The Development of a Preference for Cocaine over Food Identifies Individual Rats with Addiction-Like Behaviors

<div><p>Rationale</p><p>Cocaine dependence is characterized by compulsive drug taking that supercedes other recreational, occupational or social pursuits. We hypothesized that rats vulnerable to addiction could be identified within the larger population based on their preference for cocaine over palatable food rewards.</p><p>Objectives</p><p>To validate the choice self-administration paradigm as a preclinical model of addiction, we examined changes in motivation for cocaine and recidivism to drug seeking in cocaine-preferring and pellet-preferring rats. We also examined behavior in males and females to identify sex differences in this “addicted” phenotype.</p><p>Methods</p><p>Preferences were identified during self-administration on a fixed-ratio schedule with cocaine-only, pellet-only and choice sessions. Motivation for each reward was probed early and late during self-administration using a progressive-ratio schedule. Reinstatement of cocaine- and pellet-seeking was examined following exposure to their cues and non-contingent delivery of each reward.</p><p>Results</p><p>Cocaine preferring rats increased their drug intake at the expense of pellets, displayed increased motivation for cocaine, attenuated motivation for pellets and greater cocaine and cue-induced reinstatement of drug seeking. Females were more likely to develop cocaine preferences and recidivism of cocaine- and pellet-seeking was sexually dimorphic.</p><p>Conclusions</p><p>The choice self-administration paradigm is a valid preclinical model of addiction. The unbiased selection criteria also revealed sex-specific vulnerability factors that could be differentiated from generalized sex differences in behavior, which has implications for the neurobiology of addiction and effective treatments in each sex.</p></div

The behavior of cocaine- and pellet-preferring rats diverges after the development of cocaine preferences.

<p>Early in self-administration, there are few differences between pellet preferring (PP) and cocaine preferring (CP) rats in the number of rewards earned during the pellet-only and cocaine-only sessions (A) and choice session (B). Late in self-administration, the behavior of PP and CP rats is different in the pellet-only and cocaine-only sessions (C) and non-overlapping in the choice session (D). Each point represents data from a single male (M) or female (F), whereas the horizontal lines represent the means for each sex collapsed across preference groups (PP- white, CP- black). Significant difference between PP and CP rats (# p<0.05), significant difference between early and late time points in PP (** p<0.05) and CP (* p<0.05) rats, and significant difference between the number of pellets and infusions earned within the choice session or between the two single reward sessions in PP (∧∧ p<0.05) and CP (∧ p<0.05) rats. PP females (n = 6), PP males (n = 10), CP females (n = 6) and CP males (n = 2).</p

The estrous cycle modulates motivation for pellets, but not cocaine.

<p>A. Cocaine preferring (CP) females (black bars) have greater motivation for cocaine than pellet preferring (PP) females (white bars), and neither group displays changes in motivation across the estrous cycle. B. PP females have greater motivation for pellets than CP females during every stage of the cycle. PP females in proestrus/estrus (P/E) have reduced motivation for pellets compared to during diestrus 1 (D1), diestrus 2 (D2) or metestrus (M), whereas there is no effect of the cycle in CP females. (# p<0.05, PP vs. CP; * p<0.05, P/E vs. other stages; ∧ p<0.05, cocaine nose pokes vs. pellet nose pokes). PP females (n = 6) and CP females (n = 6). Vertical lines represent +SEM.</p

Overview of the choice self-administration paradigm and experimental time line.

<p>A. Daily choice self-administration tests are 2.5 hours in duration and consist of 3 active sessions in which reward(s) are available on a fixed ratio (FR) 1 or FR5 schedule with a 40-second time out. The two variants (v.1 and v.2) only differ by the order of the pellet-only and cocaine-only sessions. B. The choice self-administration paradigm (FR1/FR5) was used to identify individual preferences and patterns of intake over time. Motivation was probed early and late in self-administration using a series of progressive ratio (PR) schedules (pPR = pellet-only PR, cPR = cocaine-only PR and PR = concurrent PR). Extinction and reinstatement tests were conducted at the end to examine relapse vulnerability.</p

Cocaine preferring rats have increased motivation for cocaine and reduced motivation for pellets.

<p>Motivation to self-administer cocaine and pellets in pellet preferring (PP) and cocaine preferring (CP) rats (white and black bars, respectively). Differences between males (M) and females (F) were not examined. Significant difference between PP and CP rats (# p<0.05). Significant difference between early and late in self-administration (* p<0.05). Significant difference between pellet nose pokes (NP) and cocaine nose pokes (NP) within a given group and time (∧ p<0.05). PP females (n = 6), PP males (n = 10), CP females (n = 6) and CP males (n = 2). Vertical lines represent +SEM.</p

Reinstatement of drug and pellet seeking is influenced by preference and sex.

<p>Cocaine seeking and pellet seeking during the first 5 minutes (left side of all figures) and the entire 2 hours (right side of all figures) in male (M) and female (F) pellet preferring (PP) and cocaine preferring (CP) rats (white and black bars, resp.). A. Cue-induced reinstatement (CUE). B. Cocaine-induced reinstatement (COCAINE). C. Pellet-induced reinstatement (PELLET). (* p<0.05, extinction (EXT) vs. reinstatement test; # p<0.05, PP vs. CP; $ p<0.05, M vs. F; ∧ p<0.05, cocaine nose pokes (NP) vs. pellet nose pokes(NP)). PP females (n = 6), PP males (n = 8), CP females (n = 6) and CP males (n = 3). Vertical lines represent +SEM.</p

Females are more likely to develop a preference for cocaine.

<p>A. The development of cocaine preferences in male (open circles) and female (filled circles) rats (n = 12 per sex). Significant increase in the proportion of cocaine preferring (CP) females between the second and last FR5 tests (* p<0.05). The proportion of CP females was greater than males ($ p<0.05). B. The stability of preferences in PP rats and CP rats (both before and after CP developed). Significant difference between PP and CP rats within same preference category (# p<0.05). Significant difference in preference category before and after CP developed (* p<0.05). Significant difference between the “preference for cocaine” and “preference for pellets” categories within a given group (∧ p<0.05). PP rats (n = 16) and CP rats (n = 8). C. Representative self-administration behavior in a pellet preferring (PP) rat over the 21 FR sessions, displaying the number of infusions (grey) and pellets (black) earned each day during the cocaine-only or pellet-only sessions (closed symbols) and the choice session (open symbols). D. Representative self-administration behavior in a CP rat (CP criteria met on day 11 in this case).</p