The role of dopaminergic transmission through D1-like and D2-like receptors in amphetamine-induced rat ultrasonic vocalizations

Rationale

Systemic amphetamine (AMPH) administration increases the rate of 50-kHz ultrasonic vocalizations (USVs) in adult rats and preferentially enhances the ‘trill’ subtype; these effects of AMPH critically depend on noradrenergic transmission, but the possible contributions of dopamine are unclear.

Objective

To assess the role of dopamine in 50-kHz USVs emitted drug-free and following systemic AMPH administration.

Methods

Adult male Long–Evans rats pre-selected for high AMPH-induced calling rates were tested with AMPH (1 mg/kg, intraperitoneal (IP)) and saline following pretreatment with the following dopamine receptor antagonists: SCH 23390 (0.005–0.02 mg/kg, subcutaneous (SC)), SCH 39166 (0.03–0.3 mg/kg, SC), haloperidol (0.1, 0.2 mg/kg, IP), sulpiride (20–80 mg/kg, SC), raclopride (0.1–0.5 mg/kg, SC), clozapine (4 mg/kg, SC), risperidone (0.5 mg/kg, SC), and pimozide (1 mg/kg, IP). The dopamine and noradrenaline reuptake inhibitors (GBR 12909 and nisoxetine, respectively) were also tested, alone and in combination.

Results

SCH 23390, SCH 39166, haloperidol, and raclopride dose-dependently inhibited vocalizations under AMPH and suppressed the proportion of trill calls. Sulpiride, however, had no discernable effect on call rate or profile, even at a high dose that reduced locomotor activity. Single doses of clozapine, risperidone, and pimozide all markedly decreased calling under saline and AMPH. Finally, GBR 12909 and nisoxetine failed to promote 50-kHz USVs detectably or alter the subtype profile, when tested alone or in combination.

Conclusions

The rate of 50-kHz USVs and the call subtype profile following systemic AMPH administration depends on dopaminergic neurotransmission through D1-like and D2-like receptors. However, inhibiting dopamine and/or noradrenaline reuptake appears insufficient to induce calling.     

Dopamine on D2-like receptors “reboosts” dopamine D1-like receptor-mediated behavioural activation in rats licking for a isotonic NaCl solution

Rationale

We recently suggested that dopamine on D1-like receptors is involved in the activation of goal-directed responses and the level of response activation is “reboosted” on the basis of an evaluation process involving D2-like receptors assessing “response efficacy”. A main piece of evidence in support of this hypothesis was the observation of an “extinction mimicry” effect in the time course of licking bursts after dopamine D2-like receptor blockade in rats licking for sucrose.

Objectives

The aim of this study was to determine whether the pattern of licking observed with sucrose as a reward could be reproduced in rats licking for a different reward (0.9 % NaCl).

Materials and methods

We investigated the effects of the dopamine D1-like receptor antagonist SCH 23390 (0.01–0.04 mg/kg) and of the dopamine D2-like receptor antagonist raclopride (0.025–0.25 mg/kg) on the microstructure of licking for a 0.9 % NaCl solution in 12-h water-deprived rats in 30-min sessions.

Results

As previously observed with sucrose as a reward, raclopride reduced the size of licking bursts and produced on the burst number time course an “extinction mimicry” effect, while SCH 23390 reduced licking exclusively by reducing burst number.

Conclusions

These results are consistent with the proposed hypothesis and provide support to the use of the study of licking microstructure as a valid model not only for the investigation of the mechanisms governing ingestive behaviour but also for the investigation of the mechanisms underlying behavioural activation and the related evaluation processes.     

CB1 receptor knockout mice display reduced ethanol-induced conditioned place preference and increased striatal dopamine D2 receptors.

