Alpha 1-noradrenergic system role in increased motivation for cocaine intake in rats with prolonged access

Abstract

In rodents, extended access to cocaine produces an escalation in cocaine self-administration that has face and construct validity for human compulsive drug intake. Here we report that rats with six-hour access (long access, LgA) to cocaine self-administration produced a higher breakpoint for cocaine using a progressive-ratio schedule than rats with one-hour access (short access, ShA), and prazosin (alpha 1 receptor antagonist) reduced the higher breakpoint for cocaine in LgA rats. Additionally, the number of neurons with alpha 1-adrenergic receptor-like immunoreactivity in the bed nucleus of stria terminalis (BNST) was found to be much lower in LgA rats than in ShA and drug-naive rats. In contrast, UK14304 (alpha 2 receptor agonist) and betaxolol (beta 1 receptor antagonist) had no effect on cocaine self-administration in either group. The data suggest that activation of the alpha 1-noradrenergic system, perhaps in the BNST, is associated with increased motivation for cocaine in rats with extended access.

Figure 1

Self-administration of cocaine by rats under a fixed-ratio schedule during the escalation period. Data are expressed as the number of injections on the left axis and mg/kg on the right axis. The upper panel represents data from entire sessions, and the lower panel represents data from the first hour of sessions. Error bars are SEM values. Filled circles indicate self-administration by rats in 6 h sessions (long access, LgA), and open circles indicate self-administration by rats in 1 h sessions (short access, ShA). *p<0.05 compared to session 1.

Figure 2

Dose-response function of cocaine by rats responding under a PR schedule. Test sessions under a PR schedule ended when rats did not achieve reinforcement within 1 h. Data are expressed as the number of injections/session on the left axis and the ratio per injection on the right axis. Error bars are SEM values. Open bars indicate responding by short access (ShA) rats, and filled bars indicate responding by long access (LgA) rats. *p<0.05 compared to ShA rats at each dose of cocaine.

Figure 3

Effect of prazosin, an α₁-noradrenergic receptor antagonist, on the break-point for 0.5 mg/kg/injection of cocaine under a PR schedule. Prazosin was intraperitoneally injected 10 min before a session. Data are expressed as the number of injections/session on the left axis and the ratio per injection on the right axis. Error bars are SEM values. The upper panel represents data from long access (LgA) rats, and the lower panel represents data from short access (ShA) rats. *p<0.05 compared to vehicle treatment. #p<0.05 compared to ShA rats.

Figure 4

Effect of UK14304, an α₂-noradrenergic receptor agonist, on the break-point for 0.5 mg/kg/injection of cocaine under a PR schedule. UK14304 was intraperitoneally injected 10 min before a session. Data are expressed as the number of injections/session on the left axis and the ratio per injection on the right axis. Error bars are SEM values. The upper panel is the data from long access (LgA) rats, and the lower panel is the data from short access (ShA) rats.

Figure 5

Effect of betaxolol, a β₁-noradrenergic receptor antagonist, on the break-point for 0.5 mg/kg/injection of cocaine under a PR schedule. Betaxolol was subcutaneously injected 30 min before a session. Data are expressed as the number of injections/session on the left axis and the ratio per injection on the right axis. Error bars are SEM values. The upper panel is the data from long access (LgA) rats, and the lower panel is the data from short access (ShA) rats. The number in parentheses above 10 mg/kg of betaxolol indicates the number of rats that were tested with the dose of the drug.

Figure 6

Quantification ofα₁-noradrenergic receptors in the frontal cortex (FC), bed nucleus of the stria terminalis (BNST), and ventral tegmental area (VTA) across drug-naive, short access (ShA), and long access (LgA) rats (n=5 in each group). A–F: Schematic of a coronal section through the striatum (A) indicating the areas examined for quantitative analysis (area 1 is dorsal-mediolateral BNST; area 2 is ventral-mediolateral BNST), α₁-adrenergic neurons in the dorsal-mediolateral BNST from a drug naive (B) and LgA rat (C). Schematic of a coronal section through the hippocampus (D) used for quantitative analysis (area 3 is the VTA), α₁-noradrenergic neurons in the VTA from a drug naive (E) and LgA rat (F). Quantitative neuron counts are expressed as mean ± SEM of the total number of immunoreactive neurons/mm². #p<0.01 compared to the dorsal BNST of the drug-naive group in (G) and #p<0.01 compared to the mPFC of the drug naive group in (H). *p<0.001 compared to drug-naive and ShA groups within each brain region. Scale bar in C is 10 μm (applies to B–C, E–F).