From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long-term adverse consequences of drug use?

Abstract

Addictive drugs can profoundly affect social behaviour both acutely and in the long-term. Effects range from the artificial sociability imbued by various intoxicating agents to the depressed and socially withdrawn state frequently observed in chronic drug users. Understanding such effects is of great potential significance in addiction neurobiology. In this review we focus on the 'social neuropeptide' oxytocin and its possible role in acute and long-term effects of commonly used drugs. Oxytocin regulates social affiliation and social recognition in many species and modulates anxiety, mood and aggression. Recent evidence suggests that popular party drugs such as MDMA and gamma-hydroxybutyrate (GHB) may preferentially activate brain oxytocin systems to produce their characteristic prosocial and prosexual effects. Oxytocin interacts with the mesolimbic dopamine system to facilitate sexual and social behaviour, and this oxytocin-dopamine interaction may also influence the acquisition and expression of drug-seeking behaviour. An increasing body of evidence from animal models suggests that even brief exposure to drugs such as MDMA, cannabinoids, methamphetamine and phencyclidine can cause long lasting deficits in social behaviour. We discuss preliminary evidence that these adverse effects may reflect long-term neuroadaptations in brain oxytocin systems. Laboratory studies and preliminary clinical studies also indicate that raising brain oxytocin levels may ameliorate acute drug withdrawal symptoms. It is concluded that oxytocin may play an important, yet largely unexplored, role in drug addiction. Greater understanding of this role may ultimately lead to novel therapeutics for addiction that can improve mood and facilitate the recovery of persons with drug use disorders.

Figure 1

Schematic showing the possible interaction between central oxytocin release and addiction-relevant brain regions. (a) depicts dendritic release of oxytocin from the SON and its interaction with distal oxytocin receptor containing brain regions (volume transmission). (b) indicates both dendritic release of oxytocin from magnocellular PVN neurons and/or classical neurotransmission from PVN parvocellular oxytocinergic projections to forebrain, midbrain and spinal regions. Prosocial drugs (that is MDMA) release 5-HT via raphefugal fibres within PVN and SON and cause oxytocin release while oxytocinergic projections from the PVN to the VTA and NAS may modulate mesolimbic dopamine activity. PVN, paraventricular hypothalamic nucleus; SON, supraoptic hypothalamic nucleus; NAS, nucleus accumbens; LS, lateral septum; BNST, bed nucleus of the stria terminalis; MPO, medial preoptic area; VMH, ventromedial hypothalamus; CeA, central amygdaloid nucleus; MeA, medial amygdaloid nucleus; VTA, ventral tegmental area; SN, substantia nigra pars compacta; brainstem nuclei; spinal cord. AC, anterior commissure; OT, olfactory tract, SC, superior colliculus, IC, inferior colliculus; Hippo, hippocampus; DA, dopamine; CSF, cerebrospinal fluid.

Figure 2

(a) Sketch of typical OT-mediated ‘adjacent lying' behaviour seen in pairs of rats given low doses of MDMA. (b) The facilitation of social interaction produced by acute MDMA (5 mg kg⁻¹, i.p.) is reversed by intracerebroventricular administration of the OT receptor antagonist tocinoic acid (TOC, 20 μg). When administered alone tocinoic acid did not affect social interaction. Redrawn from Thompson et al., 2007. (c) Picture of the supraoptic nucleus of the hypothalamus showing staining for OT (brown) and Fos (black). MDMA (10 mg kg⁻¹ significantly increases the number of double-labelled (oxytocin+Fos) neurons (see Thompson et al., 2007) (d) Administration of MDMA (8 mg kg⁻¹, i.p.), methamphetamine (METH, 8 mg kg⁻¹, i.p.) or the combination of MDMA (4 mg kg⁻¹, i.p.)+METH (4 mg kg⁻¹, i.p.) once per week for 16 weeks to rats causes a long-term decline in baseline social interaction measured 7 weeks after the last drug dose was administered. Redrawn from data presented by Clemens et al., 2007. ^*P<0.05, ^***P<0.001.