The current study was designed to analyze the roles of both α7 and α4β2 nicotinic receptors (nAChRs) in behavioral sensitization and its effects on Brain Derived Neurotrophic Factors (BDNF) and the mammalian target of rapamycin (mTOR) in the neonatal quinpirole model of schizophrenia. Animals were treated neonatally with either quinpirole (1 mg/kg) or saline starting on P1 and treatment persisted through P21. Starting on P33, animals were sensitized to nicotine (0.5 mg/kg free base) every other day up to P49. Following sensitization, brains were harvested at 1 h and 24 h post-drug treatment and BDNF protein and total mTOR activity were assessed in the nucleus accumbens. Results revealed that α7 antagonism failed to block nicotine sensitization regardless of neonatal quinpirole treatment, and appears to block the initial hypoactive response to nicotine in males but not females. In addition, α7 antagonism effectively blocked the enhanced BDNF response to nicotine in both saline and quinpirole treated animals but was ineffective at blocking mTOR at the 1 h time point, and resulted in decreases of mTOR at the 24 h time point. Antagonism of the α4β2 nAChR effectively blocked nicotine sensitization in both males and females but the higher dose resulted in a significant initial hypoactive response to nicotine. In addition, α4β2 nAChR antagonism blocked nicotine induced increases in BDNF. Total mTOR revealed that neonatal quinpirole produced a decrease in mTOR that was reversed by nicotine at the 1h but not the 24h time point and antagonism of nAChRs resulted in sex dependent effects. There results have implication towards the mechanisms underlying enhanced smoking in schizophrenia.

Neonatal quinpirole (QUIN; dopamine D2/D3 agonist) administered from postnatal days (P)1-21 results in an increase of dopamine D2 receptor sensitivity, similar to schizophrenia and is now an established rodent model of schizophrenia. The day after birth, male and female Sprague-Dawley rats were given a daily 1 mg/kg injection of either QUIN or saline from P1-21. One subset of these animals were behaviorally tested on PPI, referred to as first generation (F0). A different subset of animals were allowed to reach adult age (P60) and female and male QUIN-treated pairs from separate litters were bred. Their offspring were also used as subjects (F1 generation). Prepulse inhibition (PPI) is a measure of sensorimotor gating reduced in individuals diagnosed with schizophrenia. Trial types were defined as prepulse trials (73, 76, 82dB), startle stimuli trials (120 dB), or no stimulus (70 dB white noise; no prepulse or pulse). Animals were tested for six consecutive days and given an ip saline injection 10 min before testing, followed by testing for another six consecutive days and given an ip nicotine (0.5 mg/kg free base) or saline injection 10 min before testing. PPI testing for F0 generation animals occurred between P35-46, and testing for F1 generation animals occurred between P44-55. In one subset of generation F1 animals, rats were ip injected with a 0.1 mg/kg dose of quinpirole and immediately observed for 60 min and the number of yawns were recorded at P60. Yawning is a behavioral event mediated by the dopamine D2 receptor. Results revealed that neonatal QUIN resulted in PPI deficits throughout the six days of testing in the F0 generation regardless of the prepulse stimulus, but females demonstrated a less robust PPI deficit as compared to males. Nicotine given during the final 6 days of testing partially alleviated the PPI deficits in both males and females. The F1 generation also demonstrated PPI deficits, but the impairment was only in males and dissipated by day 6. Nicotine did not affect PPI in these animals. Finally, F1 generation rats demonstrated a robust increase in yawning compared to controls, demonstrating an increase in D2 receptor sensitivity. Brain tissue is being analyzed for changes in the dopamine D2 receptor signaling pathway.

Schizophrenia is a debilitating psychiatric disorder that affects approximately 1% of the global population. Schizophrenia is highly comorbid with other psychiatric disorders such as Alcohol Use Disorder (AUD) with a prevalence rate of 27% - 65%, which is significantly higher than AUD exhibited by the general population (6%). Research indicates that a higher rate of AUD in individuals suffering from schizophrenia may be related to the common neuronal pathways that underlie the expression of both disorders. The present study will determine whether the neonatal quinpirole (NQ) rodent model of schizophrenia will approximate the human condition and exhibit increased EtOH consumption. Rats will be treated neonatally with quinpirole or saline. Following the treatment period, rats will be tested for EtOH consumption using a 24-hour two-bottle free-access paradigm. The proposed research will test the hypothesis that rats neonatally treated with quinpirole will consume significantly greater amounts of EtOH than their saline counterparts.

