Narcolepsy is a disabling sleep disorder that is characterized by persistent sleepiness, and cataplexy – an involuntary loss of waking muscle tone. Cataplexy and narcolepsy are caused by the loss of hypocretin containing neurons in the hypothalamus. However, it is hypothesized that dopamine is also involved in sleep and motor control and plays a role in cataplexy. This study investigated how manipulating dopamine affected sleep and cataplexy in narcoleptic mice devoid of hypocretin. We used d-amphetamine to increase endogenous dopamine levels and quinpirole (D2 agonist) to agonize D2 receptor sites. Amphetamine promoted wakefulness while decreasing sleep in wild-type mice, but was less effective in narcoleptic mice. Amphetamine also reduced cataplexy as well as sleep attacks (an indicator of sleepiness) in narcoleptic mice. Quinpirole had no effect on sleep or wakefulness; however, it potently increased cataplexy without affecting sleep attacks in narcoleptic mice.

Quinpirole is a dopamine D2 receptor agonist that if administered to rats from postnatal day (P)1-21 results in increased dopamine D2 receptor sensitivity throughout the animal’s lifetime. This increase in receptor sensitivity is consistent with schizophrenia. This model has additional consistencies with human schizophrenia, including sensorimotor gating deficits, enhanced behavioral and neurobiological responses to nicotine, and protein alterations consistent with the disorder. In this study, a second generation of the neonatal quinpirole (NQ) rodent model was created to investigate if long term changes caused by NQ treatment would be passed to offspring. NQ treated rats were mated and their offspring left untreated. To investigate if dopamine D2 receptor hypersensitivity was transmitted from the first to the second generation of the model, yawning behavior was assayed after acute quinpirole treatment. Prepulse inhibition (PPI) is a test of sensorimotor gating, and PPI testing was performed on adolescent second generation rats. Behavioral sensitization and conditioned place preference to nicotine (0.5 mg/kg and 0.6 mg/kg respectively) were examined in adolescence in both generations of the model. Several neurobiological assays were performed in both nicotine naïve and animals sensitized to nicotine (0.5 mg/kg) in order to investigate consistencies with the NQ model, which has shown enhanced responses to nicotine. These include enzyme linked immunosorbent assays (ELISAs) for brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB), as well as quantitative PCR (qPCR) to quantify messenger RNA (mRNA) of regulator of G-protein signaling 9 (rgs9). Results indicated that second generation rats of NQ-treated rats demonstrated increased yawning behavior in response to acute quinpirole treatment. PPI deficits and enhanced behavioral responses to nicotine were also observed. Increased BDNF expression was observed in the nucleus accumbens following nicotine sensitization, consistent with past work in first generation NQ-treated rats. CREB expression was also increased in both generations of the model, an effect linked to alterations in PPI and other schizophrenia-like symptomology. Rgs9 expression was generally unaltered in either generation of the model. This study provides basis for utilization of a second generation of the NQ model to study epigenetic influences in schizophrenia and drug abuse vulnerability.

This study was designed to investigate the effects of acute eticlopride (0.02 mg/kg, D2 antagonist) treatment, given immediately before training, in rats neonatally treated with quinpirole, which has been shown to produce long-term D2 receptor supersensitization. Rats were given quinpirole (1mg/kg) or saline treatment from P1-21. Beginning on P22, rats were administered eticlopride or saline (i.p.) fifteen mins before each of seven days of training. Rats were tested on the Morris water task (MWT). For the first three consecutive days, rats were tested on the place version of the MWT with a stationary platform. Animals were given 24 training trials followed by a probe trial, and swim patterns were analyzed with platform removed. The next day, animals began testing on the match-to-place version for four consecutive days and two daily trials were given with the platform moved to a new location each day. On both the search time and target visit measures of the probe trial, animals neonatally treated with quinpirole demonstrated a deficit, and eticlopride eliminated this deficit. Interestingly, animals neonatally treated with saline but given eticlopride before training also demonstrated a deficit on both measures. On the match-to-place version, the difference in latency to locate the platform between the two daily trials served as the dependent measure. Similar to the MWT place version, eticlopride treatment eliminated deficits produced by neonatal quinpirole treatment on this task, and eticlopride produced a deficit in saline controls. This study demonstrates that in a model of dopamine D2 supersensitivity, it appears that the increased sensitivity of the D2 receptor is important for cognitive function.

Rationale and objectives: Because of known and imputed roles of dopaminergic and nicotinic cholinergic systems in a variety of neurological and neuropsychiatric disorders, combined neurochemical and behavioral methods assessments were made to study the intermodulatory roles of these neurochemical systems. Methods: Rats were treated daily during postnatal ontogeny with the dopamine D2/D3 agonist, quinpirole (QNP) HCl (1.0 mg/kg/day), for the first 3 weeks from birth. This priming process replicated previous findings of behavioral sensitization, manifested as hyperlocomotion, increased paw treading with jumping, and increased yawning. Results: All effects were partially or totally blocked by acute treatment with nicotine (0.3 mg/kg, i.p.). The effects of nicotine, in turn, were partially or totally blocked by the nicotinic antagonist, mecamylamine (1.0 mg/kg, i.p.). In concert with these behavioral actions, QNP-primed rats displayed greater binding of [3H]cytisine in midbrain and cerebellum and greater [125I]α- bungarotoxin binding in hippocampus and striatum. Conclusions: Accordingly, these selective ligands for α4β2 and α7 nicotinic receptors, respectively, demonstrate that nicotinic receptors are altered by dopamine D2/D3 agonist treatment of rats with primed dopamine receptors. We propose that nicotinic agonists may have a therapeutic benefit in behavioral disorders brought about by central dopaminergic imbalance.

