Russell W. Brown

Adulthood nicotine treatment alleviates behavioural impairments in rats neonatally treated with quinpirole: possible roles of acetylcholine function and neurotrophic factor expression

Increases in dopamine D2 receptor sensitivity are known to be common in drug abuse and neurological disorders. Past data from this laboratory have shown that long‐term increases in D2 sensitivity can be produced by quinpirole treatment (a D2/D3 agonist) during early development. The present investigation was designed to test the hypothesis that nicotine administration in adulthood would reduce both cognitive and skilled reaching impairments produced by increases in D2 sensitivity. Female Sprague–Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal day 1 (PD 1) to PD 21. Beginning in adulthood (PD 61), rats were treated with nicotine (0.3 mg/kg free base) or saline twice daily for 14 consecutive days before behavioural testing commenced. Animals neonatally treated with quinpirole demonstrated performance deficits on the Morris water task and a skilled reaching task compared to controls. Deficits on both tasks were completely alleviated by adulthood nicotine treatment. Animals neonatally treated with quinpirole demonstrated a significant 36% decrease of ChAT in the hippocampus compared to saline controls that was partially eliminated by nicotine. Additionally, neonatal quinpirole produced a significant decrease in hippocampal NGF content compared to controls, however, nicotine failed to alleviate this decrease in NGF. The results of this investigation demonstrate that long‐term increases in dopamine D2 receptor sensitivity produce significant decreases in hippocampal cholinergic and NGF expression that may result in cognitive impairment. Nicotine alleviates both cognitive and skilled reaching impairments caused by increases in D2 sensitivity, but the mechanism through which nicotine is acting is currently unknown.

Ontogenetic quinpirole treatments produce spatial memory deficits and enhance skilled reaching in adult rats.

There is a paucity of data on neurochemical abnormalities and associated effects on cognition and motor performance in rats ontogenetically treated with quinpirole, a rodent model of dopaminergic hyperfunction. The objective of the current study was to analyze the cognitive and motor effects produced by ontogenetic administration of quinpirole, a dopamine D(2)/D(3) receptor agonist. Past research from this laboratory has shown that ontogenetic quinpirole treatment sensitizes D(2) receptors and produces a variety of characteristic stereotypic behaviors in adult rats. In the current study, rats received quinpirole HCl (1 mg/kg/day) or saline from postnatal day (PD) 1 to PD 11 and went otherwise untreated until adulthood (PD 60). In Experiment 1, cognitive performance was assessed on the standard and matching-to-place versions of the Morris water task (MWT). In Experiment 2, skilled motor performance was assessed on the Whishaw reaching task and locomotor activity was also analyzed. We found that ontogenetically quinpirole-treated rats displayed a deficit on the probe trial given at the end of training of the standard version of the MWT but that there were no significant differences from control on the matching-to-place task. Additionally, rats treated in ontogeny with quinpirole showed significant enhancement in reaching accuracy on the Whishaw reaching task as well as increased locomotor activity relative to saline controls. These findings demonstrate that ontogenetic quinpirole treatments produce cognitive deficits, enhanced skilled reaching and hyperlocomotion. The behavioral changes produced by ontogenetic quinpirole treatment are consistent with dopaminergic hyperfunction, and possible mechanisms are discussed.

Neonatal methamphetamine administration induces region-specific long-term neuronal morphological changes in the rat hippocampus, nucleus accumbens and parietal cortex

Previous studies have demonstrated that rats exposed to methamphetamine (MA) during the neonatal period display deficits in spatial learning and memory. The underlying correlates are unknown; therefore, this study was devised to determine whether neuronal changes occur in the dentate gyrus (DG), nucleus accumbens (NAcc) and cortex of adult rats exposed to 10 mg/kg MA administered four times daily from P11–20 using Golgi–Cox staining [Gibb, R. & Kolb, B. (1998) J. Neurosci. Meth., 79, 1–4]. The DG and NAcc demonstrated a decrease in the number of spines per neuron and the NAcc showed an associated decrease in dendritic length. Selective changes in cortex were observed because increased dendritic length in the parietal cortex occurred with no change in the number of spines, and no differences were noted for either dendritic length or spines in the medial frontal cortex. The data suggest a potential cause for the learning and memory deficits induced by neonatal MA exposure; however, the underlying mechanism that produces these neuronal changes is unknown.