Cannabinoids and ethanol activate the same reward pathways, and recent advances in the understanding of the neurobiological basis of alcoholism suggest that the CB1 receptor system may play a key role in the reinforcing effects of ethanol and in modulating ethanol intake. In the present study, male CB1 receptors knockout mice generated on a CD1 background displayed decreased ethanol-induced conditioned place preference (CPP) compared to wild-type (CB1(+/+)) mice. Ethanol (0.5, 1.0, 1.5, and 2.0 g/kg) induced significant CPP in CB1(+/+) mice at all doses tested, whereas it induced significant CPP only at the highest dose of ethanol (2.0 g/kg) in CB1(-/-) mice. However, there was no genotypic difference in cocaine (20 mg/kg)-induced CPP. There was also no genotypic difference, neither in cocaine (10-50 mg/kg) nor in D-amphetamine (1.2-5 mg/kg)-induced locomotor effects. In addition, mutant and wild-type mice did not differ in sensitivity to the anxiolytic effects of ethanol (1.5 g/kg) when tested using the elevated plus maze. Interestingly, this decrease in ethanol efficacy to induce CPP in CB1(-/-) mice was correlated with an increase in D2/D3 receptors, as determined by [3H]raclopride binding, whereas there was no difference in D1-like receptors, as determined by [3H]SCH23390 binding, measured in the striatum from drug-naive mice. This increase in D2/D3 binding sites observed in CB1 knockout mice was associated with an altered locomotor response to the D2/D3 agonist quinpirole (low doses 0.02-0.1 mg/kg) but not to an alteration of quinpirole (0.1-1.0 mg/kg)-induced CPP compared to wild-type mice. Altogether, the present results indicate that lifelong deletion of CB1 receptors reduced ethanol-induced CPP and that these reduced rewarding effects of ethanol are correlated to an overexpression of striatal dopamine D2 receptors.     

Vendor differences in alcohol consumption and the contribution of dopamine receptors to Pavlovian-conditioned alcohol-seeking in Long-Evans rats

Rationale

Drug-associated environmental stimuli elicit craving in humans and drug-seeking in animals.

Objectives

We tested the hypothesis that Pavlovian-conditioned alcohol-seeking is mediated by dopamine, using rats from two vendors.

Methods

Male, Long–Evans rats (220–240 g) from Charles River (St-Constant, QC, Canada) and Harlan Laboratories (Indianapolis, IN, USA) received 21 sessions of intermittent, 24-h access to ethanol (15 %, v/v) and water in the home-cage. Subsequently, rats were trained to discriminate between one conditioned stimulus (CS+) that was paired with ethanol (0.2 ml per CS+) and a second stimulus (CS?) that was not. Entries into a fluid port where ethanol was delivered were recorded. Next, rats were exposed to a different context where cues and ethanol were withheld. At test, responding to the CS+ and CS? without ethanol was assessed in the second, non-alcohol context. Injections (1 ml/kg; s.c.) of the dopamine D1-receptor antagonist SCH 23390 (0, 3.33, and 10 μg/kg) or dopamine D2-receptor antagonist eticlopride (0, 5, and 10 μg/kg) were administered before test.

Results

Home-cage alcohol consumption was higher in Harlan rats than Charles River rats. At test, saline-treated rats responded more to the alcohol-predictive CS+ than the CS?. While SCH 23390 attenuated CS+ responding in rats from both vendors, eticlopride reduced CS+ responding in Harlan rats only. Subsequently, SCH 23390 but not eticlopride attenuated CS+ responding when the CS+ was again paired with ethanol.

Conclusions

These results indicate important differences in alcohol consumption in Long–Evans rats from different suppliers, and highlight a novel role for dopamine in Pavlovian-conditioned alcohol-seeking.     

Reinstatement of cocaine seeking in rats by the pharmacological stressors, corticotropin-releasing factor and yohimbine: role for D1/5 dopamine receptors

Rationale

Two pharmacological stressors commonly used in the study of stress-induced reinstatement of drug seeking are central injections of the stress peptide, corticotropin-releasing factor (CRF), and systemic administration of the ??₂-adrenoceptor antagonist, yohimbine. Despite the widespread use of these stressors, the neurochemical systems mediating their ability to reinstate cocaine-seeking behaviour have not been fully characterized.

Objective

The present study was designed to characterize the role, specifically, of dopamine transmission in the reinstating effects of CRF and yohimbine on cocaine seeking.

