Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use - PubMed (original) (raw)

Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use

Ingo Willuhn et al. Proc Natl Acad Sci U S A. 2012.

Abstract

Drug addiction is a neuropsychiatric disorder that marks the end stage of a progression beginning with recreational drug taking but culminating in habitual and compulsive drug use. This progression is considered to reflect transitions among multiple neural loci. Dopamine neurotransmission in the ventromedial striatum (VMS) is pivotal in the control of initial drug use, but emerging evidence indicates that once drug use is well established, its control is dominated by the dorsolateral striatum (DLS). In the current work, we conducted longitudinal neurochemical recordings to ascertain the spatiotemporal profile of striatal dopamine release and to investigate how it changes during the period from initial to established drug use. Dopamine release was detected using fast-scan cyclic voltammetry simultaneously in the VMS and DLS of rats bearing indwelling i.v. catheters over the course of 3 wk of cocaine self-administration. We found that phasic dopamine release in DLS emerged progressively during drug taking over the course of weeks, a period during which VMS dopamine signaling declined. This emergent dopamine signaling in the DLS mediated discriminated behavior to obtain drug but did not promote escalated or compulsive drug use. We also demonstrate that this recruitment of dopamine signaling in the DLS is dependent on antecedent activity in VMS circuitry. Thus, the current findings identify a striatal hierarchy that is instantiated during the expression of established responses to obtain cocaine.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Drug-taking behavior over the course of weeks. (A) Depiction of a rat connected to voltammetric recording equipment and infusion pump for i.v. delivery of cocaine during an approach to the active nose-poke port in the operant chamber. (B) A nose poke (dashed line) into the active port elicits an infusion of cocaine (0.5 mg/kg per infusion) and the presentation of a CS (yellow box) during a 20-s time-out. (C) Nose pokes into the active port, inactive port, and during the time-out period over 20 d of self-administration (n = 18). (D) The number of reinforced nose pokes did not change significantly across weeks, whereas the number of nonreinforced responses decreased (E), and the ratio of reinforced over total number of nose pokes (efficiency) increased (F) in the second and third weeks compared with the first week. *P < 0.05, ***P < 0.001; n.s., not significant.

Fig. 2.

Dopamine signaling in the VMS over the course of weeks. (A) Phasic dopamine release in the VMS following responses into the active nose-poke port was observed during all 3 wk of cocaine self-administration (n = 10). (B) Dopamine signals decreased in amplitude over the course of 3 wk. (C) Dopamine signals following responses into the active nose-poke port were larger than signals following inactive responses. (D) Noncontingent delivery of the CS induced dopamine release. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig. 3.

Dopamine signaling in DLS over the course of weeks. (A) Phasic dopamine release in the DLS following responses into the active nose-poke port was observed during the second and third weeks of cocaine self-administration (n = 15). (B) Dopamine signals in the second and third weeks were greater in amplitude than those in the first week. (C

)

Dopamine signals following responses into the active nose-poke port were larger than signals following inactive responses during the second and third weeks but not during the first week. (D) Noncontingent delivery of the CS induced dopamine release. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig. 4.

Blockade of dopamine receptors in the DLS disrupts discriminated drug-taking behavior. (A_–_C) The rate of reinforced nose pokes remained stable across weeks (A), but the rate of nonreinforced nose pokes was decreased (B), and response efficiency increased (C) during the second and third weeks compared with the first week. (D) Infusion of flupenthixol (FLU) into the DLS produced an increase in reinforced nose pokes in both the first (n = 16) and the third weeks (n = 16). (E) The average number of nonreinforced responses was increased after flupenthixol only during the third but not during the first week. (F) Consequently, response efficiency was decreased after flupenthixol at the late but not at the early time point. *P < 0.05, **P < 0.01, ***P < 0.001; VEH, vehicle.

Fig. 5.

VMS lesion prevents development of phasic dopamine signaling in the DLS. (A) Phasic dopamine release was observed in the DLS contralateral to the unilateral lesion of the VMS following responses into the active nose-poke port during the second and third weeks of cocaine self-administration (n = 17). (B) Dopamine release in the ipsilateral DLS was not significantly increased in any week (n = 11). (C) In the contralateral DLS, phasic signaling in the second and third weeks was larger in amplitude than signals detected in the first week (Left), whereas signals did not change in amplitude across weeks in the ipsilateral DLS (Right). Emergence of such signaling had significantly different patterns of dopamine release between hemispheres. A direct post hoc comparison between ipsilateral and contralateral hemispheres showed greater dopamine release in the contralateral hemisphere in the second and third weeks of training but not in the first week (#P < 0.05). (D and E) Noncontingent delivery of the CS consistently induced DLS dopamine release contralateral (D) but not ipsilateral (E) to the VMS lesion. *P < 0.05, **P < 0.01, ***P < 0.001.

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Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use - PubMed (original) (raw)