Compulsive drug use is associated with imbalance of orbitofrontal- and prelimbic-striatal circuits in punishment-resistant individuals

Abstract

Substance use disorders (SUDs) impose severe negative impacts upon individuals, their families, and society. Clinical studies demonstrate that some chronic stimulant users are able to curtail their drug use when faced with adverse consequences while others continue to compulsively use drugs. The mechanisms underlying this dichotomy are poorly understood, which hampers the development of effective individualized treatments of a disorder that currently has no Food and Drug Administration-approved pharmacological treatments. In the present study, using a rat model of methamphetamine self-administration (SA) in the presence of concomitant foot shocks, thought to parallel compulsive drug taking by humans, we found that SA behavior correlated with alterations in the balance between an increased orbitofrontal cortex-dorsomedial striatal "go" circuit and a decreased prelimbic cortex-ventrolateral striatal "stop" circuit. Critically, this correlation was seen only in rats who continued to self-administer at a relatively high rate despite receiving foot shocks of increasing intensity. While the stop circuit functional connectivity became negative after repeated SA in all rats, "shock-resistant" rats showed strengthening of this negative connectivity after shock exposure. In contrast, "shock-sensitive" rats showed a return toward their baseline levels after shock exposure. These results may help guide novel noninvasive brain stimulation therapies aimed at restoring the physiological balance between stop and go circuits in SUDs.

Keywords: compulsive behavior; foot shock punishment; frontostriatal functional circuits; functional connectivity; methamphetamine self-administration.

Fig. 1.

Experimental design and behavioral results. (A) Two groups of rats METH (n = 18) and SAL (n = 11) experienced four distinct conditions designed to model the addiction cycle: baseline, SA training (9 h/d for 20 d, FR-1, 0.1 mg/kg per infusion of METH/SAL), SA plus foot shock, and withdrawal (cue-reactivity tests performed on withdrawal days 3 and 30). MRI data were collected at the end of each phase. (B) The METH SA rats increased lever pressing during the SA development phase (one-way ANOVA, P < 0.001 for both groups), and SA behavior decreased when foot shocks were introduced (one-way ANOVA, P < 0.001 for both groups). Drug intake was computationally modeled, and the estimated infusion on the last punishment day was normalized to that on the last SA development day to define a CI. (C) K-mean clustering on the CI differentiated METH rats into SR (n = 7) and SS (n = 11) subgroups. While both subgroups reduced drug taking after shock imposition, the SR but not the SS subgroup “recovered” and took more drug after the second shock day. There was no difference in SA behavior between the two subgroups before shock imposition. (D) The SR group showed significantly higher CI than the SS subgroup. (E) The total number of drug infusions during the SA development phase did not predict the subsequent categorization of SR and SS rats. (F) The total number of lever presses normalized by drug infusions (seek/take ratio) during SA phase did not differ between subgroups. (G) While both SS and SR rats significantly reduced drug intake at the end of SA+FS phase, the SR group took more drug than did the SS group, although there was no difference between them at the end of SA phase. #P < 0.1; *P < 0.05; **P < 0.01; ***P < 0.001; NS, not significant; error bar stands for SEM.

Fig. 2.

Changes in the OFC circuit in the SR, SS, and SAL groups, along the cycle of addiction. (A) OFC seed definition. (B) ANOVAs [(GROUP: SR, SS, SAL) × (SESSION: baseline, SA, SA+FS, withdrawal)] revealed a significant GROUP-by-SESSION interaction in rsFC between the OFC and MS (i); the average rsFC from the MS mask was plotted as a function of addiction cycle in each group for illustrative purpose (ii). (C) Post hoc one-way ANOVAs across groups indicated that rsFC in the three groups did not differ at baseline (i) or following 30-d withdrawal (iv). However, a significant difference was shown in OFC-MS rsFC after SA phase (ii), which was maintained after foot shock (iii). Paired t tests demonstrated an increase in OFC-MS rsFC after SA phase in both SR (v) and SS (vi) rats compared with the SAL control group. The punishment did not differentiate the two SA subgroups, such that both the SR and SS rats continued to demonstrate increased OFC-MS rsFC compared with the SAL group (Lower Right). Results were corrected for whole-brain multiple comparisons at P < 0.05. Error bar stands for SEM.

Fig. 3.

Changes in the PrL rsFC circuit in the SR, SS, and SAL groups, along the cycle of addiction. (A) PrL seed definition. (B) ANOVA [(GROUP: SR, SS, SAL) × (SESSION: baseline, SA, SA+FS, withdrawal)] revealed a significant GROUP-by-SESSION interaction in rsFC between the PrL and VS. (C) Post hoc one-way ANOVAs across groups indicated that rsFC in the three groups did not differ at baseline or following 30-d withdrawal. However, a significant difference was shown in PrL-VS rsFC after SA development phase, which was maintained after foot shock (Left). Paired t tests demonstrated a lower negative PrL-VS rsFC after SA development in both SR and SS rats compared with SAL control group (Upper Right). The punishment differentiated the two METH subgroups, such that the SR but not the SS rats continued to demonstrate lower negative PrL-VS rsFC, significantly different from the SAL group (Lower Right). Results were corrected for whole-brain multiple comparisons at P < 0.05. Error bar stands for SEM.

Fig. 4.

The [go (-) stop] circuitry balance. (A) Illustration of the OFC-MS go and PrL-VS stop circuits and the concept of [go (-) stop] balance. (B) The [go (-) stop] balance changed similarly in SS and SR rats except that the balance was reduced toward baseline level after shock in the SS rats (paired t test, shock vs. SA, P = 0.014), but not in the SR rats (paired T, shock vs. SA, P = 0.96). Error bar stands for SEM.

Fig. 5.

The relationship between the [go (-) stop] rsFC balance and the CI (Fig. 1B). (A) The cross-sectional [go (-) stop] balance significantly correlated with CI in SR rats (P = 0.047), with the go circuit significantly potentiating compulsive-like behavior (P = 0.014). (B) Longitudinal change in the [go (-) stop] balance after punishment positively correlated with the CI but only in the SR individuals (P = 0.0008), with a positive correlation with the go circuit change (P = 0.006) and negative correlation with the stop circuit change (P = 0.018). The CI was not correlated with rsFC change of the [go (-) stop] balance, nor any single circuit in the SS rats. *P < 0.05; **P < 0.01; ***P < 0.001.