This rodent study (2022) assessed the extent to which drugs that increase synaptic dopamine, norepinephrine, and serotonin enhance the positive reinforcing effects of social contact. Rats were given doses of a selective dopamine reuptake inhibitor, a selective norepinephrine reuptake inhibitor, a selective serotonin reuptake inhibitor, cocaine, d-amphetamine and MDMA. It was found that increases in extracellular dopamine, but not extracellular norepinephrine or serotonin, increase the positive reinforcing effects of social contact.
Abstract
“Drug use is highly concordant among members of adolescent and young adult peer groups. One potential explanation for this observation is that drugs may increase the reinforcing effects of social contact, leading to greater motivation to establish and maintain contact with other members of the peer group. Several classes of drugs, particularly drugs that increase synaptic dopamine, increase the reinforcing effects of contextual stimuli, but the extent to which these drugs enhance the reinforcing effects of social contact is not known. The purpose of this study was to determine the extent to which drugs that increase synaptic dopamine, norepinephrine, and serotonin enhance the positive reinforcing effects of social contact. To this end, male and female Long-Evans rats were pretreated with acute doses of the 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. Ten minutes later, the positive reinforcing effects of 30-s access to a same-sex social partner was examined on a progressive ratio schedule of reinforcement. To determine whether the reinforcement-altering effects of these drugs were specific to the social stimulus, the reinforcing effects of a non-social stimulus (30-s access to an athletic sock of similar size and colouring as another rat) was determined in control subjects. WIN-35,428, d-amphetamine, and cocaine, but not atomoxetine, fluoxetine, or MDMA, dose-dependently increased breakpoints maintained by a social partner under conditions in which responding maintained by a non-social stimulus was not affected. These data indicate that increases in extracellular dopamine, but not extracellular norepinephrine or serotonin, increase the positive reinforcing effects of social contact in both male and female rats. These data also provide support for the hypothesis that some drugs with high abuse liability increase the motivation to establish and maintain contact with social peers.”
Authors: Jessica L. Sharp & Mark A. Smith
Summary
INTRODUCTION
Several factors contribute to the high concordance rate of drug use within peer groups, including self-selection processes and social-learning processes. One potential factor is that some drugs increase the motivation to establish and maintain contact with social peers.
Social contact with a social partner is reinforcing and has positive incentive value. It can also reverse a cocaine-induced conditioned place preference and prevent the reinstatement of a cocaine-induced place preference following extinction.
Dopamine, norepinephrine, and serotonin play important roles in social behavior. In the present study, we examined how drugs targeting dopamine, norepinephrine, and serotonin influence the positive reinforcing effects of social contact relative to a non-social stimulus in both male and female rats.
The effects of atomoxetine, fluoxetine, cocaine, d-amphetamine, and MDMA were examined on the positive reinforcing effects of 30-s access to a same-sex social partner on a progressive ratio (PR) schedule of reinforcement.
Animals
16 experimentally naive adult Long Evans rats were kept in polycarbonate cages with environmental enrichment and received ad libitum access to water and food. They were tested during the light portion of the 12:12 h light-dark cycle.
Apparatus and Chemicals
Testing occurred in operant conditioning chambers from Med Associates, which contained a house light, one response lever, and an attached social compartment. A white noise machine was also used throughout training and testing.
Cocaine, d-amphetamine, MDMA, and WIN-35,428 were obtained from the National Institute on Drug Abuse and dissolved in sterile saline for injection.
Lever-Press Training
Rats were food restricted to 90% of their free-feeding weight and trained to lever press using food reinforcement. All rats completed at least four training sessions and no rat failed to acquire lever pressing.
Social Assignment and Partnering
Twelve rats were placed in a neutral cage with one social partner of the same sex for 15 min.
Four rats were assigned to a control group and were exposed to a black-and-white athletic sock as a reinforcing stimulus.
Social Reinforcement Training and Testing
Social reinforcement training and testing began 1 week following lever-press training. Rats were initially trained to press on a fixed ratio (FR1) schedule of reinforcement, but were then changed to a PR schedule of reinforcement, which increased the ratio value systematically following each reinforcer.