Methods

Male Long-Evans rats were trained to self-administer cocaine (0.23?mg/kg/infusion) for 8?C10?days. Subsequently, responding for drug was extinguished, and tests for CRF- (0.5???g; i.c.v.) and yohimbine-induced (1.25?mg/kg; i.p.) reinstatement were conducted following pretreatment with the dopamine D1/5 receptor antagonists, SCH23390 (0.05, 0.1?mg/kg; i.p.) and/or SCH31966 (0.2?mg/kg; i.p.), and the D2/3 receptor antagonist, raclopride (0.25, 0.5?mg/kg; i.p.).

Results

Pretreatment with SCH23390, but not raclopride, blocked CRF-induced reinstatement of cocaine seeking. Pretreatment with SCH23390 and SCH31966, but not raclopride, blocked yohimbine-induced reinstatement of cocaine seeking.

Conclusions

These findings demonstrate that transmission at D1/5, but not D2/3, receptors mediates the reinstatement of cocaine seeking induced by CRF and yohimbine.     

The effect of dopamine receptor blockade on motor behavior in Aplysia californica

The mammalian D1- and D2-like receptor blockers SCH-23390 and raclopride were used to block receptors in Aplysia californica, and the effect on reflexes and escape behavior was examined. Four groups of 20 young adults were each injected with SCH-23390, raclopride, SCH-23390+raclopride, or seawater. The drug (0.0125 mg/g of body weight) was injected 2 mm anterior to the parapodia. After the injection of either SCH-23390 or SCH-23390+raclopride, there was a significant increase in parapodia opening (P<.001), siphon withdrawal (P<.05), and galloping following tail pinch (P<.01) compared to raclopride-injected or control animals. The data showed that blockade of receptors by SCH-23390, but not raclopride, produced significant changes in motor behavior in A. californica.     

Dopamine on D2-like receptors “reboosts” dopamine D1-like receptor-mediated behavioural activation in rats licking for sucrose

Background

The analysis of licking microstructure provides measures, such as duration and number of licking bouts, which might reveal the former an evaluation process and the latter an approach response. Dopamine D2-like receptor antagonists reduce the duration of licking bouts and mimic the effect of reducing sucrose concentration, while conflicting results are reported on the effects of dopamine D1-like receptor antagonists. The aim of this study is to examine the roles of dopamine D1-like and D2-like receptors in the activation of reward-associated responses and in reward evaluation, through the study of licking microstructure.

Methods

The effects of the dopamine D2-like receptor antagonists raclopride (0.025-0.25 mg/kg), the D1-like antagonist SCH 23390 (0.01-0.04 mg/kg) and the antipsychotic drug haloperidol (0.02-0.05 mg/kg), have been examined on the microstructure of licking for a 10% sucrose solution in rats.

Results

The results confirm that dopamine D2-like receptor antagonists reduce the duration of licking bouts and reveal that while SCH 23390 reduced licking exclusively by reducing bout number, raclopride produced on this measure an extinction mimicry effect similar to that observed in instrumental responding for different rewards.

Discussion

These results are consistent with the hypothesis that the level of activation of the responses to the reward-associated cues depends on dopamine D1-like receptor stimulation, and is updated, or “reboosted”, on the basis of a dopamine D2-like receptor-mediated evaluation process occurring during the consummatory transaction with the reward.     

Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement

Rationale

Orexin-1 receptor antagonists have been shown to block the reinforcing effects of drugs of abuse and food. However, whether blockade of orexin-2 receptor has similar effects has not been determined. We have recently described the in vitro and in vivo effects of JNJ-10397049, a selective and brain penetrant orexin-2 receptor antagonist.

Objective

The goal of these studies was to evaluate whether systemic administration of JNJ-10397049 blocks the rewarding effects of ethanol and reverses ethanol withdrawal in rodents. As a comparison, SB-408124, a selective orexin-1 receptor antagonist, was also evaluated.

Methods

Rats were trained to orally self-administer ethanol (8% v/v) or saccharin (0.1% v/v) under a fixed-ratio 3 schedule of reinforcement. A separate group of rats received a liquid diet of ethanol (8% v/v) and withdrawal signs were evaluated 4?h after ethanol discontinuation. In addition, ethanol-induced increases in extracellular dopamine levels in the nucleus accumbens were tested. In separate experiments, the acquisition, expression, and reinstatement of conditioned place preference (CPP) were evaluated in mice.