Repeated ontogenetic treatment with quinpirole produces enhanced quinpirole-induced yawning and antinociceptive actions in adult rats. We now report the occurence of a bizarre behavior jumping inrats so treated. Rats were treated daily from birth with quinpirole HCl (3.0 mg/kg per day × 28 days i.p., salt form) or saline vehicle. After each daily injection, the rats were observed for at least 1 h. Starting on the 18th day after birth, quinpirole treatment was associated with the appearance of jumping behavior. On the 20th day after birth a dose-effect relationship was found for quinpirole HCl (0.10-3.0 mg/kg), with maximal jumping activity occurring between 30 and 150 min after the 3.0 mg/kg dose. On the 26th day after birth, both spiperone HCl (0.30 mg/kg i.p.) and SCH 23390 HCl (0.30 mg/kg i.p.) attenuated the quinpirole effect. At 34 days the jumping response was virtually absent. The age-related jumping behavior appears to be another manifestation of the abnormal responses meduated by supersensitized dopamine receptors in quinpirole-primed rats. Based on the ability of dopamine D1 and D2 receptor antagonists to attenuate this effect, quinpirole-induced jumping behavior may be a reflection of cooperativity of dopamine D1 and D2 receptor types.

Repeated postnatal treatment of rats with the dopamine receptor agonist, quinpirole results in exaggeration of selected behaviors that are induced by quinpirole in adulthood. To determine whether the antinociceptive response to quinpirole could be similarly enhanced, rats were treated daily from birth with quinpirole HCl (3.0 mg/kg per day i.p. × 28 days) and their response time in the hot plate analgesia test was determined at 4 months. An acute dose of quinpirole HCl (100 or 1000 μg/kg i.p.) produced an analgesic response in the neonatally primed rats and in the vehicle controls. More significantly, the effect was substantially greater in the quinpirole-primed group at each of these two doses of quinpirole. This effect of quinpirole was fully attenuated in both groups by treatment with the dopamine receptor antagonist, spiperone HCl (0.30 mg/kg i.p., 1 h before quinpirole). The analgesic effect of morphine sulfate (6.0 mg/kg i.p.) was not greater in the quinpirole-primed group. These findings demonstrate that the ontogenetic sensitization of quinpirole receptors results in enhanced antinociceptive responses to quinpirole in adulthood. This animal model may be useful for studying the involvement of dopamine systems in algesia and a analgesia.

Research has revealed that schizophrenics are significantly more likely to smoke cigarettes than the general population, and consume nicotine products at a much more prevalent rate. Further exacerbating this issue, it has been previously demonstrated in clinical populations that the type of antipsychotic treatment administered (typical versus atypical) may result in either an increase or a decrease of already heightened smoking behavior within the schizophrenic population. With these clinical issues in mind, the present study sought to examine the effects of antipsychotic treatment upon the associative reward of nicotine within the neonatal quinpirole model of schizophrenia. We found that treatment with the typical antipsychotic haloperidol blocked the associative reward of nicotine. Clozapine, an atypical antipsychotic, merely reduced the rewarding effects. These findings illustrate the centrality of the dopamine system, specifically the D2 receptor subtype, as an underlying mechanism of the rewarding effects of nicotine among rodents neonatally treated with quinpirole.

Aims: Neonatal quinpirole (a dopamine D2-like agonist) treatment to rats has been shown to increase dopamine D2 receptor sensitivity throughout the animal’s lifetime, and increased dopamine D2 sensitivity is a hallmark of schizophrenia. Schizophrenics are 3 to 4 times more likely to smoke than the normal population, but there is no delineating mechanism. Aim 1: Behaviorally test a rewarding versus averisve dose of nicotine in adolescent rats neonatally treated with quinpirole tested in a place preference paradigm; Aim 2: Analyze phosphorylated cylic AMP response element bidning protein (CREB) in brain areas that mediate drug reward. Methods: Rats were neonatally treated with quinpirole from postnatal days (P)1- 21. After two drug free preferene tests were given in a place preference shuttle box at P41-42, animals were conditioned with saline, a 0.6 or a 1.8 mg/kg free base dose of nicotine for eight consecutive days. A post-conditioning test was given 24 h after conditioning. Time in the paired and unpaired context were measured. Approximately 24 h after the post-condioning test, brain tissue was harvested, flash frozen, and later analyzed for pCREB in the dorsal and nucleus accumbens. Results: Results revealed that neonatal quinpirole enhanced the rewarding associative effects of the lower dose of nicotine compared to animals neonatally treated with saline and conditioned with the same dose of nicotine, which showed a slight place preference. Interestingly, although neonatal saline animals conditioned with the higher dose of nicotine demonstrated conditioned place aversion, neonatal quinpirole treated animals demonstrated no aversion to this same dose. Analyses for p-CREB will be presented. Conclusions: Rats neonatally treated with quinpirole demonstrate an enhancement of the rewarding properties of nicotine, but do not demonstrate an aversion to higher doses of nicotine. These data are congruent with recent self-administration data in our lab, and suggest that increases of dopamine D2 sensitivity may blunt aversive aspects of nicotine.

