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. 2014 Oct 31;18(1):pyu009.
doi: 10.1093/ijnp/pyu009.

Oxytocin reduces cocaine seeking and reverses chronic cocaine-induced changes in glutamate receptor function

Luyi Zhou  1 , Wei-Lun Sun  1 , Amy B Young  1 , Kunhee Lee  1 , Jacqueline F McGinty  1 , Ronald E See  2
Affiliations

Oxytocin reduces cocaine seeking and reverses chronic cocaine-induced changes in glutamate receptor function

Luyi Zhou et al. Int J Neuropsychopharmacol. .

Erratum in

  • Erratum.
    [No authors listed] [No authors listed] Int J Neuropsychopharmacol. 2016 Apr 27;19(10):pyw031. doi: 10.1093/ijnp/pyw031. Int J Neuropsychopharmacol. 2016. PMID: 27207904 Free PMC article. No abstract available.

Abstract

Background: Oxytocin, a neurohypophyseal neuropeptide, is a potential mediator and regulator of drug addiction. However, the cellular mechanisms of oxytocin in drug seeking remain unknown.

Methods: In the present study, we used a self-administration/reinstatement model to study the effects of oxytocin on cocaine seeking and its potential interaction with glutamate function at the receptor level.

Results: Systemic oxytocin dose-dependently reduced cocaine self-administration during various schedules of reinforcement, including fixed ratio 1, fixed ratio 5, and progressive ratio. Oxytocin also attenuated reinstatement to cocaine seeking induced by cocaine prime or conditioned cues. Western-blot analysis indicated that oxytocin increased phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor GluA1 subunit at the Ser 845 site with or without accompanying increases in phosphorylation of extracellular signal-regulated kinase, in several brain regions, including the prefrontal cortex, bed nucleus of the stria terminalis, amygdala, and dorsal hippocampus. Immunoprecipitation of oxytocin receptor and GluA1 subunit receptors further demonstrated a physical interaction between these 2 receptors, although the interaction was not influenced by chronic cocaine or oxytocin treatment. Oxytocin also attenuated sucrose seeking in a GluA1- or extracellular-signal-regulated kinase-independent manner.

Conclusions: These findings suggest that oxytocin mediates cocaine seeking through interacting with glutamate receptor systems via second messenger cascades in mesocorticolimbic regions.

Keywords: cocaine; glutamate receptor; oxytocin; reinstatement; self-administration..

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Figures

Figure 1.
Figure 1.
Timeline of experiments 1, 2, and 3. Phases of self-administration, extinction, and reinstatement are shown. Arrows indicate the administration of vehicle or oxytocin (OT).
Figure 2.
Figure 2.
Oxytocin (OT) effects on cocaine self-administration and reinstatement. Data are shown for active lever presses and cocaine intake during cocaine self-administration on fixed ratio 1 (a-b) and fixed ratio 5 (c-d) schedules of reinforcement, and lever presses and breakpoint on progressive ratio schedule of reinforcement (e-f). Significant differences are indicated for OT treatment compared with vehicle controls (*P<.05) (n=9–11/group).
Figure 3.
Figure 3.
Oxytocin (OT) effects on cocaine seeking during reinstatement. Active lever presses in cocaine-primed (a) or cue-induced (b) reinstatement to cocaine seeking are shown, respectively. Significant differences are indicated for OT treatment compared with vehicle controls (*P<.05) (n=9–10/group).
Figure 4.
Figure 4.
Acquisition of self-administration and oxytocin (OT) effects on primed reinstatement in rats used for Western-blot analysis. Data (n=6–8/group) are shown for active and inactive lever presses and number of reinforcers received during cocaine (a) or sucrose (b) self-administration. Active lever presses during cocaine- (c) or sucrose-primed (d) reinstatement are shown. Significant differences are indicated for OT treatment (filled bar) compared with vehicle controls (open bar) (*P<.05) and cocaine compared with yoked-saline (†P<.05).
Figure 5.
Figure 5.
Oxytocin (OT) effects on phosphorylation of GluA1 at Ser845 (p-GluA1) protein levels after cocaine prime in multiple brain regions. Data (n=6–8/group) are shown for integrated density of p-GluA1 normalized with total GluA1 (t-GluA1) in prefrontal cortex (PFC) (a), bed nucleus of the stria terminalis (BNST) (b), amygdala (Amy) (c), and dorsal hippocampus (dHip) (d). Significant differences are indicated for OT treatment (filled bar) compared with vehicle controls (open bar) (*P<.05) and cocaine self-administration compared with yoked-saline (†P<.05).
Figure 6.
Figure 6.
Oxytocin (OT) effects on phospho-ERK-1/2 (p-ERK) protein levels after cocaine prime in multiple brain regions. Data (n=6–8/group) are shown for integrated density of p-ERK normalized with total ERK (t-ERK) in prefrontal cortex (PFC) (a), bed nucleus of the stria terminalis (BNST) (b), amygdala (Amy) (c), and dorsal hippocampus (dHip) (d). Significant differences are indicated for OT treatment (filled bar) compared with vehicle controls (open bar) (*P<.05) and cocaine self-administration compared with yoked-saline (†P<.05).
Figure 7.
Figure 7.
Oxytocin (OT) effects on physical interaction between OT receptors (OTRs) and GluA1 subunit in prefrontal cortex (PFC) (a) and dorsal hippocampus (dHip) (b). Data (n=4/group) are shown for integrated density of OTR normalized with total GluA1 (t-GluA1).
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