Dopamine D2 Receptor Sensitivity Research Articles

Reinstatement of nicotine conditioned place preference in a transgenerational model of drug abuse vulnerability in psychosis: Impact of BDNF on the saliency of drug associations.

Psychotic disorders such as schizophrenia are often accompanied by high rates of cigarette smoking, reduced quit success, and high relapse rates, negatively affecting patient outcomes. However, the mechanisms underlying altered relapse-like behaviors in psychosis are poorly understood. The present study analyzed changes in extinction and reinstatement of nicotine conditioned place preference (CPP) and resulting changes in brain-derived neurotrophic factor (BDNF) in a novel heritable rodent model of psychosis, demonstrating increased dopamine D2 receptor sensitivity, to explore mechanisms contributing to changes in relapse-like behaviors. Male and female offspring of two neonatal quinpirole-treated (1mg/kg quinpirole from postnatal day (P)1-21; QQ) and two neonatal saline-treated (SS) Sprague-Dawley rats (F1 generation) were tested on an extended CPP paradigm to analyze extinction and nicotine-primed reinstatement. Brain tissue was analyzed 60min after the last nicotine injection for BDNF response in the ventral tegmental area (VTA), the infralimbic (IfL) and prelimbic (PrL) cortices. F1 generation QQ offspring demonstrated delayed extinction and more robust reinstatement compared to SS control animals. In addition, QQ animals demonstrated an enhanced BDNF response to nicotine in the VTA, IfL and Prl cortices compared to SS offspring. This study is the first to demonstrate altered relapse-like behavior in a heritable rodent model with relevance to comorbid drug abuse and psychosis. This altered pattern of behavior is hypothesized to be related to elevated activity-dependent BDNF in brain areas associated with drug reinforcement during conditioning that persists through the extinction phase, rendering aberrantly salient drug associations resistant to extinction and enhancing relapse vulnerability.

Cocaine shifts dopamine D2 receptor sensitivity to gate conditioned behaviors

Cocaine addiction is a chronic, relapsing disorder characterized by maladaptation in the brain mesolimbic and nigrostriatal dopamine system. Although changes in the properties of D2-receptor-expressing medium spiny neurons (D2-MSNs) and connected striatal circuits following cocaine treatment are known, the contributions of altered D2-receptor (D2R) function in mediating the rewarding properties of cocaine remain unclear. Here, we describe how a 7-day exposure to cocaine alters dopamine signaling by selectively reducing the sensitivity, but not the expression, of nucleus accumbens D2-MSN D2Rs via an alteration in the relative expression and coupling of G protein subunits. This cocaine-induced reduction of D2R sensitivity facilitated the development of the rewarding effects of cocaine as blocking the reduction in G protein expression was sufficient to prevent cocaine-induced behavioral adaptations. These findings identify an initial maladaptive change in sensitivity by which mesolimbic dopamine signals are encoded by D2Rs following cocaine exposure.

Transgenerational evidence of increases in dopamine D2 receptor sensitivity in rodents: Impact on sensorimotor gating, the behavioral response to nicotine and BDNF.

Neonatal quinpirole (NQ) treatment to rats increases dopamine D2 (DAD2) receptor sensitivity in adult animals. We investigated if increased DAD2 sensitivity would be passed to the next (F1) generation, and if these animals demonstrated sensorimotor gating deficits and enhanced behavioral responses to nicotine. Male and female rats were intraperitoneal (IP) administered quinpirole (1 mg/kg) or saline (NS) from postnatal day (P)1-21. Animals were either behaviorally tested (F0) or raised to P60 and mated, creating F1 offspring. Experiment 1 revealed that F1 generation animals that were the offspring of at least one NQ-treated founder increased yawning behavior, a DAD2-mediated behavioral event, in response to acute quinpirole (0.1 mg/kg). F1 generation rats also demonstrated increased striatal β arrestin-2 and decreased phospho-AKT signaling, consistent with increased G-protein independent DAD2 signaling, which was equal to F0 NQ-treated founders, although this was not observed in all groups. RNA-Seq analysis revealed significant gene expression changes in the F1 generation that were offspring of both NQ-treated founders compared to F0 NQ founders and controls, with enrichment in sensitivity to stress hormones and cell signaling pathways. In Experiment 2, all F1 generation offspring demonstrated sensorimotor gating deficits compared to controls, which were equivalent to F0 NQ-treated founders. In Experiment 3, all F1 generation animals demonstrated enhanced nicotine behavioral sensitization and nucleus accumbens (NAcc) brain-derived neurotrophic factor (BDNF) protein. Further, F1 generation rats demonstrated enhanced adolescent nicotine conditioned place preference equivalent to NQ-treated founders conditioned with nicotine. This represents the first demonstration of transgenerational effects of increased DAD2 sensitivity in a rodent model.