All drug testing was performed during young adulthood, from PND 70 to PND 140. Drugs were administered via intraperitoneal injection based on body weight 10 min before the test session, and the drugs remained behaviorally active for the full duration of the session.
Data Analysis
All 16 rats completed the study, which was analyzed using mixed-factor ANOVA, with sex as the between-subjects factor and dose as the within-subjects factor. In cases where a significant main effect of sex or significant sex x dose interaction was observed, exploratory analyses were conducted in males and females.
RESULTS
Rats that were maintained by social contact received more reinforcers than those maintained by access to a non-social stimulus.
A significant sex x dose interaction was observed for the selective dopamine reuptake inhibitor, WIN-35,428. This drug increased responding maintained by social contact in females and in a dose-related manner in males.
Atomoxetine and fluoxetine failed to alter responding maintained by a social stimulus at all doses tested, but fluoxetine significantly decreased breakpoints maintained by social contact in both males and females.
WIN-35,428 increased responding maintained by a non-social stimulus in females but not in males. Atomoxetine and fluoxetine failed to alter responding maintained by a non-social stimulus in both males and females at all doses tested.
D-amphetamine increased breakpoints maintained by a social stimulus similarly in males and females, with doses of 0.3 and 1.0 mg/kg increasing responding relative to saline.
Cocaine increased responding maintained by a social stimulus similarly in both males and females. Cocaine increased breakpoints in males with doses of 3.0 mg/kg and 10 mg/kg increasing responding relative to saline.
Breakpoints maintained by social contact were greater in females than males, but MDMA failed to alter breakpoints in either sex. d-Amphetamine increased responding maintained by a nonsocial stimulus, but no dose differed significantly from saline.
When responding was maintained by a non-social stimulus, cocaine increased breakpoints in females in a dose-dependent manner, whereas cocaine failed to increase breakpoints in males under any condition examined.
DISCUSSION
This study determined that drugs that target dopamine, norepinephrine, and serotonin increase the positive reinforcing effects of social contact in male and female rats at a dose that does not increase responding maintained by a non-social stimulus.
WIN-35,428 increases the reinforcing effects of social contact in both male and female rats. However, the highest dose failed to increase responding at 1.0 mg/kg due to non-specific motoric effects that interfered with responding or the recruitment of other mechanisms that countered its reinforcement-enhancing effects.
WIN-35,428 increases social play and approach in rodents, and reduces social play and approach in mice with dopamine depletion. It also increases pair bonding in monogamous prairie voles.
Both cocaine and d-amphetamine have positive reinforcing effects in humans and non-human animals. The effects of cocaine are specific to the social stimulus, whereas d-amphetamine’s effects are specific to the social stimulus in males only.
Cocaine and d-amphetamine decrease rodent pinning and pouncing but increase social exploration behaviors and prosocial vocalizations. These behaviors are likely due to increases in extracellular dopamine, which mediates the positive reinforcing effects of social contact.
Atomoxetine and fluoxetine, two drugs that block the serotonin and norepinephrine reuptake pathways, do not increase the positive reinforcing effects of social contact in humans or non-human animals.
MDMA failed to increase the positive reinforcing effects of social contact in all conditions examined, despite its action on serotonin, which may have masked any reinforcement-enhancing effects that might otherwise have been produced by its action on dopamine.
Data collected with six monoamine releasers and reuptake inhibitors indicate that increases in extracellular dopamine play the most prominent role in the positive reinforcing effects of social contact, while increases in extracellular serotonin decrease the reinforcing effects of social contact.
The progressive ratio schedule is an effective measure of the maximal amount of work (i.e., behavior output) maintained by a stimulus or event. This measure may be used to understand how social factors may influence substance use.
All drugs that increased the positive reinforcing effects of social contact functioned as robust positive reinforcers in drug self-administration studies, implying that drugs with high abuse liability may be uniquely capable of increasing the cohesion of social groups.
The study used a within-subject design to reduce the number of subjects and facilitate comparisons across test drugs. However, the study did not replicate the tests using a between-subjects design in experimentally naive subjects, and it did not include explicit measures of social interaction or general motor activity.
These findings indicate that some drugs increase the positive reinforcing effects of social contact, which in turn increases the strength of social bonds between group members, leading to further group conformity and adoption of group norms that encourage drug use.