A neural circuit underlying cocaine -seeking behavior

Abstract

Drug addiction is a relapsing disease. An animal model of relapse---the "reinstatement" model---is used to study brain mechanisms underlying addiction and has good predictive-validity to human relapse. The three principal triggers to human relapse are stress, drug, or drug-associated environmental cues. Previous work implicated various brain loci in stress-, drug-, and cue-triggered reinstatement. In the present work, a new trigger was discovered---anatomically and electrophysiologically selective electrical stimulation of the hippocampal ventral subiculum (VSUB) in rats. Theta-burst VSUB stimulation robustly reinstated cocaine-seeking behavior. Neither same-site lower-frequency stimulation nor stimulation of other loci produced reinstatement. Given the importance of the meso-accumbens dopamine (DA) medial forebrain bundle (MFB) circuit as a brain-reward substrate, reinstatement by MFB stimulation was attempted. No type of MFB stimulation triggered reinstatement. Microinjection of N-methyl-D-aspartate (NMDA) into the ventral tegmental area (VTA) (origin of the meso-accumbens MFB DA neurons) elicited reinstatement. VTA microinjection of the glutamate antagonist kynurenic acid blocked reinstatement produced by VSUB burst stimulation. These findings, coupled with the fact that the major efferent pathway from VSUB to the meso-accumbens circuit is glutamatergic, suggest involvement of glutamate in reinstatement, and suggest that glutamatergic agents are worth investigating as anti relapse pharmacotherapies.;Theta-burst VSUB stimulation produces long-duration DA enhancement in nucleus accumbens (NAC) and reinstatement. Microinjection of DA-enhancing compounds (e.g., amphetamine, morphine) into meso-accumbens loci produces long-duration NAC DA enhancement and reinstatement. VTA microinjection of the DA antagonist alpha flupenthixol (FLU), by acting on somatodendritic autoreceptors of meso-accumbens VTA DA neurons, produces long-duration NAC DA enhancement and reinstatement. MFB electrical stimulation produces brief-duration NAC DA enhancement and no reinstatement. This suggests that long-duration NAC DA enhancement is a crucial brain substrate of reinstatement. Low-frequency (2-Hz) VSUB stimulation suppresses NAC DA. 200 pulses of 2-Hz VSUB stimulation blocked reinstatement produced by VTA FLU microinjections, while 200 identical VSUB pulses in burst rhythm elicited reinstatement.;It is concluded that: (a) VSUB burst and 2-Hz stimulation represent neural encoding predictive of the future occurrence and non-occurrence of cocaine reward, respectively, and (b) long-duration NAC DA has the properties of a "stimulus trace" underlying drug-seeking behavior.