The effects of a novel inhibitor of tumor necrosis factor (TNF) alpha on prepulse inhibition and microglial activation in two distinct rodent models of schizophrenia

Increased neuroinflammation has been shown in individuals diagnosed with schizophrenia (SCHZ). This study evaluated a novel immune modulator (PD2024) that targets the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) to alleviate sensorimotor gating deficits and microglial activation employing two different rodent models of SCHZ. In Experiment 1, rats were neonatally treated with saline or the dopamine D2-like agonist quinpirole (NQ; 1 mg/kg) from postnatal day (P) 1-21 which produces increases of dopamine D2 receptor sensitivity throughout the animal’s lifetime. In Experiment 2, rats were neonatally treated with saline or the immune system stimulant polyinosinic:polycytidylic acid (Poly I:C) from P5-7. Neonatal Poly I:C treatment mimics immune system activation associated with SCHZ. In both experiments, rats were raised to P30 and administered a control diet or a novel TNFα inhibitor PD2024 (10 mg/kg) in the diet from P30 until P67. At P45-46 and from P60-67, animals were behaviorally tested on auditory sensorimotor gating as measured through prepulse inhibition (PPI). NQ or Poly I:C treatment resulted in PPI deficits, and PD2024 treatment alleviated PPI deficits in both models. Results also revealed that increased hippocampal and prefrontal cortex microglial activation produced by neonatal Poly I:C was significantly reduced to control levels by PD2024. In addition, a separate group of animals neonatally treated with saline or Poly I:C from P5-7 demonstrated increased TNFα protein levels in the hippocampus but not prefrontal cortex, verifying increased TNFα in the brain produced by Poly I:C. Results from this study suggests that that brain TNFα is a viable pharmacological target to treat the neuroinflammation known to be associated with SCHZ.

The effects of nicotine in the neonatal quinpirole rodent model of psychosis: Neural plasticity mechanisms and nicotinic receptor changes

Neonatal quinpirole (NQ) treatment to rats increases dopamine D2 receptor sensitivity persistent throughout the animal’s lifetime. In Experiment 1, we analyzed the role of α7 and α4β2 nicotinic receptors (nAChRs) in nicotine behavioral sensitization and on the brain-derived neurotrophic factor (BDNF) response to nicotine in NQ- and neonatally saline (NS)-treated rats. In Experiment 2, we analyzed changes in α7 and α4β2 nAChR density in the nucleus accumbens (NAcc) and dorsal striatum in NQ and NS animals sensitized to nicotine. Male and female Sprague-Dawley rats were neonatally treated with quinpirole (1mg/kg) or saline from postnatal days (P)1-21. Animals were given ip injections of either saline or nicotine (0.5mg/kg free base) every second day from P33 to P49 and tested on behavioral sensitization. Before each injection, animals were ip administered the α7 nAChR antagonist methyllycaconitine (MLA; 2 or 4mg/kg) or the α4β2 nAChR antagonist dihydro beta erythroidine (DhβE; 1 or 3mg/kg).Results revealed NQ enhanced nicotine sensitization that was blocked by DhβE. MLA blocked the enhanced nicotine sensitization in NQ animals, but did not block nicotine sensitization. NQ enhanced the NAcc BDNF response to nicotine which was blocked by both antagonists. In Experiment 2, NQ enhanced nicotine sensitization and enhanced α4β2, but not α7, nAChR upregulation in the NAcc. These results suggest a relationship between accumbal BDNF and α4β2 nAChRs and their role in the behavioral response to nicotine in the NQ model which has relevance to schizophrenia, a behavioral disorder with high rates of tobacco smoking.

Applications of the Neonatal Quinpirole Model to Psychosis and Convergence upon the Dopamine D2 Receptor.

This mini review focuses on the importance of the dopamine D2-like receptor family and its importance in psychosis. Past findings from this laboratory along with collaborators have been that neonatal quinpirole (a dopamine D2-like receptor agonist) results in increases in dopamine D2 receptor sensitivity that persists throughout the animal's lifetime. Findings from this model have been shown to have particular application and validity to schizophrenia, but may have broader implications toward other psychoses, which is reviewed in the present manuscript. In the present review, we also highlight other models of psychoses that have been centered on the subchronic administration of quinpirole to rats in order to model certain psychoses, which has uncovered some interesting and valid behavioral findings. This review highlights the importance of the combination of behavioral findings and neurobiological mechanisms focusing on neural plasticity in discovering underlying pathologies in these disorders that may lead to treatment discoveries, as well as the value of animal models across all psychoses.