Results

Our results indicate that JNJ-10397049 (1, 3, and 10?mg/kg, sc) dose-dependently reduced ethanol self-administration without changing saccharin self-administration, dopamine levels, or withdrawal signs in rats. Treatment with JNJ-10397049 (10?mg/kg, sc) attenuated the acquisition, expression, and reinstatement of ethanol CPP and ethanol-induced hyperactivity in mice. Surprisingly, SB-408124 (3, 10 and 30?mg/kg, sc) did not have any effect in these procedures.

Conclusions

Collectively, these results indicate, for the first time, that blockade of orexin-2 receptors is effective in reducing the reinforcing effects of ethanol.     

Possible role of dopamine D1-like and D2-like receptors in behavioural activation and evaluation of response efficacy in the forced swimming test

Based on the different effects of the dopamine D1-like and D2-like receptor antagonists SCH 23390 and raclopride on the measures of licking microstructure in rats ingesting a sucrose solution, we suggested that the behavioural activation of reward-associated responses depends on dopamine D1-like receptor stimulation, and its level is updated, or “reboosted”, on the basis of a dopamine D2-like receptor-mediated evaluation process. The aim of this study was to test this hypothesis on the forced swimming test response. The effects of the dopamine D1-like and D2-like receptor antagonists SCH 23390 (0.01–0.04 mg/kg) and raclopride (0.025–0.25 mg/kg) administered before a 15-min exposure to forced swimming, and the response to a second session performed 24 h later, were examined. SCH 23390 dose-dependently reduced climbing scores in the first session and increased them in the second session, but the within-session decline of this measure was similar to that observed in the control group in both sessions. Raclopride-treated subjects showed a slightly reduced level of climbing scores at the beginning of the first session, but persisted in emitting this costly behavioural response up to the end of the session, while no effects were observed in the second session. These results, along with our results examining licking for sucrose, are consistent with the hypothesis that behavioural activation and response effort allocation are directly mediated by dopamine D1-like receptor stimulation, but the level of this activation is updated, or “reboosted”, on the basis of a dopamine D2-like receptor-mediated mechanism of response efficacy evaluation.     

Milnacipran enhances the control of impulsive action by activating D1-like receptors in the infralimbic cortex

Rationale

Elevated impulsivity is often observed in patients with depression. We recently found that milnacipran, an antidepressant and a serotonin/noradrenaline reuptake inhibitor, could enhance impulse control in rats. However, the neural mechanisms underlying the effects of milnacipran on impulsive action remain unclear. Milnacipran increases not only extracellular serotonin and noradrenaline but also dopamine specifically in the medial prefrontal cortex, which is one of the brain regions responsible for impulsive action.

Objectives

Our goal was to identify whether D₁- and/or D₂-like receptors in the infralimbic cortex (IL), the ventral portion of the medial prefrontal cortex, mediates the milnacipran-enhanced impulse control in a three-choice serial reaction time task.

Methods

The rats were bilaterally injected with SCH23390, a selective D₁-like receptor antagonist (0.3 or 3 ng/side) or eticlopride, a selective D₂-like receptor antagonist (0.3 or 1 μg/side) into the IL after acute intraperitoneal administration of milnacipran (10 mg/kg).

Results

Intra-IL SCH23390 injections reversed the milnacipran-enhanced impulse control, whereas injections of eticlopride into the IL failed to block the effects of milnacipran on impulsive action.

Conclusions

This is the first report that demonstrates a critical role for D₁-like receptors of the IL in milnacipran-enhanced control of impulsive action.     

Methamphetamine and core temperature in the rat: Ambient temperature, dose, and the effect of a D2 receptor blocker

Rationale

Methamphetamine (METH) induces hyperthermia in warm and hypothermia in cool environments. Our first goal was to further study the role of ambient temperature in METH’s effect on core temperature in rats. Previously, these effects were primarily demonstrated in high doses; we extended this investigation to the low-dose range (1 mg/kg METH). Our second goal was to identify the role of the D2 receptor in METH’s effects in cool ambient temperatures.

Method

Rats received METH (saline, 1, 5, and 10 mg/kg), raclopride (saline, 0.3, 0.6, and 1.2 mg/kg), or a combination (all doses of raclopride combined with 10 mg/kg METH). Treatments occurred in ambient temperatures of 18, 24, or 30 °C.

