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14 décembre 2009 
Neonatal quinpirole treatment enhances locomotor activation and dopamine release in the nucleus accumbens core in response to amphetamine treatment in adulthood
Zackary A. Cope, Kimberly N. Huggins, A. Brianna Sheppard, Daniel M. Noel1, David S. Roane, Russell W. Brown
Department of Psychology, East Tennessee State University
Drinking sucrose or saccharin enhances sensitivity of rats to quinpirole-induced yawning. Serafine KM


Amphetamine sensitization and D2 priming
Neonatal quinpirole treatment to rats produces long-term increases in D2 receptor sensitivity that persists throughout the animal's lifetime, a phenomenon referred to as D2 priming. Male and female Sprague-dawley rats were administered quinpirole (1mg/kg) or saline from postnatal days (P)1-11.
At P60, all animals were given an injection of quinpirole (100 ug/kg), and results showed that rats neonatally treated with quinpirole demonstrated enhanced yawning in response to quinprole, verifying D2 receptor priming because yawning is a D2 receptor mediated event. Beginning 1-3 days later, locomotor sensitization was tested through administration of d-amphetamine (1mg/kg) or saline every other day over 14 days, and horizontal activity and turning behavior were analyzed.
Findings indicated that D2-priming enhanced horizontal activity in response to amphetamine in females compared to males at days 1 and 4 of locomotor sensitization testing, and D2-priming enhanced turning in response to amphetamine. Seven to 10 days after sensitization was complete, microdialysis of the NAcc core was performed using a cumulative dosing regimen of amphetamine (0.1 &endash; 3.0 mg/kg). D2- primed rats administered amphetamine demonstrated a 500% increase in accumbal DA overflow compared to control rats administered amphetamine.
Additionally, amphetamine produced a significant increase in NE overflow compared to controls, but this was unaffected by D2 priming. These results indicate that D2 receptor priming as is produced by neonatal quinpirole treatment robustly enhances behavioral activation and accumbal DA overflow in response to amphetamine, which may underlie increases in psychostimulant use and abuse within the psychotic population where increased D2 receptor sensitivity is a hallmark.
Past studies have shown that neonatal quinpirole (a dopamine D2/D3 agonist) treatment to rats result in a significant increase of dopamine D2 receptor sensitivity that persists throughout the animal's lifetime, which is a phenomenon that has also been referred to as 'D2 priming' (Kostrzewa, et al., 1993;Thacker, et al., 2006). Interestingly, this change in receptor sensitivity is independent of a change in receptor number (Kostrzewa, 1995). Increases in D2 receptor sensitivity are common in several behavioral disorders, including schizophrenia, bipolar disorder, obsessive-compulsive disorder, and D2 receptor family genetic polymorphisms have been shown in attention deficit/hyperactivity disorder (ADHD) (Jimerson et al. 1987; Seeman et al. 2006; Kieling et al. 2006; Sery et al. 2006). Recently we have shown that neonatal quinpirole treatment results in a significant decrease of genetic expression of Rgs9, a regulator of Gprotein signaling at the dopamine D2 receptor, in the nucleus accumbens, striatum, and to a lesser extent, in the frontal cortex of adult rats (Maple, et al., 2007).
This significant decrease in RGS9 expression is consistent with post-mortem findings in psychosis (Seeman, et al., 2007). Additionally, we have shown that treatment with the antipsychotic olanzapine alleviates cognitive impairment and significant decreases of neurotrophic factor protein produced by neonatal quinpirole treatment (Thacker, et al., 2006), also consistent with other preclinical findings (Fumagalli, et al., 2003; Angelucci, et al., 2004). In psychotic disorders, a common comorbidity is a significant 2-5 increase in psychostimulant abuse compared to the normal population (LeDuc and Mittleman 1995; Lasser et al. 2000; Snyder et al. 2006). Psychostimulants, such as amphetamine and nicotine, are the most frequently abused drugs in these behavioral disorders.
