The Effects of Drugs on Behavior Maintained by Social Contact: Role of Monoamines in Social Reinforcement

Bravo-Rivera and colleagues frame the study around the observation that drug use among adolescents and young adults clusters strongly within peer groups. They note that established explanations include self-selection and social-learning processes, but highlight a less-studied possibility: some drugs might directly increase the incentive value of social contact, thereby increasing motivation to seek and maintain peer interactions. The introduction summarises prior evidence that social contact is a potent reinforcer in rodents and that monoamines—dopamine, norepinephrine and serotonin—have documented roles in facets of social behaviour such as approach, play, vocalisations and pair-bonding, yet their specific contributions to social reinforcement remain unclear. The study therefore set out to test how acute pharmacological manipulations of these monoamine systems alter the positive reinforcing effects of brief social contact in male and female rats, and whether any such effects are specific to social stimuli. To address this, the investigators compared responses for 30-s access to a same-sex social partner versus a non-social control stimulus (an athletic sock matched for size/colour) on a progressive ratio schedule after pretreatment with drugs that selectively or non-selectively increase extracellular dopamine, norepinephrine, or serotonin.

Sixteen experimentally naïve adult Long-Evans rats (8 male, 8 female) served as test subjects; an additional six rats (3 male, 3 female) acted as social partners and received no operant training. Animals were housed individually with enrichment, fed ad libitum except during lever-press acquisition, and tested during the light phase. All procedures were approved by the institutional animal care committee. Four rats (2 male, 2 female) were allocated to a control group in which the reinforcing stimulus was a black-and-white athletic sock intended to match non-social sensory aspects of a partner encounter. Behavioural testing used operant chambers with a single response lever opposite an enclosed social compartment separated by a metal screen and a guillotine door that allowed 30-s controlled access to the social partner (visual, auditory, olfactory and limited tactile contact). Rats were trained to lever-press for food on an FR1 schedule, then trained for three 1-hr sessions in which a single lever press produced 30-s access to the social partner (or non-social sock). After this, contingencies shifted to a progressive ratio (PR) schedule for the remainder of the study; the PR increased the ratio requirement systematically after each reinforcer. All testing occurred during young adulthood (postnatal day 70–140). Drugs tested included a selective dopamine reuptake inhibitor (WIN-35,428), the selective norepinephrine reuptake inhibitor atomoxetine, the selective serotonin reuptake inhibitor fluoxetine, the non-selective monoamine reuptake inhibitor cocaine, and the non-selective monoamine releasers d-amphetamine and MDMA. All injections were administered intraperitoneally 10 min before sessions to target peak behavioural effects; doses were presented in a pseudorandomised order with limits on consecutive ascending/descending sequences. The extracted text does not clearly report the full dose range for every drug in the Methods section, but doses referenced elsewhere in the results include WIN-35,428 at 0.1, 0.3 and 1.0 mg/kg, fluoxetine at 10 mg/kg (and other lower doses), d-amphetamine at 0.3 and 1.0 mg/kg, and cocaine at 3.0 and 10 mg/kg. The primary outcome was breakpoint, operationalised as the number of reinforcers (social-access periods) obtained on the PR schedule. Data were analysed with mixed-factor ANOVA, using sex as a between-subjects factor and dose as a within-subjects factor; where significant sex effects or interactions arose, follow-up one-way repeated-measures ANOVAs were conducted separately by sex. Planned pairwise comparisons versus saline used Holm–Bonferroni correction. All 16 test subjects completed the study.

