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Comparative Study
. 2022 Sep;27(5):e13217.
doi: 10.1111/adb.13217.

Peer-induced cocaine seeking in rats: Comparison to nonsocial stimuli and role of paraventricular hypothalamic oxytocin neurons

Affiliations
Comparative Study

Peer-induced cocaine seeking in rats: Comparison to nonsocial stimuli and role of paraventricular hypothalamic oxytocin neurons

Lindsey R Hammerslag et al. Addict Biol. 2022 Sep.

Abstract

The purpose of this study was to determine if social vs nonsocial cues (peer vs light/tone) can serve as discriminative stimuli to reinstate cocaine seeking. In addition, to assess a potential mechanism, an oxytocin (OT) promoter-linked hM3Dq DREADD was infused into the paraventricular nucleus of the hypothalamus to determine whether peer-induced cocaine seeking is decreased by activation of OT neurons. Male rats underwent twice-daily self-administration sessions, once with cocaine in the presence of one peer (S+) and once with saline in the presence of a different peer (S-). Another experiment used similar procedures, except the discriminative stimuli were nonsocial (constant vs flashing light/tone), with one stimulus paired with cocaine (S+) and the other paired with saline (S-). A third experiment injected male and female rats with OTp-hM3Dq DREADD or control virus into PVN and tested them for peer-induced reinstatement of cocaine seeking following clozapine (0.1 mg/kg). Although acquisition of cocaine self-administration was similar in rats trained with either peer or light/tone discriminative stimuli, the latency to first response was reduced by the peer S+, but not by the light/tone S+. In addition, the effect of the conditioned stimulus was overshadowed by the peer S+ but not by the light/tone S+. Clozapine blocked the effect of the peer S+ in rats receiving the OTp-hM3Dq DREADD virus, but not in rats receiving the control virus. These results demonstrate that a social peer can serve as potent trigger for drug seeking and that OT in PVN modulates peer-induced reinstatement of cocaine seeking.

Keywords: cocaine; oxytocin; self-administration; social peer.

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Conflict of interest statement

Conflict of interest statement: No conflicts to report.

