Towards an understanding of the neural mechanisms and therapeutic effects of oxytocin as a treatment for methamphetamine addiction
Methamphetamine (METH) is a highly addictive psychostimulant, and currently there are no approved pharmacotherapies for the treatment of METH addiction. The neuropeptide oxytocin has emerged as a potential candidate for translation to humans with METH use disorders, however the neurobiological mechanisms by which oxytocin ameliorates these addiction symptoms are not well understood. Additionally, it is not known whether oxytocin may be efficacious as a chronic post-treatment for existing METH-dependent users, or if the efficacy of oxytocin treatment depends upon the severity of METH addiction symptoms. Lastly, it is unclear how peripherally administered oxytocin accesses the brain. Addressing each of these uncertainties will guide the development of new addiction therapies, and the understanding of how oxytocin acts in the brain; whether it is efficacious as a chronic treatment after METH use; if its therapeutic effects depend upon the extent of addiction symptoms; and whether peripherally administered oxytocin signals to the brain via a peripheral mechanism. This was explored using a combination of intravenous self-administration, neurochemical, immunofluorescent, and pharmacological techniques in rats.
Chapter 2 investigated the role of OTRs and vasopressin V1a receptors (V1aRs) following systemic oxytocin and intra-NAcc oxytocin treatment, prior to METH-primed reinstatement. Systemic oxytocin inhibited METH-primed reinstatement, which could be prevented by systemic antagonism of the V1aR but not of the OTR. The previously discovered lack of OTR-dependency of oxytocin in the NAcc inhibiting METH-primed reinstatement was replicated, as oxytocin reduced METH-primed reinstatement, which was not prevented by OTR antagonism. Importantly, V1aR antagonism in the NAcc prevented the inhibitory effects of intra-NAcc oxytocin on METH-primed reinstatement. These results indicate that V1aR binding may be an important mechanism for the therapeutic effects of oxytocin.
Chapter 3 investigated the effects of oxytocin when infused directly into the prelimbic (PrL) subregion of the medial prefrontal cortex, a key region implicated in relapse to METHseeking behaviour, and a major excitatory input to the NAcc. Intra-PrL infusions of oxytocin reduced cue-induced and METH-primed reinstatement to METH-seeking. Furthermore, cFos immunoreactivity was used as a marker of activated NAcc neurons, which revealed that METHprimed reinstatement increased NAcc activity, and that an intra-PrL oxytocin infusion suppressed METH-induced activity in the NAcc. This suggests that oxytocin may act at the PrL to inhibit excitatory output to the NAcc during reinstatement to METH seeking.
Chapter 4 explored the effects of oxytocin when administered chronically during forced abstinence from METH self-administration. This was investigated in male and female rats which either had short (ShA) or long (LgA) daily METH. Chronic oxytocin treatment during abstinence specifically protected against the high-relapse phenotype induced by LgA in both sexes, particularly for incubation of craving, and METH-primed reinstatement. Oxytocin attenuated stress-induced reinstatement more so in female LgA rats than ShA or males. This supports the use of oxytocin as a chronic treatment for METH dependent people, and suggests that oxytocin may interact with the neurobiology that underpins a high-addiction state, as induced by LgA.
Chapter 5 investigated whether individual variation in incentive salience is predictive of later relapse-like behaviour in rats, and whether the efficacy of oxytocin treatment depends upon this underlying reward-processing trait. Rats which attribute incentive salience to rewardpredictive cues (“sign-trackers”; STs) exhibited higher reinstatement to METH-seeking following exposure to METH-associated cues, compared to rats which do not exhibit this latent incentive salience trait (“goal-trackers”; GTs). Furthermore, oxytocin treatment reduced cue-induced reinstatement to a greater extent in STs than GTs, while reducing METH-primed reinstatement to a similar extent between both phenotypes. These data indicate that pre-existing differences in incentive salience represent a latent risk for development of METH addiction, and that oxytocin treatment interacts with incentive salience processes involved in METH addiction.
Chapter 6 describes the development of custom fibre photometry equipment, including systems for alignment with behavioural events. NAcc recordings were conducted following exposure to METH or reward-paired cues, and the effect of systemic oxytocin on METH- or cueinduced NAcc activity was investigated. This data verifies the utility of in vivo fibre photometry for investigating how oxytocin, or other candidate pharmacotherapies, can modulate neural activity with the temporal specificity to interrogate distinct aspects of drug-seeking and -taking.
Chapter 7 demonstrated that, in rats which had undergone surgical resection of the subdiaphragmatic vagus nerve (SDV), the ability of peripheral oxytocin treatment to reduce METH self-administration was prevented at a low dose of oxytocin, and partially reduced at a higher oxytocin dose, in both sexes. Peripheral oxytocin treatment also reduced cue-induced and METH-primed reinstatement in sham-operated males, but this effect of oxytocin was absent in SDV males. Surprisingly, oxytocin treatment reduced reinstatement to a similar extent in both sham and SDV females, suggesting a sex difference in the interaction of the vagus nerve and oxytocin administration. Therefore, oxytocin exerts anti-addiction effects on the brain via the vagus nerve, although this interaction may be impacted by withdrawal, sex, and oxytocin dose.
Finally, Chapter 8 discussed the implications of these findings, in the context of basic science investigations into the neurobiology of METH addiction and oxytocin systems, the clinical use of oxytocin as an addiction therapy, and novel pharmacotherapeutic discovery.
