Reduced forebrain serotonin transmission is causally involved in the development of compulsive cocaine seeking in rats

Yann Pelloux, Ruth Dilleen, Daina Economidou, David Theobald, Barry J Everitt, Yann Pelloux, Ruth Dilleen, Daina Economidou, David Theobald, Barry J Everitt

Abstract

Whereas the majority of cocaine users quit as they experience the negative consequences of drug use, some lose control over their drug taking and compulsively seek drugs. We report that 20% of rats compulsively seek cocaine despite intermittent negative outcomes after escalating their cocaine self-administration. This compulsive subgroup showed marked reductions in forebrain serotonin utilization; increasing serotonin transmission reduced their compulsive cocaine seeking. Depleting forebrain serotonin induced compulsive cocaine seeking in rats with a limited cocaine taking history; this was reversed by systemic treatment with a 5-hydroxytryptamine (5-HT2C) receptor agonist and mimicked by systemic treatment with a 5-HT2C receptor antagonist in intact animals. These results indicate the causal involvement of reduced serotoninergic transmission in the emergence of compulsive drug seeking after a long cocaine-taking history.

Figures

Figure 1
Figure 1
Emergence of a compulsive cocaine-seeking subpopulation of rats after an extended cocaine-taking history (a) Timeline of the experiment. (b) Early-loading phase during free access sessions, in animals having had 12 days of 1 h (ShA: gray dots) or 6 h (LgA: black dots) daily access to cocaine. Mean±SEM of 45 and 67 animals per group. Significant difference between ShA and LgA: *Fischer's LSD P<0.05. (c) Number of seeking cycles completed before (baseline) and during punishment of NA (white squares), ShA, and LgA sensitive (gray and black squares, respectively) or resistant (gray and black triangles). Mean±SEM of 3–53 animals per group. Significant differences between sensitive and resistant. &Fischer's LSD P<0.05.
Figure 2
Figure 2
Neurochemical correlates of compulsive cocaine seeking. Utilization of 5-HT (panel a), DA (b) and NE (c) in ShA (hashed columns) and ShA (filled columns), sensitive (solid-gray columns, respectively n=19 and 15) and resistant (solid-black columns, n=3 and 9) rats. The data are mean levels (±SEM.) of both left and right hemisphere. 5-HT and DA utilization indices were determined by the ratio of the respective metabolite of the parent transmitter. Significant differences between sensitive and resistant *Fischer's LSD P<0.05.
Figure 3
Figure 3
Reinstatement of punishment sensitivity by selective serotonin reuptake inhibition. (a) Effects of increasing doses of citalopram or (b) atomoxetine on the number of seeking cycles completed under punishment (upper panels) or the concomitant nose-poke responding for sucrose (lower panels) in resistant animals, mean±SEM of five animals. Significantly different from saline: #Fischer's LSD P<0.05.
Figure 4
Figure 4
Bidirectional modulation of compulsive cocaine seeking by serotoninergic manipulations (a) Timeline of the experiment; (b) number of seeking cycles completed before (baseline) and during punishment of cocaine-seeking responding; (c) the effects of increasing doses of mCPP on the number of seeking cycles completed under punishment in the ICV 5,7-DHT and sham-operated control animals: Mean±SEM of 20 and 28 animals. *: significant differences between sham and ICV 5,7-DHT, Fischer LSD P<0.03 #: significant differences from vehicle condition, Fischer's LSD P<0.001 (d) The effect of increasing doses of SB242084 and M100907 on the number of seeking cycles completed under punishment in animals after a short history of cocaine taking. Mean±SEM of 18 animals: significant differences from vehicle condition #: Fischer LSD P<0.04.

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