Parkinson's disease: low-dose haloperidol increases dopamine receptor sensitivity and clinical response.

Background. It is known that ultra-low doses of haloperidol can cause dopamine supersensitivity of dopamine D2 receptors and related behaviour in animals. Objective. The objective was to determine whether a daily ultra-low dose of 40 micrograms of haloperidol could enhance the clinical action of levodopa in Parkinson's disease patients. Method. While continuing their daily treatment with levodopa, 16 patients with Parkinson's disease were followed weekly for six weeks. They received an add-on daily dose of 40 micrograms of haloperidol for the first two weeks only. The SPES/SCOPA scale (short scale for assessment of motor impairments and disabilities in Parkinson's disease) was administered before treatment and weekly throughout the trial. Results. The results showed a mean decrease in SPES/SCOPA scores after one week of the add-on treatment. Conclusion. SCOPA scores decreased after the addition of low-dose haloperidol to the standard daily levodopa dose. This finding is consistent with an increase in sensitivity of dopamine D2 receptors induced by haloperidol. Such treatment for Parkinson's disease may possibly permit the levodopa dose to be reduced and, thus, delay the onset of levodopa side effects.

Adolescent nicotine sensitization and effects of nicotine on accumbal dopamine release in a rodent model of increased dopamine D2 receptor sensitivity

Our laboratory has reported neonatal quinpirole (D2/D3 agonist) treatment to rats increases dopamine D2 receptor sensitivity that persists throughout the animal's lifetime. This model appears to have clinical relevance to schizophrenia, and smoking is common in this population. Male and female Sprague-dawley rats were neonatally treated with quinpirole from postnatal (P) days 1–21. After habituation from P30 to 32, animals were administered saline or nicotine (0.3, 0.5, or 0.7mg/kg free base) every other day from P33 to 49 and locomotor activity was assessed. Generally, animals neonatally treated with quinpirole and administered nicotine during adolescence demonstrated increased behavioral activity and/or sensitization compared to animals neonatally given saline and sensitized to nicotine as well as controls. However, animals neonatally treated with quinpirole and given the 0.7mg/kg dose of nicotine demonstrated elevated activity throughout testing but did not show sensitization, and only mild sex differences were reported. Therefore, microdialysis was performed on male rats sensitized to the 0.5mg/kg dose of nicotine, and results revealed that neonatal quinpirole sensitized dopamine overflow in response to nicotine to 500% above animals neonatally given saline and sensitized to nicotine at peak levels. In addition, neonatal quinpirole increased the accumbal BDNF in response to nicotine compared to all other groups, and nicotine alone also produced significant increases in striatal and accumbal BDNF. This study reveals that neonatal quinpirole enhanced adolescent nicotine sensitization, accumbal dopamine overflow, and BDNF protein in response to nicotine, which may be related to changes in the brain's reward system.

The GPR88 receptor agonist 2-PCCA does not alter the behavioral effects of methamphetamine in rats

GPR88 is a novel orphan G protein-coupled receptor that is primarily located at the striatum. Genetic knockout studies reveal phenotypes of increased dopamine D2 receptor sensitivity in mice, suggesting that GPR88 receptors may be involved in the modulation of dopaminergic system. However, there is no study that examines the pharmacological effects of GPR88 receptor ligands in in vivo preparations. This study examined the effects of a GPR88 receptor agonist, (1R, 2R)-2-pyridin-2-yl-cyclopropane carboxylic acid ((2S, 3S)-2-amino-3-methyl-pentyl)-(4′-propylbiphenyl-4-yl)-amide (2-PCCA), on the motor activity in rats and on methamphetamine-induced hyperactivity and discriminative stimulus effects. 2-PCCA (0.1–3.2mg/kg) dose-dependently decreased the locomotor activity in rats and, when studied in combination with 1.0mg/kg methamphetamine, also dose-dependently decreased methamphetamine-induced hyperactivity. However, the dose of 2-PCCA that significantly attenuated methamphetamine-induced hyperactivity was also the dose that by itself markedly decreased the baseline locomotor activity. In rats discriminating 0.32mg/kg methamphetamine, 2-PCCA (1–3.2mg/kg) itself did not produce methamphetamine-like discriminative stimulus effects and, when studied in combination, did not alter the discriminative stimulus effects of methamphetamine. Together, these data have provided the first line of evidence that activation of GPR88 receptors does not alter the behavioral effects of methamphetamine. The potential implications of these findings are also discussed.