Results and conclusions

Consistent with prior research, 5 and 10 mg/kg METH caused hyperthermia or hypothermia in a dose- and ambient temperature-dependent manner (60 min after METH). In contrast, 1 mg/kg produced similar levels of hyperthermia at all ambient temperatures. These findings suggest that a threshold METH dose exists; below this dose, METH still changes core temperature, but CNS control over temperature regulation is left intact. In our experiments regarding D2 blockade, raclopride decreased METH-induced core temperature at 30 and 24 °C (60 min after METH), consistent with previous findings. We extended these findings by demonstrating that in a cool ambient temperature (18 °C), raclopride pretreatment also lowered the core temperature response to METH. Although the D2 receptor is known to mediate hypothermia, the combination of METH and D2 blockade suggests a complex mediation of the core temperature response, perhaps involving neurotransmitter interactions.     

Dopamine receptor regulation of ethanol intake and extracellular dopamine levels in the ventral pallidum of alcohol preferring (P) rats

Sufficient evidence exists for the inclusion of the ventral pallidum (VP) into the category of a dopaminoceptive brain region. The effects of inhibiting dopamine D(1)- or D(2)-like receptors in the VP on (a) ethanol intake and (b) extracellular levels of dopamine, were investigated in the alcohol-preferring (P) rat. The D(1)-like antagonist, SCH-23390, and the D(2)-like antagonist, sulpiride (0.25-2 microg/0.5 microl) were bilaterally injected into the VP and ethanol (15%, v/v) intake was assessed in a 1 h limited access paradigm. The results indicate that microinjections of sulpiride significantly increased ethanol consumption (65% increase at the 2.0 microg dose). Whereas the D(1) antagonists SCH-23390 tended to decrease ethanol intake, the effect was not statistically significant. In a separate group of rats, reverse microdialysis of sulpiride and SCH-23390 (10-200 microM) were conducted in the VP of P rats. Local perfusion of only the 200 microM sulpiride dose significantly increased the extracellular levels of dopamine (maximal increase: 250% of baseline). On the other hand, local perfusion of SCH-23390 (10-200 microM) dose dependently increased the extracellular levels of dopamine 180-640% of baseline. Overall, the results of this study suggest that (a) tonic activation of D(2) postsynaptic receptors in VP imposes a limit on ethanol intake in the P rat; (b) there are few D(2) autoreceptors functioning in the VP; (c) there is tonic D(1)-like receptor mediated inhibitory feedback regulation of VP-dopamine release.     

Potentiation of ethanol-induced loss of the righting reflex by ascorbic acid in mice: interaction with dopamine antagonists

The present investigation was carried out to determine the effect of ascorbic acid on ethanol-induced loss of the righting reflex (LORR) and the interactions between ascorbic acid and dopamine receptor antagonists in affecting this action of ethanol in mice. To test the effect of each drug on ethanol-induced LORR, ascorbic acid (31.25, 62.5, 125, 250, 500, 1000 mg/kg intraperitoneally [IP]) and dopamine receptor antagonists (haloperidol 0.5, 1.0 mg/kg; L-sulpiride 20, 40, 80 mg/kg; clozapine 0.625, 1.25, 2.5 mg/kg; SCH 23390 0.5, 1.0, 2.0 mg/kg subcutaneously [SC]) were administered, respectively, 30 min before ethanol (4.0 g/kg IP) administration. Ascorbic acid, at the dose of 1000 mg/kg, significantly potentiated ethanol-induced LORR in mice. Dopamine D(2) antagonists haloperidol (0.5, 1.0 mg/kg SC), and L-sulpiride (80 mg/kg SC) also significantly prolonged the duration of LORR induced by ethanol. Clozapine and SCH 23390, at the doses used, did not affect ethanol-induced LORR. In the interaction study, the synergistic effect of ascorbic acid (1000 mg/kg IP) on ethanol-induced LORR was significantly enhanced by dopamine D(2) antagonists haloperidol, L-sulpiride, and clozapine, and the highest dose of dopamine D(1) antagonist SCH 23390. These results suggest that ascorbic acid may potentiate ethanol-induced LORR partially via a mechanism mainly linked to blockade of dopamine D(2) receptors.     