Baseline (non-injection) responding differed by stimulus: rats working for social contact averaged about 6–8 reinforcers per session, whereas those working for the non-social sock averaged about 3–5 reinforcers. Females achieved roughly 1–3 more reinforcers than males across conditions. Drugs with high affinity for the dopamine transporter selectively increased breakpoints maintained by a social partner. The selective dopamine reuptake inhibitor WIN-35,428 produced a significant sex x dose interaction for social responding [F(3,30)=12.968, p<0.001], with females showing greater responding than males at 0.1 mg/kg (p=0.009). In females, WIN-35,428 showed a main effect of dose [F(3,15)=18.959, p<0.001], with 0.1 and 0.3 mg/kg increasing breakpoints versus saline (p's<0.001). Males also showed a dose-related increase [F(3,15)=4.953, p=0.014], with 0.1 mg/kg (p=0.003) and 0.3 mg/kg (p=0.006) elevating breakpoints. The highest WIN dose (1.0 mg/kg) did not increase responding for either stimulus. D-amphetamine increased social breakpoints in both sexes [main effect of dose: F(3,30)=19.282, p<0.001], with 0.3 and 1.0 mg/kg raising responding relative to saline (p's<0.001); these effects were apparent in separate analyses for males [F(3,15)=6.143, p=0.006] and females [F(3,15)=17.239, p<0.001]. Cocaine also elevated social responding in both sexes [F(3,30)=26.628, p<0.001], with 3.0 mg/kg (p=0.004) and 10 mg/kg (p<0.001) increasing breakpoints overall; exploratory tests showed increases in males at 3.0 and 10 mg/kg and in females at 10 mg/kg. By contrast, MDMA did not alter breakpoints for social contact at any dose, although a main effect of sex was observed during MDMA tests [F(1,10)=13.787, p=0.004] because females exhibited higher breakpoints than males. Regarding the non-social control stimulus, most reinforcement-enhancing effects of dopaminergic drugs were absent or limited. WIN-35,428 did not robustly increase non-social responding in males, though an exploratory analysis indicated an increase in females at 0.3 mg/kg [F(3,3)=16.704, p=0.022; pairwise p=0.049]. D-amphetamine increased non-social breakpoints at 1.0 mg/kg [F(3,6)=8.927, p=0.012], an effect driven primarily by females in exploratory analyses. Cocaine produced a sex x dose interaction for non-social responding [F(3,6)=25.600, p<0.001]; in females only, cocaine increased non-social breakpoints dose-dependently [F(3,3)=73.727, p=0.003], with 10 mg/kg > saline (p=0.037). Atomoxetine failed to alter responding for either stimulus at any dose tested. Fluoxetine did not increase reinforcement; instead, a high dose of fluoxetine (10 mg/kg) significantly decreased breakpoints for social contact in both sexes [main effect of dose: F(3,30)=11.524, p<0.001; pairwise p<0.001], with follow-up tests showing decreases in males and females. MDMA did not affect responding for the non-social stimulus under any condition. Overall, the pattern shows that drugs that increase extracellular dopamine (selective DAT inhibitor WIN-35,428, d-amphetamine, and cocaine) enhanced motivation to obtain brief social contact at doses that often did not increase responding for a matched non-social stimulus, whereas atomoxetine, fluoxetine and MDMA did not produce similar selective reinforcement-enhancing effects for social contact.

Bravo-Rivera and colleagues interpret the results as evidence that increases in extracellular dopamine play a prominent role in enhancing the positive reinforcing effects of social contact. They highlight that WIN-35,428, d-amphetamine and cocaine—compounds with strong actions at the dopamine transporter—each increased breakpoints for social access at doses that were, in many cases, selective relative to a non-social control stimulus. The authors suggest these effects are consistent with prior literature showing dopamine facilitates social approach, play and pair-bonding, and with the role of nucleus accumbens dopamine in mediating reinforcement for other stimuli. By contrast, neither the selective norepinephrine reuptake inhibitor atomoxetine nor the selective serotonin reuptake inhibitor fluoxetine increased social reinforcement; a high dose of fluoxetine even reduced responding for social contact. MDMA, despite its reputation as an entactogen in humans, failed to enhance social reinforcement in this model, a null effect the authors attribute to MDMA's relatively greater serotonergic versus dopaminergic action which may mask any dopamine-mediated reinforcement enhancement. The investigators therefore propose that serotonin may counter dopamine's reinforcement-enhancing effects and that norepinephrine does not share the same role as dopamine in this context. The authors discuss the translational implication that dopaminergic drugs with high abuse liability might strengthen immediate social bonds among drug-using peers by increasing the incentive value of social contact, thereby contributing to the high concordance of drug use within peer groups and reinforcing group cohesion. They also note the methodological advantage of the progressive ratio schedule as an operational proxy of motivation to obtain an external reward. Limitations acknowledged include the within-subjects design, which could allow prior drug exposure or extended training to influence subsequent tests and thus would benefit from replication in between-subjects designs with experimentally naïve animals. The non-social control group was small (n=4), limiting power to detect sex differences in that condition. The study did not include explicit measures of social interaction (for example, duration of physical interaction) or general motor activity such as locomotion, so the possibility that high doses produced non-specific motor effects (e.g., stereotypy) that altered responding cannot be excluded; the failure of WIN-35,428 at 1.0 mg/kg to increase responding may reflect such effects. Finally, the authors call for further work using receptor-selective antagonists, additional behavioural schedules (e.g. concurrent choice or conjoint punishment schedules), and broader behavioural measures to better specify mechanisms and boundary conditions of the observed reinforcement-enhancing effects.