Hyperactivity induced by the dopamine D2/D3 receptor agonist quinpirole is attenuated by inhibitors of endocannabinoid degradation in mice

Progress in Neuro-Psychopharmacology and Biological Psychiatry

2014

Animal work on the behavioral effects of antipsychotic treatment suggests that different dosing regimens could affect drug sensitivity differently, with an intermittent treatment regimen tending to cause a sensitization effect, while a continuous treatment causing a tolerance. In this study, we explored how haloperidol (HAL) sensitization induced throughout adolescence and tested in adulthood was differentially impacted by these two dosing regimens in the conditioned avoidance response (CAR) test. We also examined how these two dosing regiments affected social interaction and social memory in adulthood. Male adolescent Sprague-Dawley rats were treated with HAL via either osmotic minipump (HAL-0.25 CONT; 0.25 mg/kg/day, n = 14) or daily injection (HAL-0.05 INT; 0.05 mg/kg/injection/day, sc, n = 14), or sterile water (n = 14) from postnatal days (PND) 44 to 71. HAL sensitization was assessed in a challenge test in which all rats were injected with HAL (0.025 and 0.05 mg/kg, sc) on PND 80 and PND 82. Two days later, half of the rats from each group (n = 7/group) were assayed in two 4-trial social interaction tests in which a subject rat was given four 5-min social encounters with a familiar or novel juvenile rat (PND 35–40) at 10 min intervals. Another half were tested in a quinpirole-induced hyperlocomotion assay to assess the potential HAL-induced change in D2-mediated function. Results show that only the intermittent dosing group under the HAL 0.05 mg/kg challenge showed a robust sensitization effect as rats in this group made significantly fewer avoidance responses than those in the vehicle and HAL-0.25 CONT groups. Adolescent HAL treatment did not affect social behavior and social memory, as rats from all 3 groups exhibited a similar level of social interaction and showed a similar level of sensitivity to the change of social stimuli. Similarly, adolescent HAL treatment also did not produce a long-lasting change in D2 function, as all 3 groups exhibited a similar level of increase in motor activity under quinpirole challenge. These findings suggest that HAL sensitization is a dosing-specific phenomenon. It is more likely to be seen under an intermittent dosing regimen than under a continuous dosing one. The findings that the intermittent HAL treatment did not impair social functioning and did not alter D2 function suggest a dissociation between drug-induced alterations in drug sensitivity and those in social function and neuroreceptors.

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Differential effects of intermittent versus continuous haloperidol treatment throughout adolescence on haloperidol sensitization and social behavior in adulthood

Progress in Neuro-Psychopharmacology and Biological Psychiatry

2014

“…This dose of PCP is shown to induce a robust hyperlocomotion effect without causing severe stereotypy (Gleason and Shannon, 1997; Kalinichev et al, 2008). The chosen quinpirole dose (1.0 mg/kg) targets post-synaptic D 2/3 receptors and causes an increase in motor activity (Koller et al, 1987; Luque-Rojas et al, 2013; Nakamura et al, 1994; Prosser et al, 1989). This dose of quinpirole was chosen based on the similar studies from our laboratory (Gao and Li, 2013; Qiao et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D₂ receptor-mediated behavioral function

Qin

2015

J Psychopharmacol

The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2–3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems.

“…Doses of RIS (1.0 and 0.3 mg/kg, for drug test and challenge respectively) and ASE (0.2 and 0.1 mg/kg, for drug test and challenge respectively) were chosen on the basis of literature review showing that these doses produce a reliable disruption of avoidance responding and cause a sensitization effect [23, 34-39]. The chosen quinpirole dose (1.0 mg/kg) targets post-synaptic D 2 receptors and causes an increase in motor activity [29, 40-42]. …”

Section: Methodsmentioning

confidence: 99%

“…We also investigated the involvement of dopamine D 2 receptor as a biological mechanism underlying antipsychotic sensitization by comparing the quinpirole-induced increase in motor activity in drug-pretreated animals to vehicle-pretreated animals. Because quinpirole is a selective D 2/3 receptor agonist, a higher level of motor activity under quinpirole challenge presumably reflects an upregulation of D 2 receptor function [28, 29]. Quinpirole-induced hyperlocomotion is also thought to be mediated through an increase in the efficacy of the post-synaptic D 2/3 transductional mechanisms [30, 31], and has been widely used to assess drug or non-drug induced changes in D 2/3 functions [32, 33].…”

Section: Introductionmentioning

confidence: 99%

Time-dependence of risperidone and asenapine sensitization and associated D2 receptor mechanism

Behavioural Brain Research

Li²

2013

When an antipsychotic drug is given repeatedly and intermittently, there is often a long-term increase in its behavioral efficacy, termed antipsychotic sensitization. With the passage of time, the magnitude of antipsychotic sensitization may increase or decrease depending on the principle of Time-Dependent Sensitization (TDS) or memory decay, respectively. In the present study, we examined the time-dependent feature and possible dopamine D2 receptor mechanism of sensitization induced by the antipsychotics risperidone and asenapine in the conditioned avoidance response test. Well-trained male adult Sprague-Dawley rats were first repeatedly treated with risperidone (1.0 mg/kg) or asenapine (0.2 mg/kg) and tested for avoidance response daily for 5 consecutive days. Eight, 18 or 38 days after the 5th drug treatment, all rats were retested drug-free to assess the residual impact of prior risperidone or asenapine treatment. Drug-pretreated rats had significantly lower avoidance than vehicle-pretreated ones on this test, and the group differences increased with the passage of time. In the subsequent drug challenge test at 10, 20 or 40 days after the 5th drug treatment, all rats were injected with a low dose of risperidone (0.3 mg/kg) or asenapine (0.1 mg/kg). Drug-pretreated rats again made significantly less avoidances than controls, confirming the drug-induced sensitization effect. Finally, in the quinpirole (a D2/3 receptor agonist, 1.0 mg/kg, sc)-induced hyperlocomotion test, risperidone-pretreated rats exhibited a significantly higher level of motor activity than the vehicle-pretreated ones. These findings suggest that risperidone and asenapine sensitization is long-lasting, follows the TDS principle, and is likely mediated by D2 receptor supersensitivity.