Dopamine antagonist effects on locomotor activity in naive and ethanol-treated FAST and SLOW selected lines of mice

The FAST and SLOW lines of mice are being selectively bred in replicate for differential sensitivities to the locomotor activating effects of ethanol. Whereas FAST-1 and FAST-2 mice are stimulated by 2.0 g/kg ethanol, SLOW-1 and SLOW-2 mice are not stimulated, and are often depressed, by this dose. The dopamine antagonists, SCH-23390 (D₁) and raclopride (D₂), produced dose-dependent decreases in the locomotor activity of EtOH-naive mice of both lines and replicates; however, FAST and SLOW mice were not differentially sensitive to these effects. The absence of a line difference in activity response to the dopamine antagonists suggests that dopamine receptor function has not been altered by selective breeding for differences in sensitivity to the stimulant effects of ethanol. The ethanol-stimulated activity of FAST-1 and FAST-2 mice was decreased by administration of the dopamine antagonists, haloperidol and raclopride, at doses that had no effect on basal locomotor activity. SCH-23390 decreased ethanol-stimulated activity of FAST-1, but not FAST-2 mice. The ethanol-induced activity changes of SLOW mice were generally unaffected by antagonist administration. These results suggest a role for dopaminergic systems in mediating ethanol-stimulated activity in selectively bred FAST mice. Coadministration of SCH-23390 and raclopride decreased ethanol-induced activation to a greater degree than either drug alone, further suggesting that both D₁ and D₂ receptor systems contribute to the full expression of the ethanol stimulant response.This work was supported by the Department of Veterans Affairs, by NIAAA grants AA06498 and AA08621 (J.C.C. and T.J.P.), and by an N. L. Tartar Research Fellowship from the Medical Research Foundation of Oregon (E.H.S.). A portion of this work was completed in partial fulfillment of the requirements for Master of Science degree, Department of Medical Psychology, Oregon Health Sciences University (E.H.S.).     

Involvement of dopamine receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats

In the present study, the effects of bilateral intrahippocampal CA1 injections of dopamine receptor agonists and antagonists on the acquisition and expression of morphine-induced place preference were examined in male Wistar rats. Subcutaneous administration of different doses of morphine sulphate (0.5-10 mg/kg) produced a conditioned place preference (CPP) dose-dependently. Using a 3-day schedule of conditioning, it was found that dopamine D1 receptor agonist, SKF 38393 (0.01-1 microg/rat), dopamine D1 receptor antagonist, SCH 23390 (0.25-1 microg/rat), dopamine D(2/3) receptor agonist, quinpirole (0.3-3 microg/rat) or dopamine D2 receptor antagonist, sulpiride (0.04-5 microg/rat) did not produce significant place preference. The administration of SKF 38393 (1 microg/rat) significantly potentiated the acquisition of morphine (0.5 and 2.5 mg/kg)-induced place preference. This potentiation was reversed by SCH 23390 (1 microg/rat) pretreatment. Quinpirole injection (0.3 microg/rat) induced CPP in combination with the lower doses of morphine but decreased the response of the higher doses of morphine. These responses of quinpirole were reversed by sulpiride (5 microg/rat) pretreatment. SCH 23390 or sulpiride reduced the acquisition of morphine (7.5 mg/kg)-induced place preference. The administration of sulpiride, but not other drugs, during acquisition showed an increase in the locomotor activity on the testing days. SKF 38393, SCH 23390 or sulpiride, but not quinpirole when used before testing, reduced the expression of morphine-induced place preference. Sulpiride, but not other drugs, increased locomotion when used before testing. It is concluded that dorsal hippocampal dopamine receptors may play an active role in morphine reward.     

