Abstract
The activation of dopamine receptors within the mesolimbic dopamine system is known to be involved in the initiation and maintenance of cocaine use. Expression of the D2 dopamine receptor subtype has been implicated as both a predisposing factor and consequence of chronic cocaine use. It is unclear whether there is a predictive relationship between D2 dopamine receptor function and cocaine sensitivity that would enable cocaine abuse. Therefore, we exploited individual differences in behavioral responses to D2 dopamine receptor stimulation to test its relationship with cocaine-mediated behaviors. Outbred, male Sprague-Dawley rats were initially characterized by their locomotor responsiveness to the D2 dopamine receptor agonist, quinpirole, in a within-session ascending dose-response regimen (0, 0.1, 0.3 & 1.0 mg/kg, sc). Rats were classified as high or low quinpirole responders (HD2 and LD2, respectively) by a median split of their quinpirole-induced locomotor activity. Rats were subsequently tested for differences in the psychostimulant effects of cocaine by measuring changes in cocaine-induced locomotor activity (5 and 15 mg/kg, ip). Rats were also tested for differences in the development of conditioned place preference to a low dose of cocaine (7.5 mg/kg, ip) that does not reliably produce a cocaine conditioned place preference. Finally, rats were tested for acquisition of cocaine self-administration and maintenance responding on fixed ratio 1 and 5 schedules of reinforcement, respectively. Results demonstrate that HD2 rats have enhanced sensitivity to the locomotor stimulating properties of cocaine, display greater cocaine conditioned place preference, and self-administer more cocaine compared to LD2 animals. These findings suggest that individual differences in D2 dopamine receptor sensitivity may be predictive of cocaine sensitivity and reward.
Highlights
Understanding why some individuals develop substance abuse or patterns of compulsive drug use while others do not is one of the most poorly understood aspects in the development of drug addiction
In an attempt to capture the behavioral complexity of pre- and postsynaptic D2 receptor stimulation, we calculated the area under the curve (AUC) for each animal across all quinpirole doses (Figure S1)
The quinpirole AUC score was used to segregate each cohort into high quinpirole sensitivity (HD2) and low quinpirole sensitivity (LD2) groups based on a median split of the entire cohort
Summary
Understanding why some individuals develop substance abuse or patterns of compulsive drug use while others do not is one of the most poorly understood aspects in the development of drug addiction. Administration of the D2 DA receptor agonist, quinpirole, produces a high degree of variability in locomotor responses in drug naıve animals We exploited these individual differences in the rat’s initial locomotor response to quinpirole as a model to test D2 DA receptor sensitivity as a vulnerability factor for subsequent cocaine-mediated behaviors. Those animals displaying robust increases in quinpiroleinduced activity were characterized as having high D2 DA receptor sensitivity (HD2), while those rats having more modest activation were characterized as having low D2 DA receptor sensitivity (LD2). Rats from each group were compared in cocaine-induced locomotion, cocaine-induced place preference, and cocaine self-administration
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
