar rats. All those antidepressants, given in a single dose, increased the MK-801-induced locomotor hyperactivity. That increase was completely antagonized by haloperidol and partly by SCH 23390 and (+/-)-sulpiride; prazosin was inactive. Repeated administration of antidepressants produced a similar but more potent (than acute one) enhancement of the action of MK-801. Also, in that case haloperidol and SCH 23390 produced the strongest antagonistic effect; (+/-)-sulpiride and prazosin had a distinctly less potent action. Another effect of MK-801, anticonvulsant activity (electroshock-induced convulsions), was not increased by the antidepressants studied. These results indicate that antidepressants with a different pharmacological profile, increased the MK-801-induced locomotor hyperactivity, this effect being probably indirectly mediated, at least in part, by a dopamine mechanism.     

Locomotor hyperactivity induced by MK-801 in rats.

The MK-801-induced hyperactivity in rats was antagonized by haloperidol and, to a lesser degree, by SCH 23390, a dopamine D-1 antagonist, and sulpiride, a dopamine D-2 antagonist. Combined treatment with MK-801 + D-amphetamine, or MK-801 + apomorphine caused a stronger locomotor hyperactivity than each of those drugs given alone. The stereotypy evoked by D-amphetamine or apomorphine was not changed by MK-801. Atropine potentiated the effect of MK-801. Prazosin, idazoxan or ritanserin did not affect the MK-801-induced hyperactivity. It was reduced by pretreatment with alpha-methyl-p-tyrosine (alpha-MT) and completely abolished by pretreatment with reserpine, or with reserpine+alpha-MT. Also combined administration of MK-801 + clonidine increased the activity of rats pretreated with reserpine+alpha-MT. Our results indicate that the dopamine system is mainly involved in the locomotor hyperactivity induced by MK-801.     

Role of the D1 receptor for the dopamine agonist-induced one-trial behavioral sensitization of preweanling rats

Rationale

The neural mechanisms mediating the ontogeny of behavioral sensitization are poorly understood.

Objective

The purpose of the present study was to determine the role of the D1 receptor for the induction of dopamine agonist-induced behavioral sensitization during the preweanling period.

Methods

In the first experiment, the early ontogeny of R-propylnorapomorphine (NPA)-induced behavioral sensitization was examined by pretreating male and female rats with saline or NPA (0.5, 1, or 2 mg/kg, intraperitoneally (IP)) before placement in activity chambers on postnatal day (PD) 12, 16, 20, or 24. One day later, rats were tested with lower doses of NPA and the occurrence of locomotor sensitization was determined. In subsequent experiments, rats were injected with saline or the D1 receptor antagonist SCH23390 (0.1, 0.5, 1, or 5 mg/kg, IP) 0, 15, 30, or 60 min before cocaine, methamphetamine (METH), or NPA pretreatment. The next day, rats were tested with the same dopamine agonist again and sensitized responding was assessed.

Results

NPA produced one-trial behavioral sensitization at all ages tested. In preweanling rats, SCH23390, regardless of dose, was ineffective at preventing the induction of cocaine-, METH-, or NPA-induced one-trial behavioral sensitization.

Conclusions

The present results are in partial contrast to adult rodent studies, in which SCH23390 blocks the induction of METH- and apomorphine-induced behavioral sensitization, but not cocaine sensitization. When these findings are considered together, it appears that D1 receptor stimulation is not necessary for the induction of behavioral sensitization during the preweanling period, although D1 receptors may play a more important role in adulthood.     

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.Portions of this paper were presented at the 1990 Society for Neuroscience meetings, St. Louis, MO, USA     

Chronic treatment with MK-801 increases the quinolinic acid-induced loss of D-1 dopamine receptors in rat striatum

Following withdrawal from short-term treatment with the non-competitive N-methyl-d-aspartate receptor antagonist MK-801 (1 mg/kg per day) there was no significant change in the Bmax or KD of [3H]SCH23390 binding to dopamine D-1 receptors in rat striatum. Intrastriatal injection of the excitotoxin quinolinic acid (100 nmol) produced a significant decrease in [3H]SCH23390 binding. In rats withdrawn from chronic MK-801 treatment quinolinic acid produced a significantly greater loss of [3H]SCH23390 binding sites than in rats not treated with MK-801. These data indicated that striatal neurons are hypersensitive to the neurotoxic actions of quinolinic acid following withdrawal from chronic MK-801 treatment.