The role of dopamine receptors in ventrolateral orbital cortex-evoked antinociception in a rat formalin test model

The present study examined the roles of dopamine and D(1)- and D(2)-like dopamine receptors in ventrolateral orbital cortex (VLO)-evoked antinociception in rats with persistent inflammatory pain. Following formalin injection into the rat unilateral hindpaw pad, the effects of dopamine receptor agonist and antagonist microinjections into the VLO on nociceptive behavior were observed. Results demonstrated that VLO microinjection of the non-selective dopamine receptor agonist apomorphine (R(-)-apomorphine hydrochloride, 1.0, 2.5 and 5.0μg) depressed later-phase nociceptive behavior induced by formalin injection; this effect was attenuated by the D(2)-like dopamine receptor antagonist S(-)-raclopride(+)-tartrate salt (raclopride, 3.0μg), but not by the D(1)-like dopamine receptor antagonist R(+)-SCH-23390 hydrochloride (SCH-23390, 1.0μg). Apomorphine-induced antinociception was mimicked by microinjection of the D(2)-like dopamine receptor agonist (-)-quinpirole hydrochloride (2.0 and 5.0μg) into the same VLO site, and this effect was antagonized by raclopride (3.0μg). In addition, microinjection of the D(1)-like dopamine receptor agonist R(+)-SKF-38393 hydrochloride (5.0μg) had no effect on formalin-induced nociceptive behavior during the later phase. However, the D(1)-like dopamine receptor antagonist SCH-23390 (2.5, 5.0 and 10μg) depressed nociceptive behavior in a dose-dependent manner. These results suggested that dopamine mediated VLO-induced antinociception via different mechanisms in the persistent inflammatory pain model; D(2)-like receptors mediated dopamine-induced antinociception, while D(1)-like dopamine receptors exhibited tonic facilitatory action on nociceptive behavior, thereby blocking D(1)-like dopamine receptors could induce antinociception.     

Influence of abstinence and intervals between extinction trials on the expression of cocaine-conditioned place preference in adolescent rats

Rationale

Disruption of acquired drug–cue associations can effectively decrease relapse. The benefits of extinction training as opposed to abstinence have been reported. Timing of extinction trials is an important variable. Finding an effective extinction regimen can optimize addiction therapies.

Objective

To determine the effects of different drug-free periods on cocaine-conditioned place preference (CPP) in rats that either did or did not receive non-reinforced exposure to drug-associated stimuli.

Materials and methods

Male adolescent rats were trained for cocaine-CPP (5, 10, or 15 mg/kg, i.p.) in a biased manner for 8 days and then tested following different intervals.

Results

Rats treated with 15 mg/kg cocaine displayed high and equal CPP on the first test, performed 1, 4, 7, or 14 days following conditioning. Expression of CPP during the test performed 1 day after conditioning was equal in the groups conditioned with 5, 10, or 15 mg/kg cocaine. When the interval before the first test was extended to 14 days, the group treated with 5 mg/kg did not show CPP. Rats treated with the three doses and tested repeatedly at 1, 7, and 14 days did not display CPP on the third test. CPP after treatment with 10 or 15 mg/kg cocaine was already extinguished in the second test but only for an interval of 1–14 days.

Conclusions

Maintenance of CPP was evident at least 2 weeks after forced abstinence. Extinguished CPP can be obtained after a single extinction trial, performed close to original training and followed by prolonged abstinence. However, with low doses of cocaine, abstinence alone may be sufficient to disrupt drug–cue associations.     

Synergistic effects between CA1 mu opioid and dopamine D1-like receptors in impaired passive avoidance performance induced by hepatic encephalopathy in mice

Background and aim

Numerous investigations have indicated that hepatic encephalopathy (HE) alters the levels of various neurotransmitters. However, comprehensive data regarding the effects of CA1 opioidergic and dopaminergic (DAergic) systems on HE-induced amnesia are still lacking.

Methods

Following intra-dorsal hippocampal (CA1) injection of mu opioid and dopamine D1- and D2-like receptors antagonists in male mice, one-trial step-down and hole-board paradigms were used to assess memory and exploratory behaviors, respectively.