The effects of adulthood olanzapine treatment on cognitive performance and neurotrophic factor content in male and female rats neonatally treated with quinpirole

Male and female Sprague–Dawley rats were administered quinpirole (1 mg/kg, i.p.) or saline once daily from postnatal day (P)1 to P21. This drug treatment has been shown to produce long‐term priming of the D2 receptor. Beginning on P62, rats were administered the atypical antipsychotic olanzapine (2.5 mg/kg) or saline twice daily (i.p.) for 28 days. One day after olanzapine treatment ceased, rats were tested on the place and match‐to‐place versions of the Morris water maze (MWM) for seven consecutive days. Dopamine D2 receptor priming was verified through a yawning behavioural test, a D2 receptor‐mediated event, before olanzapine was administered as well as after olanzapine treatment and behavioural testing were complete. Results showed that neonatal quinpirole treatment induced D2 priming that was eliminated by olanzapine treatment. On the MWM place version, D2‐primed rats demonstrated a significant impairment that was eliminated by olanzapine treatment, but olanzapine treatment to animals neonatally treated with saline produced a significant deficit on the place version of the MWM. There were no significant deficits on the match‐to‐place version. Brain tissue analyses revealed that neonatal quinpirole treatment produced a significant decrease in hippocampal NGF, BDNF and ChAT that was eliminated by olanzapine treatment. Neonatal quinpirole treatment produced a significant decrease in BDNF and ChAT in the frontal cortex that was unaffected by olanzapine treatment. These results show that olanzapine eliminates D2 receptor priming and cognitive impairment and also alleviates decreases in neurotrophins and acetylcholinergic markers produced by D2 priming in the hippocampus.

Ontogenetic quinpirole treatment produces long-lasting decreases in the expression of Rgs9, but increases Rgs17 in the striatum, nucleus accumbens and frontal cortex

Ontogenetic treatment of rats with the dopamine D2‐like receptor agonist quinpirole produces a significant increase in dopamine D2 receptor sensitivity that persists throughout the animals lifetime, a phenomenon known as D2 priming. The present study was designed to investigate the effects of priming of the D2 receptor on the expression of three different members of the regulator of G‐protein signaling (RGS) family: Rgs4, Rgs9 and Rgs17. Male offspring were ontogenetically treated with quinpirole or saline from postnatal days (P)1–21 and raised to adulthood. On ∼ P65, animals were given an acute quinipirole injection (0.1 mg/kg) and the number of yawns was recorded for 1 h after the injection. Yawning has been shown to be a behavioural event mediated by the dopamine D2/D3 receptor. Animals ontogenetically treated with quinpirole demonstrated a significant 2.5‐fold increase in yawning as compared to controls. Rgs transcripts were analysed through in situ hybridization several weeks later. Rats ontogenetically treated with quinpirole demonstrated a significant decrease in Rgs9 expression in the frontal cortex, but a more robust decrease in the striatum and nucleus accumbens as compared to controls. Regarding Rgs17, ontogenetic quinpirole produced a modest but significant increase in expression in the same brain areas. There were no significant differences in Rgs4 expression produced by drug treatment in any of the brain regions analysed. This study demonstrates that ontogenetic quinpirole treatment, which results in priming of the D2 receptor, results in significant decreases in Rgs9, which has been shown to regulate G‐protein coupling to D2 receptors.

Dopamine receptor supersensitivity: Development, mechanisms, presentation, and clinical applicability

The process of receptor supersensitivity (RSS) has a long history and is an epiphenomenon of neuronal denervation. Dopamine (DA) RSS (DARSS) similarly occurs after DA-denervation, and this process is invoked in neuropsychiatric and neurodegenerative disorders. From studies largely over the past 25 years, much has been learned regarding DARSS. For example, overt D1 DARSS occurs after perinatal destruction of nigrostriatal DA fibers. However, following perinatal destruction of DA innervation, the mostprominent behavioral effects of a D1 agonist are observed after a series of D1 agonist treatments- a process known aspriming of D1DA receptors. Moreover, perinatal lesioning of DA fibers produces prominent serotonin (5-HT) RSS, and in fact 5-HT RSS appears to modulate D1 DA RSS. In rodents, receptor supersensitization by these means appears to be irreversible. In contrast to the observedD1 DARSS, D2 DARSS apparently does not occur after perinatal DA denervation. Also, while repeated D1 agonist treatment of intact rats has no observable effect, repeated D2 agonist treatments, during or after the ontogenetic phase, produces prominent life-long D2 RSS. The process may have an association with substance abuse. Therefore, production of D1 and D2 DARSS occurs by different means and under different circumstances, and in association with perhaps different neuronal phenotypes, and with greater incidence in either intact (D2) or DA-lesioned counterparts (D1). The physiological consequence of RSS are multiple.

Mecamylamine blocks enhancement of reference memory but not working memory produced by post-training injection of nicotine in rats tested on the radial arm maze.

The focus of this study was to analyze whether the psychostimulant nicotine would enhance reference and working memory consolidation in rats tested on the 8-arm radial arm maze. Mecamylamine, a nicotine antagonist, was used to attempt to block the enhancement of memory consolidation. All rats were given one training trial/day for 12 consecutive days, and 4 arms were baited. Rats were separated into five groups: the saline-nicotine group received an intraperitoneal (i.p.) injection of saline immediately after each trial followed 15 min later by an subcutaneous (s.c.) injection of nicotine (0.6 mg/kg free base); the nicotine-delay group received an s.c. injection of nicotine 2 h after each training trial, two groups received an i. p. injection of one of two different doses of mecamylamine (2.5 and 6.0 mg/kg) immediately after each trial, which was followed 15 min later by an s.c. nicotine injection, and a control group received an i.p. injection of saline immediately and 15 min after each training trial. Results showed that the saline-nicotine group made fewer reference and working memory errors than the saline- or nicotine-delay groups, but only the effect of nicotine on reference memory was blocked by the higher dose of mecamylamine. It appears from these results that nicotines effects on reference and working memory may be mediated through different mechanisms.

