Detrimental effects of the 'bath salt' methylenedioxypyrovalerone on social play behavior in male rats

Abstract

Methylenedioxypyrovalerone (MDPV) is the most popular synthetic cathinone found in products marketed as 'bath salts', widely abused among teenagers and young adults. Synthetic cathinones have pharmacological effects resembling those of psychostimulants, which are known to disrupt a variety of social behaviors. However, despite the popular use of MDPV by young people in social contexts, information about its effects on social behavior is scarce. To investigate the impact of MDPV on social behavior at young age, and the underlying neurobehavioral mechanisms, we focused on social play behavior. Social play behavior is the most characteristic social behavior displayed by young mammals and it is crucial for neurobehavioral development. Treatment with MDPV reduced social play behavior in both juvenile and young adult male rats, and its play-suppressant effect was subject to tolerance but not sensitization. As the behavioral effects of MDPV have been ascribed to dopaminergic and noradrenergic neurotransmission, and given the role of these neurotransmitters in social play, we investigated the involvement of dopamine and noradrenaline in the play-suppressant effects of MDPV. The effects of MDPV on social play were blocked by either the α2 adrenoceptor antagonist RX821002 or the dopamine receptor antagonist flupenthixol, given alone or together at sub-effective doses. In sum, MDPV selectively suppresses the most vigorous social behavior of developing rats through both noradrenergic and dopaminergic mechanisms. This study provides important preclinical evidence of the deleterious effects of MDPV on social behavior, and as such increases our understanding of the neurobehavioral effects of this popular cathinone.

Fig. 1. Acute administration of MDPV (0.5 mg/kg) suppresses social play behavior without affecting general social exploration and locomotor activity in both juvenile and young adult rats.

MDPV (0.5 mg/kg) suppressed pinning (a) and pouncing (b) behaviors in juvenile (i.e., 28–30-day-old) rats. Social exploration (c) and locomotor activity (i.e., the number of crossings (d)) were not affected by MDPV. Similarly, MDPV reduced play-related behaviors (e) without affecting social exploration (f) in young adult (i.e., 80-day-old) rats (juveniles: n SAL = 10, n MD0.025 = 7, n MD0.05 = 7, n MD0.1 = 11, n MD0.25 = 8, n MD0.5 = 10; young adults: n SAL = 6, n MD0.025 = 6, n MD0.05 = 5, n MD0.1 = 5, n MD0.25 = 6, n MD0.5 = 5). Data represent mean values ± SEM; *p < 0.05, **p < 0.01 vs SAL group (Student–Newman–Keuls post-hoc test).

Fig. 2. MDPV reduces social play behavior regardless of the treatment received by the test partner, affecting social play in vehicle-treated animals as well.

When behavior of the members of a pair was scored separately, there was a reduction in pinning (a) and pouncing (b) either when one or both rats in a pair were treated with MDPV. In addition, MDPV-treated rats affected behavior of their saline-treated partners: saline-treated rats interacting with MDPV-treated partners showed indeed reduced pinning (a) and pouncing (b) frequency. These results suggest that MDPV-treated rats displayed both reduced initiation to play and responsiveness to play solicitation, indirectly decreasing playfulness in their saline-treated partners as well. Social exploration was unaffected (c). n SAL–SAL = 16, n SAL–MD = 12, n MD–SAL = 12, n MD–MD = 18. Data represent mean values ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001 vs SAL–SAL group (Student–Newman–Keuls post-hoc test). ‘Subject’ represents the treatment of the animal whose behavior was scored; ‘Partner’ represents the treatment of its test partner.

Fig. 3. Following repeated treatment, tolerance occurs to the play-suppressant effects of MDPV.

Acute administration of MDPV (0.5 mg/kg, i.p.) decreased the amount of pinning (a) and pouncing (b) in animals pretreated with saline (SAL–MD0.5 group) but not in animals pretreated with MDPV (MD0.5–MD0.5 group), indicating that tolerance to the effect of MDPV had occurred. Social exploration was not affected by either the repeated and acute treatment (c) (n SAL–SAL = 7, n SAL–MD0.5 = 8, n MD0.5–SAL = 7, n MD0.5–MD0.5 = 8). Data represent mean values ± SEM; **p < 0.01 vs SAL–SAL group (Student–Newman–Keuls post-hoc test).

Fig. 4. Following repeated treatment, sensitization to the play-suppressant effects of MDPV does not occur.

Acute administration of a low dose of MDPV (0.1 mg/kg, i.p.) did not affect pinning (a) and pouncing (b) in rats repeatedly pretreated with an effective dose of MDPV (0.5 mg/kg, i.p.), revealing that sensitization to the effects of MDPV on social play behavior had not occurred. Social exploration was not affected by either the repeated and acute treatment (c) (n SAL–SAL = 7, n SAL–MD0.1 = 8, n MD0.5–SAL = 7, n MD0.5–MD0.1 = 8). Data represent mean values ± SEM.

Fig. 5. The effects of MDPV on social play depend on both dopaminergic and noradrenergic neurotransmission.

The effects of MDPV on pinning (a, d) and pouncing (b, e) were blocked by either the dopamine receptor antagonist flupenthixol (0.125 mg/kg i.p.; n SAL–SAL = 9, n SAL–MD = 8, n FLU–SAL = 7, n FLU–MD = 6) or the α2 adrenoceptor antagonist RX821002 (0.2 mg/kg i.p.; n SAL–SAL = 6, n SAL–MD = 7, n RX–SAL = 5, n RX–MD = 6). Moreover, combined administration of sub-effective doses of the α2 noradrenergic receptor antagonist RX821002 (0.1 mg/kg i.p.) and the dopamine receptor antagonist flupenthixol (0.06 mg/kg i.p.) antagonized the effects of MDPV on pinning (g) and pouncing (h) (n SAL–SAL = 6, n SAL–MD = 8, n FLU/RX–SAL = 8, n FLU/RX–MD = 8). Social exploration was not affected by treatments (c, f, i). Data represent mean values ± SEM; *p < 0.05, **p < 0.01 vs SAL–SAL group (Student–Newman–Keuls post-hoc test).