Repeated daily treatments of perinatal rats with the dopamine D2-receptor (D2-R) agonist quinpirole for a week or more produces the phenomenon of ‘priming’—gradual but long-term sensitization of D2-R. In fact a daily dose of quinpirole as low as 50 µg/kg/day is adequate for sensitizing D2-R. Primed rats as neonates and in adolescence, when acutely treated with quinpirole display enhanced eating/gnawing/nursing on dams, also horizontal locomotor activity. Between 3 and 5 weeks of age, acute quinpirole treatment of primed rats produces profound vertical jumping with paw treading—a behavior that is not observed in control rats. At later ages acute quinpirole treatment is associated with enhanced yawning, a D2-R-associated behavior. This long-term D2-R supersensitivity is believed to be life-long, despite the relatively brief period of D2-R priming near the time of birth. D2-R supersensitivity is not associated with an increase in the number or affinity of D2-R, as assessed in the striatum of rats; nor is it induced with the D3-R agonist 7-OH-DPAT. However, quinpirole-induced D2-R supersensitivity is associated with cognitive deficits, also a deficit in pre-pulse inhibition and in neurotrophic factors, and low levels of the transcript regulator of G-protein signaling (RGS) RGS9 in brain; and acute reversal of these alterations by the antipsychotic agent olanzapine. In sum, rats ontogenetically D2-R supersensitized have face validity, construct validity and predictive ability for schizophrenia.

Schizophrenics are significantly more likely to smoke cigarettes than the general population. In Experiment 1, we analyzed the effects of a rewarding versus an aversive dose of nicotine using the neonatal quinpirole (QUIN; dopamine D2/D3 agonist) model of schizophrenia. In Experiment 2, we examined the effects of antipsychotic treatment upon the associative reward of nicotine within this same model. Neonatal QUIN treatment to rats results in increased dopamine D2 receptor sensitivity throughout the rat’s lifetime, consistent with schizophrenia. Rats were neonatally treated with QUIN (1 mg/kg dose) or saline from postnatal days (P)1-21. Animals were then raised to P41 without any further drug treatment. Subjects were administered two consecutive pre-conditioning drug free preference tests in a three chamber shuttle box on P41 and P42 to determine initial preference. In Experiment 1, beginning on P43, animals were conditioned with saline, a 0.6 mg/kg or a 1.8 mg/kg free base dose of nicotine for eight consecutive days. A drug free post-conditioning preference test was given on P51. Approximately 24 h following the post-conditioning test, brain tissue was harvested and analyzed for mammalian target of rapamycin (mTOR) and phosphorylated-CREB (pCREB) in the nucleus accumbens. In Experiment 2, animals were treated identically as in Experiment 1, but were conditioned with nicotine which was preceded by an injection of either a typical antipsychotic (haloperidol, 0.5 mg/kg dose) or an atypical antipsychotic (clozapine, 2.5 mg/kg dose) for a period of eight days which was followed by a drug free preference test. In both experiments, the difference between time spent in the paired context between pre-test and post-test was utilized as a measure of associative reward. Results revealed that neonatal QUIN enhanced the rewarding effects of nicotine, but neutralized the aversive effects compared to controls. Neonatal QUIN also significantly decreased accumbal mTOR and pCREB results will be presented. In Experiment 2, we found that treatment with clozapine reduced the enhancement of nicotine conditioned place preference, but haloperidol completely reduced nicotine place preference to control levels. These findings show that neonatal QUIN enhances the rewarding associative effects of nicotine, and that the typical antipsychotic haloperidol was more effective at eliminating the associative rewarding effects of nicotine likely due to its potent D2 antagonistic effects.

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.