The Roles of Dopamine and α1-Adrenergic Receptors in Cocaine Preferences in Female and Male Rats - PubMed (original) (raw)

The Roles of Dopamine and α1-Adrenergic Receptors in Cocaine Preferences in Female and Male Rats

Adam N Perry et al. Neuropsychopharmacology. 2015 Nov.

Abstract

Cocaine dependence is characterized by compulsive drug taking and reduced involvement in social, occupational, or recreational activities. Unraveling the diverse mechanisms contributing to the loss-of-interest in these 'non-drug' pursuits is essential for understanding the neurobiology of addiction and could provide additional targets for treating addiction. The study objectives were to examine changes in cocaine-induced dopamine (DA) overflow in the nucleus accumbens (NAc) over the course of self-administration and determine the roles of α1- and β-adrenergic receptors (AR) in the loss-of-interest in food rewards following the development of an addicted phenotype in male and female rats. Subjects were given access to cocaine and palatable food pellets in a choice self-administration paradigm to identify 'addicted' cocaine-preferring (CP) individuals and resistant pellet-preferring (PP) individuals based on their patterns of self-administration over 7 weeks. Cocaine-induced DA overflow in the NAc was examined with microdialysis early and late during self-administration (weeks 2 and 7). Subjects were treated in counter-balanced order with propranolol (β-AR antagonist), terazosin (α1-AR antagonist), or vehicle for an additional 3 weeks of self-administration. CP rats displayed increased motivation for cocaine and attenuated motivation for pellets following the development of cocaine preferences. In females, the estrous cycle affected pellet, but not cocaine, self-administration. CP rats displayed attenuated cocaine-induced DA overflow in the NAc. Propranolol enhanced cocaine reinforcement and reduced pellet intake, whereas terazosin enhanced motivation for pellets and reversed preferences in a subset of CP rats. The implications of these results for the treatment of addiction are discussed.

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Figures

Figure 1

Changes in motivation for cocaine and food pellets over the course of self-administration. (a) Cocaine BP. (b) Pellet BP. Time blocks that do not share a letter are different from one another within a give preference group (p<0.05). The far right section in each panel represents the same data from the 25 CP rats segregated by whether individuals were still ‘pellet preferring' (open circles, ‘before CP') or were displaying cocaine preferences (closed circles, ‘after CP') at each time. The numbers associated with each point represent the number of CP individuals in each subgroup in each given week. Significant difference from PP (*p<0.05) and ABST rats (#p<0.05). Vertical lines represent SEM. ABST, abstaining; BP, breaking point; CP, cocaine preferring.

Figure 2

The estrous cycle affected pellet intake and weight gain, but not cocaine intake. (a) The number of pellets earned in the pellet-only sessions was affected by the estrous cycle, whereas there was no effect of preference. In contrast, infusion number was affected by preference, but not the estrous cycle. The lack of a preference effect on pellet intake likely reflects averaging across multiple weeks, during which not all CP females were displaying cocaine preferences. The same effects were observed for intake during choice sessions (data not shown). (b) Weight gain was robustly affected by the estrous cycle in all preference groups, which confirms that females continued to cycle normally throughout self-administration. Therefore, the lack of estrous cycle effects on cocaine intake cannot be attributed to alterations in hormone fluctuations across the cycle (at least in regard to those affecting weight and food intake). Data were averaged across the last 5 weeks of self-administration and aligned to the proestrous/estrous (PE) stage of the cycle. The two days before PE (−2 and −1) correspond with diestrus I and diestrus II, whereas the day after PE (+1) corresponds with metestrus or sometimes estrus (see text for details). Stages without common letters are significantly different from one another. Intake in CP rats was significantly different from PP and ABST rats (*p<0.05 for each). Intake in PP rats was significantly different from CP and ABST rats (#p<0.05 for each). Vertical lines represent SEM. ABST, abstaining; CP, cocaine preferring.

Figure 3

Changes in cocaine-induced DA overflow in the NAc over self-administration. (a) Rats received a single non-contingent cocaine infusion (1.2 mg/kg, i.v.) early (Week 2, solid lines) and again late during self-administration (Week 7, dashed lines). Cocaine-induced DA overflow was significantly attenuated in CP rats during Week 7 compared with their earlier response (*p<0.05) and the late responses of ABST and PP rats (#p<0.05 compared with late CP). Data are repeated measures from 11 ABST rats (5 female, 6 male, white circles), 5 PP rats (2 female, 3 male, gray circles) and 9 CP rats (5 female, 4 male, black circles). Basal DA values in pg per 10 min sample were not different between groups at either time point: ABST rats (early: 7.2±1.9, late: 11.4±2.7), PP rats (early: 6.3±1.6, late: 4.4±1.3), and CP rats (early: 9.3±1.2, late: 11.9±3.2). (b) Both CP males and females displayed attenuated cocaine-induced DA overflow during Week 7 compared with Week 2 (*p<0.05). Vertical lines represent SEM. ABST, abstaining; CP, cocaine preferring; DA, dopamine; NAc, nucleus accumbens; PP, pellet preferring.

Figure 4

Effects of propranolol (PRO) and terazosin (TER) on cocaine and pellet intake. (a) Cocaine-only sessions: PRO reduced cocaine infusions in both PP and CP rats. (b) Choice session infusions: PRO reduced cocaine infusions in CP rats. The intake of the four CP rats most affected by TER (_n_=4, white circles in far right section of each panel) was substantially lower than their intake during VEH and PRO treatments, which is not apparent in the overall CP group mean and SEM. (c) Pellet-only sessions: PRO reduced pellet intake in PP and CP rats, whereas TER increased pellet intake in CP rats. (d) Choice session pellets: PRO reduced pellet intake in PP rats, whereas TER increased pellet intake in CP rats, which was largely due to the four CP individuals that reverted to pellet preferences during TER. For all panels, preference groups without common letters are significantly different from one another within a given treatment (p<0.05). Treatment differs from vehicle (VEH) condition within a given preference group (*p<0.05). Vertical lines represent SEM. Comparisons were not made between preference groups with different treatments. ABST, abstaining; CP, cocaine preferring; PP, pellet preferring.

Figure 5

Effects of propranolol (PRO) and terazosin (TER) on motivation for cocaine and pellets. (a) PRO increased cocaine BP in CP rats and reduced them in ABST rats. (b) TER increases pellet BP in all groups; however, pair-wise comparisons were only significant in CP rats, which most likely reflects a power issue, as effect sizes were all relatively large (Cohen's _d_=1.84, 0.78 and 0.83 for ABST, PP, and CP, respectively). The far right section of each panel shows the data for the CP rats that shifted to pellet preferences during TER treatment (_n_=4, white circles), which shows that pellet BP were generally shifted upwards in all CP rats, not just the four most affected individuals. Preference groups without common letters are significantly different from one another within a given treatment (p<0.05). Treatment differs from vehicle (VEH) condition within given preference group (*p<0.05). Vertical lines represent SEM. Comparisons were not made between preference groups with different treatments. ABST, abstaining; CP, cocaine preferring; PP, pellet preferring.

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The Roles of Dopamine and α1-Adrenergic Receptors in Cocaine Preferences in Female and Male Rats - PubMed (original) (raw)