Neonatal quinpirole treatment impairs morris water task performance in early postweanling rats: relationship to increases in corticosterone and decreases in neurotrophic factors

BACKGROUND Past studies from this laboratory have shown that quinpirole administration from postnatal day (P) 1-21 produces persistent supersensitization of the dopamine D2 receptor that persists throughout the animals lifetime. METHODS In Experiment 1, both male and female rats were treated with quinpirole or saline from P1-21 and tested on the place and match-to-place versions of the Morris water task (MWT) from P22-28. In Experiment 2, both male and female rats were administered either acute or chronic injections of quinpirole (1 mg/kg) or saline beginning on P1 until analysis for corticosterone (CORT) on P7, 14, or 21. RESULTS Neonatal quinpirole treatment produced deficits on both versions of the MWT compared with saline control. One day after behavioral testing, brain tissue was harvested, and the hippocampus was analyzed for nerve growth factor (NGF) and brain-derived nerve growth factor (BDNF); NGF was found to be significantly decreased by neonatal quinpirole treatment. Acute or chronic quinpirole treatment on P14 produced a larger increase in CORT than controls and produced larger increases in CORT than control rats on P21. CONCLUSIONS These results demonstrate that neonatal quinpirole treatment produces cognitive deficits that could be related to decreases in hippocampal NGF and increases in CORT, resulting in abnormalities in hippocampal development.

Schizophrenia and Substance Abuse Comorbidity: Nicotine Addiction and the Neonatal Quinpirole Model

This review focuses on nicotine comorbidity in schizophrenia, and the insight into this problem provided by rodent models of schizophrenia. A particular focus is on age differences in the response to nicotine, and how this relates to the development of the disease and difficulties in treatment. Schizophrenia is a particularly difficult disease to model in rodents due to the fact that it has a plethora of symptoms ranging from paranoia and delusions of grandeur to anhedonia and negative affect. The basis of these symptoms is believed to be due to neurochemical abnormalities and neuropathology in the brain, which most models have attempted to emulate. A brief review of findings regarding nicotine use and abuse in schizophrenics is presented, with findings using rodent models that have been able to provide insight into the mechanisms of addiction. A common clinical approach to the treatment of nicotine addiction in the schizophrenic population has been that these drugs are used for self-medication purposes, and it is clear that self-medication may actually be directed at several symptoms, including cognitive impairment and anhedonia. Finally, our laboratory has reported across a series of studies that neonatal treatment with the dopamine D2/D3 receptor agonist quinpirole results in long-term increases in dopamine-like receptor sensitivity, consistent with data reporting increases in dopamine D2 receptor function in schizophrenia. Across these studies, we have reported several behavioral, neurochemical, and genetic consistencies with the disease, and present a hypothesis for what we believe to be the basis of psychostimulant addiction in schizophrenia.

Nicotine sensitization and analysis of brain-derived neurotrophic factor in adolescent ß-arrestin-2 knockout mice

Nicotine sensitization and levels of brain‐derived neurotrophic factor (BDNF) were analyzed in adolescent ß‐arrestin‐2 knockout (ßA‐2 KO) and wild type (WT) mice. The ß‐arrestin‐2 protein has been shown to be important in G‐protein hydrolysis and receptor internalization. Four‐ to five‐week‐old adolescent ßA‐2 KO and WT C57/Bl6 mice were administered either nicotine (0.5 mg/kg free base) or saline 10 min before being placed into a locomotor arena on each of 7 (Experiment 1) or 14 (Experiment 2) consecutive days. A nicotine challenge was given 7 days after sensitization was complete. In Experiment 1, ßA‐2 KO mice administered nicotine or saline and WT mice administered nicotine demonstrated significant hypoactivity during early in testing, and neither WT nor ßA‐2 KO mice administered nicotine demonstrated sensitization. On the nicotine challenge, WT mice administered nicotine demonstrated significantly higher activity levels compared to all groups, and this same group demonstrated significantly higher levels of accumbal BDNF compared to all groups. In Experiment 2, ßA‐2 KO mice were again hypoactive compared to WT mice, whereas WT mice administered nicotine demonstrated significant hypoactivity during initial testing and significantly higher levels of activity compared to all other groups late in testing. On the nicotine challenge, WT mice that received nicotine demonstrated a significant increase in activity compared to all groups, and showed increased accumbal BDNF compared to all groups. These results show that the ß‐arrestin‐2 protein is important in induction and expression of nicotine sensitization as well as nicotines effects on accumbal BDNF. Synapse 63:510–519, 2009.