Figures

Figure 1:
Figure 1:
Acquisition and reinstatement of cocaine self-administration using peer discriminative stimuli and cue light CS in Experiment 1A (n = 10). (A) Schematic of the apparatus showing the two potential discriminative stimulus peers (S+ and S−) in the right side and the self-administering rat with the cue light CS in the left side of the dual-chambered apparatus. (B) Active lever presses during twice-daily self-administration sessions; one session was with cocaine and the peer S+, while the other session was with saline and the peer S−. (C) Latency to the first active lever press, with y-axis presented on a logarithmic scale. (D) Active lever pressing on reinstatement tests in the presence or absence of the discriminative stimulus peer (S+ or S−) and in the absence or presence of the CS (open vs. striped). (E) Latency to the first active lever press during reinstatement tests, shown collapsed across CS condition on a logarithmic scale. For panels B and C: *p < 0.05 effect of drug within FR. For panels D and E: +p < 0.05 effect of peer S+ versus no peer; p < 0.05 effect of peer S+ versus peer S−. Note that, unlike the peer discriminative stimulus, the CS did not occur until after the first active press, so it was not relevant for the analysis in panel E. Also note that only rats trained to self-administer cocaine (not the peers), received reinstatement tests. All data presented as mean ± SEM.
Figure 2:
Figure 2:
Acquisition and reinstatement of cocaine self-administration using light/tone discriminative stimuli and cue light CS in Experiment 1B (n = 9). (A) Schematic of the apparatus showing the two potential discriminative stimulus light/tone patterns (S+ or S−), constant or flashing, in the right side and the self-administering rat with the cue light CS in the left side of the dual-chambered apparatus. (B) Active lever presses during twice-daily self-administration sessions; one session was with cocaine and the light/tone S+, while the other session was with saline and the light/tone S−. (C) Latency to the first active lever press, with y-axis presented on a logarithmic scale. (D) Active lever pressing on reinstatement tests in the presence or absence of the discriminative stimulus light/tone (S+ or S−) and in the absence or presence of the CS (open vs. striped). (E) Latency to the first active lever press during reinstatement tests, shown collapsed across CS condition on a logarithmic scale. For panel B: *p < 0.05 effect of drug within FR. For panel D: +p < 0.05 effect of light/tone S+ versus no light/tone; #p < 0.05 effect of CS vs no CS. Note that, unlike the light/tone discriminative stimulus, the CS did not occur until after the first active press, so it was not relevant for the analysis in panel E. Also note that only rats trained to self-administer cocaine (not the peers), received reinstatement tests. All data presented as mean ± SEM.
Figure 3:
Figure 3:
Verification of viral infection of OT neurons in the PVN in Experiment 2. (A) Schematic of the PVN viral injection site [AP −1.8, ML ±0.3, DV −8.0; (Paxinos and Watson, 2013)] and the two AAV1/2 viruses used. (B) Example image taken from a rat receiving the control DREADD virus (20x; scale bar = 100μm), with OT pseudo-colored green (left), mCherry pseudo-colored red (middle), and DAPI colored blue (in merged image, right). (C) Example image taken from a rat receiving the activation DREADD virus (20x; scale = 100μm) with a section digitally zoomed to 50x for visualization of the co-labeled signal and OT pseudo-colored green (left), mCherry pseudo-colored red (middle), and DAPI colored blue (in merged image, right). Images were acquired with a Nikon Ti microscope, using the 20x objective. For visualization purposes, LUTS were adjusted to 0.75 for each channel and each image received the same background subtraction using NIS elements software; overall brightness was increased by 40%.
Figure 4:
Figure 4:
Acquisition of cocaine self-administration using peer discriminative stimuli in active and control virus groups in Experiment 2 (n = 9 mCherry, 8 hM3Dq). (A) Schematic of the apparatus showing the two potential discriminative stimulus peers (S+ or S−) in the right side and the self-administering rat in the left side of the dual-chambered apparatus; note the absence of the cue light CS in this experiment. (B) Active lever presses during twice-daily self-administration sessions; one session was with cocaine and the peer S+, while the other session was with saline and the peer S−. (C) Latency to the first active lever press, with y-axis presented on a logarithmic scale. For panels B and C: *p < 0.05 effect of drug within FR. All data presented as mean ± SEM.
Figure 5:
Figure 5:
Peer-induced reinstatement following vehicle or clozapine administration in active and control virus groups in Experiment 2 (n = 9 mCherry, 8 hM3Dq). (A) Active lever pressing on reinstatement tests in the presence or absence of the discriminative stimulus peer (S+ or S−) following pretreatment with vehicle or clozapine (0.1 mg/kg; open vs. striped). (B) Latency to the first active lever press during reinstatement tests, presented on a logarithmic scale. For panel A, +p < 0.05 effect of peer S+ versus no peer; p < 0.05 effect of peer S+ versus peer S−; ^p < 0.05 clozapine vs vehicle (a priori Tukey’s test). Note that only rats trained to self-administer cocaine (not the peers), received reinstatement tests. All data presented as mean ± SEM, collapsed across sex, with filled bars indicating rats that received the activation virus (OTp-hM3Dq) and empty bars indicating rats that received the control virus.
Figure 6:
Figure 6:
Acquisition of cocaine self-administration and reinstatement using peer discriminative stimuli in females and males in Experiment 2 (n = 9 females, 8 males; collapsed across virus condition). (A) Active lever presses during twice-daily self-administration sessions; these data are the same as presented in Figure 4B, but with females (half-filled circles) and males (filled triangles) graphed separately. (B) Active lever pressing on reinstatement tests in the presence or absence of the discriminative stimulus peer (S+ or S−); these data are the same as presented in Figure 5A, but collapsed across virus condition and only using data following vehicle pretreatment, thus yielding 9 females and 8 males. For panels A and B: *p < 0.05 effect of drug within FR; ^p < 0.05 effect of sex on slope within FR, collapsed across drug; +p < 0.05 effect of peer S+ versus no peer; p < 0.05 effect of peer S+ versus peer S−. Note that only rats trained to self-administer cocaine (not the peers), received reinstatement tests. All data presented as mean ± SEM.

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References

    1. Heilig M, Epstein DH, Nader MA, Shaham Y. Time to connect: Bringing social context into addiction neuroscience. Nature reviews Neuroscience. 2016;17(9):592–599. - PMC - PubMed
    1. Venniro M, Zhang M, Caprioli D, et al. Volitional social interaction prevents drug addiction in rat models. Nature neuroscience. 2018;21(11):1520–1529. - PMC - PubMed
    1. Pelloux Y, Giorla E, Montanari C, Baunez C. Social modulation of drug use and drug addiction. Neuropharmacology. 2019;159:107545. - PubMed
    1. Smith MA, Cha HS, Griffith AK, Sharp JL. Social Contact Reinforces Cocaine Self-Administration in Young Adult Male Rats: The Role of Social Reinforcement in Vulnerability to Drug Use. Front Behav Neurosci. 2021;15:771114. - PMC - PubMed
    1. Peartree NA, Hatch KN, Goenaga JG, et al. Social context has differential effects on acquisition of nicotine self-administration in male and female rats. Psychopharmacology. 2017;234(12):1815–1828. - PMC - PubMed

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