Drug-taking in a socio-sexual context enhances vulnerability for addiction in male rats

Abstract

Vulnerability to develop addiction is influenced by numerous factors, including social behavior. Specifically, in human users, drug taking in a socio-sexual context appears to enhance further drug-seeking behavior. Users report heightened sexual pleasure as a motivation for further drug use and display risk behaviors even when tested in drug-free state. Here, using a preclinical model of limited voluntary drug use in rats, the hypothesis was tested that methamphetamine (Meth)-taking concurrently with socio-sexual experience increases vulnerability to addiction. Male Sprague Dawley rats were socially housed and underwent limited-access Meth self-administration (maximum 1 mg/kg/session). Meth-taking was either concurrent or non-concurrent with sexual behavior: concurrent animals were mated with a receptive female immediately after each session, while non-concurrent animals gained equivalent sexual experience the week prior. Next, drug-seeking behaviors were measured during cue reactivity, extinction, and reinstatement sessions using different extinction and reinstatement protocols in 4 separate studies. Both groups equally acquired Meth self-administration and did not differ in total Meth intake. However, drug-seeking behavior was significantly higher in concurrent animals during cue reactivity tasks, extinction sessions, and cue- or Meth-induced reinstatement tests. In addition, sexual behavior in the absence of Meth triggered reinstatement of drug-seeking in concurrent animals. These results indicate that Meth-taking in a socio-sexual context significantly enhances vulnerability for drug addiction in male rats. This preclinical paradigm of drug self-administration concurrent with socio-sexual behavior provides a useful model for studying the underlying neurobiology of socially driven vulnerability to drug addiction.

Fig. 1

Concurrent, but not non-concurrent, Meth self-administration and sex leads to increased drug-seeking behavior during operant extinction and sex reinstatement. a Experimental design. b Operant behavior (closed markers: active responses, open markers: inactive responses) and c Meth infusions earned during the final 5 sessions of Meth self-administration for the two experimental groups, d Active lever responses during 30 min cue reactivity test. e Concurrent animals displayed significantly increased drug-seeking behavior during sessions 1, 3, 4, 5, and 7 of operant extinction (indicated by *). f Active lever responses during Sex Reinstatement compared with the last day of extinction. The concurrent group showed significant reinstatement of active lever responding compared to the last day of extinction (indicated by *) and compared to the non-concurrent group (indicated by #). All data are expressed as Mean + SEM. Sample sizes: concurrent n = 8; non-concurrent n = 7

Fig. 2

Concurrent Meth self-administration and sex leads to increased drug-seeking behavior during cue extinction and Meth-primed reinstatement. a Experimental design. b Operant behavior (closed markers: active responses, open markers: inactive responses) and c Meth infusions earned during the final 5 sessions Meth self-administration. d Concurrent animals displayed significantly increased drug-seeking behavior (active lever responses) during the first 30 min of the first cue extinction session (indicated by *). e Concurrent animals displayed significantly increased drug-seeking behavior during sessions 1, 2, and 12 of cue extinction (indicated by *). f Sex Reinstatement and g Meth Reinstatement active lever responding. The concurrent group displayed significant reinstatement vs the last day of extinction (indicated by *) and vs the non-concurrent group during Meth Reinstatement (indicated by #). All data are expressed as Mean + SEM. Sample sizes: concurrent n = 10; non-concurrent n = 11

Fig. 3

Prior, non-concurrent sexual experience does not deminish drug-seeking. a Experimental design. b Operant behavior during acquisition of Meth self-administration for the two groups (Solid blue circles: Non-concurrent active resp; solid black squares: Meth-only group active resp; open blue circles: non-concurrent inactive resp; open black squares: Meth-only group inactive resp). c Meth infusions earned. d Operant behavior during 10 extinction sessions. Non-concurrent animals (solid blue circles) displayed significantly higher responses on active lever then Meth only males (solid black squares) during sessions 1and 2 (indicated by *). Inactive levers are shown with open blue circles (Non-concurrent) and open black squares (Meth only). e Operant behavior during Cue reinstatement (solid blue and black) compared with the last day of extinction (Ext; white bars). Both groups showed significant reinstatement (indicated by *). f Operant behavior during Sex Reinstatement (solid blue) or Cue reinstatement (solid black) compared with the last day of extinction (Ext; white bars). All data are expressed as Mean + SEM. Sample sizes: non-concurrent n = 6, Meth only n = 5