Dopamine D2 receptor and transptor mechanism in the prefrontal cortex of the susceptibility to heroin addiction

Objective To establish the rats model of different susceptibility of heroin addiction,and to explore the possible dopamine D2 receptor (D2R) and dopamine transptor (DAT) mechanism leading to the different susceptibility. Methods 130 male SD rats were carried out CPP training,and the rats were randomly assigned into heroin exposure group (n = 100) and saline control group (SC, n = 30). Heroin exposure group were re-classified into two groups according to the numerical value of the CPP-Pre (the testing score minus that of the pretest):high preference group(HP group) and low preference group(LP group) ,each accounting for 30% of the total rats.The D2R and DAT protein expression of high and low preference group and saline control group rats were detectedwith immunohistochemical method in PFC at 30 minutes and on the 1st,3rd,7th, 14th days after the last injection(149.33 ±2.51 vs 135.83 ±1.78 vs99.33 ±2.84,141.83 ±2.50 vs 131.67 ± 1.87 vs99.17 ±3.61,132.83 ±2.40 vs 122.00 ±2.67 vs 100.33 ±4.26,125.67 ±2.22 vs 113.17 ±2.81 vs 98.33 ±3.25,116.86 ± 1.94 vs 108.63 ± 2.31 vs 98.17 ± 3.82 , respectively, P＜0.05). The D2R protein expressions of HP rats were significantly lower than those of the LP and control group rats (P ＜ 0. 05), and those of LP rat were than lower than those ferent among three groups on addiction phase and 1st,3rd days after the last injection of heroin respectively, respectively (P ＜ 0. 05). The DAT protein expressions of HP and LP rats were significantly lower than those of controlgroup rats (P＜ 0. 05). At all testing time-points, the DAT protein expressions had no significant difference betweenHP and LP group(P＞0. 05). Conclusion D2R and DAT of the rats show appears down-regulation in the PFC after chronic heroin exposure. Different individuals have different D2R sensitivity or receptor levels ,and lower D2R related to the high susceptibility to heroin. Susceptibility to heroin addiction may not be directly related to the expression of DAT. Key words: Heroin; Dopamine D2 receptor; Dopamine transport; Prefrontal cortex

Hypothalamic–pituitary–adrenal axis responses to stress in subjects with 3,4-methylenedioxy-methamphetamine (‘ecstasy’) use history: correlation with dopamine receptor sensitivity

Fifteen 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) users who did not have other drug dependencies or prolonged alcohol abuse and 15 control subjects were studied. All the subjects were exposed to the same psychosocial stressor (Stroop Color–Word Interference Task, public speaking and mental arithmetic in front of an audience) 3 weeks after MDMA discontinuation. Plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol were measured immediately before the tests began and at their end, 30 min later. Growth hormone (GH) responses to the dopaminergic agonist bromocriptine and psychometric measures (Tridimensional Personality Questionnaire, Minnesota Multiphasic Personality Inventory, Buss–Durkee Hostility Inventory) were also obtained 4 weeks after MDMA discontinuation for the same subjects. ACTH and cortisol basal levels were significantly higher in ecstasy users than in control subjects. In contrast, ACTH and cortisol responses to stress were significantly blunted in MDMA users. The sensitivity of dopamine D2 receptors, reflected by GH responses to bromocriptine challenge, was reduced in MDMA users compared with controls. The responsiveness of the hypothalamic–pituitary–adrenal (HPA) axis (ACTH and cortisol delta peaks) correlated directly with GH areas under curves in response to bromocriptine, and inversely with psychometric measures of aggressiveness and novelty seeking. No correlation was found between hormonal measures and the extent of MDMA exposure. Reduced D2 receptor sensitivity, HPA basal hyperactivation and reduced responsiveness to stress may represent a complex neuroendocrine dysfunction associated with MDMA use. The present findings do not exclude the possibility that dopamine dysfunction partly predated MDMA exposure.

