Oxytocin prevents detrimental cardiac effects of social isolation in monogamous prairie voles

1
Oxytocin prevents detrimental cardiac effects of
social isolation in monogamous prairie
voles Angela J. Grippo, Damon G. Lamb, Stephen W.
Porges, C. Sue Carter Dept. Psychiatry and
Brain-Body Center, Univ. of Illinois at Chicago
Introduction
Summary
Autonomic Blockade
Basal ECG Responses

• Social isolation (4 weeks) in female prairie
  voles induces
• Increased resting heart rate and decreased
  resting heart rate variability
• Increased heart rate reactivity to a novel
  social stressor (resident-intruder test)
• Reduced parasympathetic (vagal) regulation of
  the heart
• Anhedonia (reduced responsiveness to sucrose)
• Daily oxytocin administration during isolation (2
  weeks)
• Prevents the behavioral and cardiac disruptions
  in isolated animals
• Does not appear to affect the behavioral or
  cardiac responses of paired animals

Social isolation led to a reduction in cardiac
vagal tone and a slight change in sympathetic
tone these changes were prevented by oxytocin
administration in isolated animals (Figure 4).
Social isolation increased heart rate and reduced
heart rate variability long-term oxytocin
prevented these changes in isolated animals
(Figure 2).

• The prairie vole is a socially monogamous
  rodent species that engages in social
  interactions similar to humans, including living
  in family groups and forming adult pair bonds
  1. These animals also appear to exhibit a
  resting autonomic balance that mirrors that of
  humans, including a predominant parasympathetic
  influence regulating resting heart rate 2.
• This species provides a valuable model system
  for studying the role of the social environment
  in regulating behavior and cardiac function.
• Our previous research has demonstrated that
  social isolation in female prairie voles induces
  several functional cardiac alteration as well as
  depression-like behaviors 3. These changes
  suggest that negative social interactions in
  particular the disruption of social bonds and
  social isolation may play a role in the link
  between mood disorders and cardiovascular
  dysregulation.

A
C
B
A
B

• Hypothesis of the current study
• Long-term administration of oxytocin, a peptide
  involved in the regulation of social behavior,
  will prevent the detrimental cardiac and
  behavioral responses to the disruption of social
  bonds and social isolation in female prairie
  voles.

Conclusions
Figure 2. Mean ( SEM) heart rate (Panel A),
SDNN index (Panel B), and amplitude of RSA (Panel
C) in paired or isolated animals treated with
either daily oxytocin (OT 20 mg/50 ml/vole, sc)
or vehicle (V 50 ml/vole, sc). P lt 0.05 vs.
Paired V, Paired OT, and Isolated OT groups
at the same time point P lt 0.05 vs. respective
baseline value.

• The disruption of social bonds, including
  social isolation, induces behavioral and cardiac
  disruptions.
• The behavioral and cardiac responses to
  isolation are prevented by long-term exogenous
  oxytocin administration.
• Oxytocin may mediate cardiac and behavioral
  responses to negative social stressors and the
  disruption of established social bonds.
• The present results provide insight into
  peptide regulation of social behavior,
  depression-like signs, and cardiac function in
  females.

Figure 4. Mean ( SEM) heart rate prior to drug
administration and following atropine (4 mg/kg,
ip Panel A) and atenolol (8 mg/kg, ip Panel B)
in paired or isolated animals treated with either
daily oxytocin (OT 20 mg/50 ml/vole, sc) or
vehicle (V 50 ml/vole, sc). P lt 0.05 vs. Paired
V, Paired OT, and Isolated OT groups at the
same time point.
Procedures
Acute Stress Responses
Social Isolation and Oxytocin Administration
Behavioral Responses
Relative to paired animals, isolated animals
displayed an exaggerated tachycardic response
during and following a resident-intruder
stressor oxytocin administration prevented these
changes in isolated animals (Figure 3).

• Adult, female prairie voles (Figure 1) were
  either isolated from a same-sex sibling or
  remained paired (control conditions) for 4 weeks.
  
• During weeks 3 and 4 of the isolation period,
  paired and isolated animals were administered
  oxytocin (20 mg/50 ml/vole, sc) or vehicle (50
  ml/vole, sc) daily for 14 days.

Social isolation induced anhedonia (significant
reduction in consumption of 2 sucrose) oxytocin
prevented this depression-like behavior (Figure
5).
References
Figure 1. Two prairie voles.
1 Carter CS, DeVries AC, Getz L. Physiological
substrates of mammalian monogamy the prairie
vole model. Neurosci Biobehav Rev 19 303-314,
1995. 2 Grippo AJ, Lamb DG, Carter CS, Porges
SW. Cardiac regulation in the socially monogamous
prairie vole. Physiol Behav 90 386-393,
2007. 3 Grippo AJ, Lamb DG, Carter CS, Porges
SW. Social isolation disrupts autonomic
regulation of the heart and influences negative
affective behaviors. Biol Psychiatry, in press.

• Radiotelemetry Recordings and Measurement of
  Autonomic Variables
• Prior to isolation or pairing, radiotelemetry
  transmitters were implanted intraperitoneally
  into a subset of animals (n 13 paired and 13
  isolated) for the recording of electrocardiogram
  (ECG).
• Autonomic inputs to the heart were selectively
  blocked following 4 weeks of isolation or pairing
  using atenolol (8 mg/kg, ip) and atropine methyl
  nitrate (atropine 4 mg/kg, ip). ECG data were
  recorded continuously.
• Animals were exposed to a 5-minute
  resident-intruder test following 4 weeks of
  social isolation or pairing. ECG data were
  recorded continuously.
• Measurement of Depression-Like Behaviors
• Prior to isolation or pairing, a subset of
  animals (n 16 paired and 15 isolated) was
  adapted to the taste of 2 sucrose, and a
  baseline sucrose intake test was conducted.
• Sucrose intake was monitored again following 4
  weeks of social isolation or pairing in all
  animals.

• The authors would like to thank L. Sanzenbacher,
  P. Suppatkul, D. Trahanas, B. Zimmerman, and Data
  Sciences International for assistance
• Support MH73233 (AJG), MH72935 (CSC), MH67446
  (SWP), HD48390 (CSC)
• Contact Angela Grippo with comments or questions
  agrippo_at_psych.uic.edu

Figure 3. Mean ( SEM) heart rate prior to,
during, and following a 5-minute stressor
(resident-intruder test) in paired or isolated
animals treated with either daily oxytocin (OT
20 mg/50 ml/vole, sc) or vehicle (V 50 ml/vole,
sc), versus baseline (pre-isolation) heart rate.
P lt 0.05 vs. Paired V, Paired OT, and
Isolated OT groups at the same time point.
Figure 5. Mean ( SEM) intake of 2 sucrose at
baseline and following 4 weeks of isolation or
pairing in prairie voles treated with either
daily oxytocin (OT 20 mg/50 ml/vole, sc) or
vehicle (V 50 ml/vole, sc). P lt 0.05 vs.
Paired V, Paired OT, and Isolated OT groups.