Results

Our data demonstrated that HE impairs memory 24 days after bile duct ligation (BDL). Furthermore, while the higher dose of DA D1-like receptor antagonist (SCH23390, 0.5 μg/mouse) induced amnesia and anxiogenic-like behaviors, mu receptor antagonist (naloxone: 0.0125, 0.025 and 0.05 μg/mouse) and DA D2-like receptor antagonist (sulpiride: 0.0625, 0.125 and 0.25 μg/mouse) by themselves, could not exert an effect on memory performance in passive avoidance task. On the other hand, pre-test injection of all drugs reversed the HE-induced amnesia 24 days after BDL, while having no effect on exploratory behaviors. Pre-test co-administration of the subthreshold dose SCH23390 (0.25 μg/mouse) and sulpiride (0.0625 μg/mouse) or naloxone (0.0125 μg/mouse) could likewise reverse the BDL-induced amnesia. However, when the subthreshold sulpiride plus naloxone were co-administered, BDL-induced amnesia was not blocked.

Conclusions

Memory performance is impaired 24 days post BDL and CA1 mu opioid and DA D1-like receptors antagonist synergistic effects are likely involved in this phenomenon     

Assessment of the impact of pattern of cocaine dosing schedule during conditioning and reconditioning on magnitude of cocaine CPP, extinction, and reinstatement

Rationale and objective

We sought to examine the impact of differing cocaine administration schedules and dosing on the magnitude of cocaine conditioned place preference (CPP), extinction, and stress- and cocaine-induced reinstatement of CPP.

Methods

First, in C57Bl/6J mice, we investigated whether total cocaine administration or pattern of drug exposure could influence the magnitude of cocaine CPP by conditioning mice with a fixed-low dose (F_L; 7.5 mg/kg; total of 30 mg/kg), a fixed-high dose (F_H; 16 mg/kg; total of 64 mg/kg), or an ascending dosing schedule (Asc; 2, 4, 8, and 16 mg/kg; total of 30 mg/kg). Next, we investigated if cocaine or saline is more effective at extinguishing preference by reconditioning mice with either a descending dosing schedule (Desc; 8, 4, 2, and 1 mg/kg) or saline. Finally, we examined if prior conditioning and reconditioning history alters stress (~2–3-min forced swim test) or cocaine-induced (3.5 mg/kg) reinstatement.

Results

We replicated and extended findings by Itzhak and Anderson (Addict. Biol. 17(4): 706–16, 2011) demonstrating that Asc conditioning produces a greater CPP than either the F_L or F_H conditioning schedules. The magnitude of extinction expressed was similar in the Desc reconditioned and saline groups. Moreover, only the saline, and not the Desc reconditioned mice, showed stress and cocaine-induced reinstatement of CPP.

Conclusions

Our results suggest that the schedule of cocaine administration during conditioning and reconditioning can have a significant influence on the magnitude of CPP and extinction of preference and the ability of cocaine or a stressor to reinstate CPP.     

Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating

Rationale

Inhibitors of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the mammalian striatum, enhance activity in direct (dopamine D1 receptor-expressing) and indirect (D2 receptor-expressing striatal output) pathways. The ability of such agents to act to potentiate D1 receptor signaling while inhibiting D2 receptor signaling suggest that PDE10A inhibitors may have a unique antipsychotic-like behavioral profile differentiated from the D2 receptor antagonist-specific antipsychotics currently used in the treatment of schizophrenia.

Objectives

To evaluate the functional consequences of PDE10A inhibitor modulation of D1 and D2 receptor pathway signaling, we compared the effects of a PDE10A inhibitor (TP-10) on D1 and D2 receptor agonist-induced disruptions in prepulse inhibition (PPI), a measure of sensorimotor gating disrupted in patients with schizophrenia.

Results

Our results indicate that, in rats: (1) PDE10A inhibition (TP-10, 0.32–10.0 mg/kg) has no effect on PPI disruption resulting from the mixed D1/D2 receptor agonist apomorphine (0.5 mg/kg), confirming previous report; (2) Yet, TP-10 blocked the PPI disruption induced by the D2 receptor agonist quinpirole (0.5 mg/kg); and attenuated apomorphine-induced disruptions in PPI in the presence of the D1 receptor antagonist SCH23390 (0.005 mg/kg).

Conclusions

These findings indicate that TP-10 cannot block dopamine agonist-induced deficits in PPI in the presence of D1 activation and suggest that the effect of PDE10A inhibition on D1 signaling may be counterproductive in some models of antipsychotic activity. These findings, and the contribution of TP-10 effects in the direct pathway on sensorimotor gating in particular, may have implications for the potential antipsychotic efficacy of PDE10A inhibitors.