A preliminary study of dopamine-mediated prolactin inhibition in generalised social phobia

The biology of social phobia has been little studied, but a possible role for dopamine has been implicated in this disorder. The aim of this study was to examine central dopaminergic function in patients with generalised social phobia using the prolactin response to quinagolide, a dopamine D2 receptor agonist, and to compare responses with those of normal controls. The study included 14 patients with moderate or severe generalised social phobia and 14 healthy age- and gender-matched comparison subjects. Quinagolide (0.5 mg) was administered orally and prolactin responses were measured over 4 h. There was no significant difference between prolactin responses in patients and healthy controls, nor was there a correlation between prolactin response and age, sex, or severity of illness. This would suggest that tuberoinfundibular dopamine D2 receptor sensitivity is normal in this disorder.

Evidence for reduced dopamine D2 receptor sensitivity in postwithdrawal alcoholics.

Dopamine D2 receptor sensitivity was assessed in the postwithdrawal period in alcoholics. Growth hormone (GH) responses to dopamine D2 agonist bromocriptine were measured in eight DSM-III-R alcohol-dependent subjects who were 2 weeks or more postalcohol withdrawal. Their responses were compared with eight nonalcoholic controls. After an overnight fast, each subject received 1.25 mg of bromocriptine orally, and serial samples of GH were taken over a 3-hr period. There was a significantly blunted delta GH response (mean +/- SE) in the alcoholic group, 2.3 mU/liter (+/- 1.4) relative to controls, 7.7 mU/liter (+/- 1.2) (t = 2.96, df = 14, p = 0.01). There was a significantly blunted peak GH response (mean +/- SE) in the alcoholic group, 5.36 mU/liter (+/- 2.1) relative to controls, 9.04 mU/liter (+/- 5.0). This difference also reached statistical significance (t = 2.32, df = 14, p = 0.035). A repeated-measures ANOVA yielded a significant within-subjects effect of time [F(4,54) = 4.08, p = 0.0057], a significant within-subjects effect of group [F(1,14) = 5.6, p = 0.0329], and an almost significant group x time interaction [F(4,54) = 2.45, p = 0.056]. This result implies a relative dopamine D2 receptor subsensitivity in alcoholics in the postwithdrawal period.

Subsensitivity to rewarding and locomotor stimulant effects of a dopamine agonist following chronic mild stress.

Chronic exposure to very mild unpredictable stress has previously been found to reduce or abolish the acquisition of place preference conditioning. In the present study, chronic mild stress was found to abolish the acquisition of preferences for a distinctive environment paired with systemic administration of amphetamine (0.5 mg/kg) or quinpirole (100-400 micrograms/kg) or with quinpirole (0.75 micrograms) administered bilaterally within the nucleus accumbens. The locomotor stimulant effects of quinpirole (100-400 micrograms/kg) were also attenuated in stressed animals. The result suggest that decreased sensitivity to reward following chronic mild stress results from a decreased sensitivity of dopamine D2 receptors within the nucleus accumbens.

Chronic mild stress-induced anhedonia: A realistic animal model of depression

Chronic sequential administration of a variety of mild stressors causes a decrease in responsiveness to rewards in rats, which is reversed by chronic administration of antidepressant drugs. This paper reviews the validity of chronic mild stress-induced anhedonia as an animal model of depression, and the evidence that changes in hedonic responsiveness in this model are mediated by changes in the sensitivity of dopamine D2 receptors in the nucleus accumbens. The review opens with an analysis of the design features of animal models of depression, and ends with a brief account of other animal models of anhedonia.

Repeated treatment with antidepressant drugs and/or electroconvulsive shock (ECS) does not affect the quinpirole-induced elevation of the serum corticosterone concentration in rats

The selective dopamine D2 receptor agonist quinpirole (0.03-1 mg/kg intra peritoneally) increased dose-dependently the serum corticosterone level in rats. The effect of the maximum dose of quinpirole (0.3 mg/kg intraperitoneally) was antagonized in a dose- dependent manner by the selective D2 receptor antagonist sulpiride (3-30 mg/kg intra peritoneally), but not by the selective D(1) receptor antagonist SCH-23390 (3 mg/kg intra peritoneally). Imipramine and amitriptyline (10 mg/kg per os), administered acutely or repeatedly (twice daily for 14 days), did not affect the corticosterone response to quinpirole (0.1 mg/kg intraperitoneally). The response was modified neither in animals treated repeatedly with electroconvulsive shock (ECS) (seven shocks every 2 days), nor after their combined repeated treatment with imipramine and ECS. The above results indicate that repeated treatment with antidepressant drugs and/or ECS does not affect the sensitivity of dopamine D2 receptors involved in the corticosterone response to quinpirole.