Prolonged prenatal exposure to ethanol produces long-lasting alterations in the level of endogenous brain biogenic amines in rats. To test whether there might be long-lived alterations in the reactivity to dopaminergic, serotoninergic or muscarinic agonists in rats exposed prenatally to ethanol, the following study was done. Wistar rats were given 10% (v/v) ethanol in drinking water, starting 10 days before mating and continuing to the end of pregnancy. Male offspring were tested at 3 months for characteristic behavioral effects (oral activity) known to be induced by agonists acting at central dopamine D2 (quinpirole), serotonin 5-HT2C (m-chlorophenylpiperazine, m-CPP) and muscarine (pilocarpine) receptors. Dose-effect curves demonstrated that oral activity responses to quinpirole HCl (0.05-0.40 mg/kg i.p.) and m-CPP 2HCl (0.3-6.0 mg/kg i.p.) were greatly reduced (P < .001) in rats that were exposed to ethanol in utero. Responses to pilocarpine HCl (0.1-3.0 mg/kg) remained unaltered. The findings indicate that prenatal ethanol exposure alters behavioral responses to D2 and 5-HT2C agonists in male rats tested three months after birth. We propose that prenatal ethanol diminishes reactivity of receptors for dopamine D2 and serotonin 5-HT2C receptors.

No description available.

Repeated treatment in ontogeny with the dopamine (DA) D2/D3 receptor agonist quinpirole is associated with enhanced quinpirole-induced yawning and other behaviors such as vacuous chewing, vertical jumping, and antinociception. To determine if the reputedly DA D3 agonist (±)-2-(dipropylamino)-7-hydroxy-1,2,3,4-tetrahydronaphthalene (7-OH-DPAT) would prime for yawning in a manner analogous to that for quinpirole, rats were treated for the first 11 days after birth with an equimolar dose of either quinpirole or 7-OH-DPAT (195.4 nmol/kg/day) and tested for agonist-induced yawning in adulthood. While enhanced quinpirole-induced and 7-OH-DPAT-induced yawning was observed in quinpirole-primed rats, acute treatments with quinpirole and 7-OH-DPAT did not produce an enhanced yawing response in 7-OH-DPAT-'primed' rats. Our findings indicate that 7-OH-DPAT, unlike quinpirole, does not prime for quinpirole- or 7-OH-DPAT-induced yawning in rats.

This study evaluated the effects of chronic olanzapine treatment on cognitive performance and neurochemical function in a rodent model of schizophrenia. Animals were neonatally treated with quinpirole, a dopamine D2 receptor agonist, or saline. Quinpirole treatment produces an increase of dopamine D2 receptor sensitivity that extends into adulthood, known as D2 receptor priming, similar to a phenomenon that occurs in schizophrenia. These same rats were treated in adulthood for 28 days with olanzapine, an atypical antipsychotic, or saline. Dopamine D2- primed rats demonstrated significant deficits on a cognitive task that were alleviated by olanzapine treatment. Brain tissue analysis revealed that D2-primed animals demonstrated a significant decrease in the neurotrophins nerve growth factor (NGF) in the hippocampus and brain-derived neurotrophic factor (BDNF) in the frontal cortex. Olanzapine treatment alleviated the decrease in NGF. The results suggest that olanzapine eliminates cognitive impairment and may have neuroprotective properties in the hippocampus of D2-primed rats.

Aims: We have established that neonatal treatment with quinpirole, a dopamine D2/D3 agonist, results in increases of dopamine D2 receptor sensitivity throughout the animal’s lifetime and has a number of consistencies with schizophrenia. Aim 1: Analyze the roles of α7 and α4β2 nicotinic receptors in nicotine sensitization in adolescent male and female rats neonatally treated with quinpirole. Aim 2: The roles of the α7 and α4β2 nicotinic receptors were analyzed in their effects on Brain-Derived Neurotrophic Factor (BDNF) and mammalian target of rapamycin (mTOR) in rats neonatally treated with quinpirole and sensitized to nicotine. Methods: Animals were neonatally treated with quinpirole or saline from postnatal days (P)1-21. Beginning on P33, animals were ip injected with nicotine (0.5 mg/kg free base) or saline and tested every second day from P33-49. Approximately 15-30 min before the nicotine or saline injection, animals were ip injected with either the α7 nicotinic receptor (nAChR) antagonist methllycacontine (MLA; 2 or 4 mgkg) or the α4β2 nAChR antagonist dihyro-β (DhβE; 1 or 2.5 mg/kg) erythrodine. Brain tissue was taken 24 h after the last day of testing. Results: Neonatal quinpirole enhanced nicotine sensitization and DhβE blocked nicotine sensitization regardless of neonatal treatment and was more effective in blocking sensitization in males versus females. MLA failed to block nicotine sensitization. Howeer, MLA blocked the acute hypoactive response to nicotine in males, and the higher dose of MLA reduced sensitization in males. Neonatal quinpirole sensitized the accumbal BDNF response to nicotine, but neonatal quinpirole resulted in a decrease of mTOR in both brain areas. Conclusions: The α4β2 receptor plays a critical role in adolescent nicotine sensitization. Interstingly, the α7 nAChR appears to be important in the acute response to nicotine and is more important in nicotine sensitization in males. Both nAChRs appear to be important in accumbal BDNF and their roles will be analyzed in the mTOR response.

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.