Persistent brain region-specific up-regulation of the vasopressin V1a receptor following chronic cocaine and morphine administration and withdrawal in mice

Panos Zanos, Hannah Hobson, Majet Alshehri, Raphaelle Winsky-Sommerer, Ian Kitchen, Alexis Bailey. University of Surrey, Guildford, UK

Recent findings have suggested a key role for arginine vasopressin (AVP) in the modulation of cocaine and opioid seeking, withdrawal and reinstatement behaviours1-4. However, the regulatory control of vasopressin receptors under different phases of drug addiction is unknown. The present study aims to investigate the effect of chronic cocaine and morphine administration and withdrawal on the vasopressin receptors in different brain regions.

For both the cocaine and opioid studies, male C57BL/6J mice (20-23g) were separated into treatment groups (n = 6 per group). For the cocaine study, one group was treated with a 14-day “binge” saline or escalating dose cocaine administration paradigm (3 x 15-30mg/kg i.p. per day). The other groups were treated with a 14-day “binge” saline or escalating dose cocaine administration paradigm (3 x 15-30mg/kg i.p. per day) and spontaneously withdrawn for a period of either 1 or 14 days. For the morphine study one group was treated with a 7-day “intermittent” saline or escalating dose morphine administration paradigm (2 x 20-100mg/kg i.p. per day). The other groups were treated with a 7-day “intermittent” saline or escalating dose morphine administration paradigm (2 x 20-100 mg/kg i.p. per day) and spontaneously withdrawn for a period of either 1 or 7 days. Quantitative autoradiographic brain mapping of the vasopressin V1a and V1b receptors (V1aR and V1bR) was carried out using 10nM [3H]AVP radioligand. To discriminate between V1aR and V1bR, a selective V1bR antagonist, SSR149,514 (30nM) was used.

In both cocaine and morphine experiments, a significant effect of treatment (p<0.001), brain region (p<0.001) and treatment x brain region interaction (p<0.01) was found (2-way ANOVA). Bonferroni post-hoc test revealed chronic cocaine administration significantly increased V1aR binding within the amygdala, nucleus accumbens, piriform cortex, vertical limb of diagonal band of Broca (p<0.01) and lateral septum (p<0.05). This up-regulation persisted following 1 day and 14 days withdrawal. Significant upregulation of the V1aR binding was also observed within the olfactory tubercle (p<0.05) and hypothalamus (p<0.01) during long-term withdrawal. Chronic morphine treatment significantly increased V1aR binding within the amygdala and the piriform cortex (p<0.01). Acute withdrawal from morphine significantly increased V1aR binding within the amygdala, piriform cortex (p<0.01), nucleus accumbens, olfactory tubercle (p<0.05), and lateral septum (p<0.001), while 7-day morphine withdrawal increased V1aR binding within the amygdala, lateral septum, nucleus accumbens, paraventricular thalamus, olfactory tubercle (p<0.001), piriform cortex (p<0.01), and hypothalamus (p<0.05). No detectable V1bR binding sites were observed in the brain regions analyzed in any of the treatment groups.

These results indicate a prolonged activation of the vasopressin V1a receptors after chronic cocaine and morphine administration that persists or triggered after acute- and long-term withdrawal within brain regions associated with reward, sociability, stress and anxiety. These data strongly suggest that alteration of the V1a receptor may be a common neurobiological mechanism involved in the pathophysiology of cocaine and opioid addiction and craving after abstinence.

1. Laorden et al. (2003), J Neuroendocrinol, 15(6), 586-91.

2. Rodriguez-Borrero et al. (2010), Neuropharmacology, 58(1), 88-101.

3. Zhou et al. (2008), Neuropsychopharmacolog,y 33(2), 226-36.

4. Zhou et al. (2011), Neuropsychopharmacology, 36(10), 2062-75.