Despite these observations no definitive explanation for the high level of drug abuse in this population exists, and few investigations have been done into the neural correlates of psychostimulant abuse in these populations. Interestingly, imaging studies in schizophrenics have shown that treatment with amphetamine produces a significant increase in striatal dopamine release, which is most pronounced during episodes of illness exacerbation (Laruelle, et al., 1996; Abi Dargham, et al., 1998). This result suggests that schizophrenics may be vulnerable to abuse of psychostimulants due to an increased dopaminergic response to drugs of addiction, which presumably would produce increased behavioral activation and positive reinforcement in response to the drug. Consistent with this past work, a collaborating laboratory has shown that acute amphetamine to rats D2-primed with quinpirole as neonates resulted in a four-fold increase in striatal dopamine release compared to controls administered amphetamine (Nowak, et al., 2001).
However, this past study did not analyze sex differences or locomotor sensitization, and although the dorsal striatum plays a role in mediating locomotor activation and positive reinforcement, the nucleus accumbens has been shown to central to the reinforcement properties of addictive drugs as well as mediate behavioral activating aspects of psychostimulants (DiChiara, 1993). The present study was designed to analyze amphetamine locomotor sensitization as well as DA and NE microdialysis in male and female rats D2-primed as neonates with the D2/D3 agonist quinpirole. Locomotor sensitization has been prominently used as a behavioral assay to analyze underlying behavioral mechanisms of addiction (Robinson and Berridge, 1993; Pierce and Kalivas, 1995). An additional focus of this study was to analyze the effects of previous exposure to amphetamine on dopamine release in the nucleus accumbens core in animals D2 receptor primed as neonates.
The rationale for choosing the NAcc core is based on findings that have shown that the core, but not the NAcc shell, has been implicated in dopamine release in psychostimulant locomotor sensitization (Cadoni, et al., 2000; Ito, et al., 2000), and the NAcc core is preferentially innervated by nuclei that process motor information (Heimer, et al., 1991). Finally, direct injections of dopamine to this region produce a more robust locomotor response than the shell of the NAcc (Campbell, et al., 1997). Based on the focus of this study on locomotor behavioral senstization and the role of the NAcc core in locomotor behavior, we chose to focus on the NAcc core as the brain area for microdialysis.
Male and female rats were used as subjects, as several past studies have reported a sex difference in both the behavioral and neurochemical response to amphetamine (Becker, et al., 1999; 2001). Additionally, both dopamine (DA) and norepinephrine (NE) levels were analyzed, because although increases in dopaminergic activity have been shown to be central to primary drug reinforcement and locomotor sensitization (for review, see Vetulani, 2001), amphetamine has also been shown to increase NE in the NAcc core which may be related to behavioral effects produced by amphetamine (McKittrick and Abercrombie, 2007). Further, several studies have shown alterations in the NE system in post-mortem analyses of the nucleus accumbens in psychosis, specifically in schizophrenia, (Farley, et al., 1978; Bridge, et al., 1985, for review see Yamamoto & Hornykiewicz, 2004) but it is unclear whether this change is an increase or decrease of noradrenergic functioning within the accumbens.
In conclusion, there are several consistencies between the present study and other nonclinical and clinical literature analyzing the effects of amphetamine on DA levels in model of psychosis and in psychotic individuals. In pre-clinical work, past studies using the neonatal ventral hippocampal lesion (NVHL) model of schizophrenia in rats have also shown hyperresponsiveness to amphetamine both behaviorally and in enhanced DA release in the NAcc core. Clinically, both schizophrenics and schizotypal personality disorder have shown an enhanced DA response in the dorsal striatum measured using PET. Moreover, these studies revealed a correlation between the exaggerated response of the striatal dopaminergic system to acute amphetamine and a transient exacerbation of positive symptoms in patients with schizophrenia, underscoring the clinical relevance of this alteration in DA-mediated transmission.