Development of cocaine sensitization before pregnancy affects subsequent maternal retrieval of pups and prefrontal cortical activity during nursing

doi:10.1016/j.neuroscience.2007.05.026

Neuroscience

Volume 148, Issue 2, 24 August 2007, Pages 400-412

https://doi.org/10.1016/j.neuroscience.2007.05.026 Get rights and content

Abstract

Pups are a highly rewarding stimulus for early postpartum rats. Our previous work supports this notion by showing that suckling activates the mesocorticolimbic system in mothers. In the present study, we tested whether development of behavioral sensitization to cocaine before pregnancy affects the neural response to pups during the early postpartum days (PD). Virgin rats were repeatedly administered cocaine for 14 days (15 mg kg⁻¹) and withdrawn from treatment during breeding and pregnancy. The neural response to suckling was measured at PD 4–8 using blood-oxygen-level-dependent (BOLD) MRI or microdialysis. Our results show that BOLD activation in the medial prefrontal cortex (PFC), septum and auditory cortex was curtailed in cocaine-sensitized dams. No differences between cocaine sensitized and saline control dams were observed in the nucleus accumbens, olfactory structures, or in 48 additional major brain regions that were analyzed. Baseline, but not pup-stimulated, dopamine (DA) levels in the medial PFC were lower in cocaine-sensitized dams than in controls. When tested for maternal behaviors, cocaine-sensitized dams showed significantly faster retrieval of pups without changes in other maternal behaviors such as grouping, crouching and defending the nest. Taken together, the present findings suggest that maternal motivation to retrieve pups was enhanced by repeated cocaine exposure and withdrawal, a result reminiscent of ‘cross-sensitization’ between the drug and a natural reward. Changes in retrieval behavior in cocaine-sensitized mothers might be associated with a hypo-responsive medial PFC.

Section snippets

Animals

Adult Sprague–Dawley females were purchased from Charles River Laboratories (Charles River, MA, USA). Virgin rats were bred in the animal resource facilities of the University of Massachusetts Medical School. Dams were housed with their litters in a temperature- and humidity-controlled room, under a 12-h light/dark cycle with lights off at 18:00 h. Water and Purina rat chow (Harlan, Boston, MA, USA) were provided ad libitum. Animals were acquired and cared for in accordance with the guidelines

Cocaine-induced behavioral sensitization

Prior to cocaine administration on days 1 through 14, all animals displayed in place activities or were in a normal, alert state (categories 3 and 4 of the Ellinwood and Balster rating scale). As shown in Fig. 1B, repeated cocaine administration across 14 days resulted in behavioral sensitization. On day 1, cocaine administration resulted in normal, alert activity, hyperactivity and slow patterned exploration of the testing cages (median category 6, ranging from 4 to 7), while saline-injected

Discussion

The present study provides evidence that development of behavioral sensitization to cocaine before pregnancy alters maternal retrieval during the early postpartum period. Under similar testing conditions, cocaine pre-exposed females displayed shorter latency to obtain pups than control mothers, in a manner suggestive of increased sensitization to pups. Interestingly, the faster retrieval behavior was not accompanied by alterations in other maternal behaviors, such as grouping, hovering over

Conclusions

Repeatedly treating female rats with cocaine prior to pregnancy had lasting effects on medial PFC activation during nursing and altered maternal retrieval behavior. In addition to differential BOLD responses in the medial PFC, we also observed that the auditory cortical and septal neural response followed along the same lines, a reduced activation in cocaine-experienced dams. The findings of the auditory cortex may have an important functional basis since this area has been studied for its role

Acknowledgments

The authors thank Ms. Tara Messenger-Stolberg for her excellent technical assistance through the course of the study. This work was supported by grants from the National Institute on Drug Abuse to C. F. Ferris (DA13517) and M. Febo (DA019946).

References (63)

C.E. Beyer et al.
Dopamine depletion in the medial prefrontal cortex induces sensitized-like behavioral and neurochemical responses to cocaine
Brain Res
(1999)
O.J. Bosch et al.
Release of oxytocin in the hypothalamic paraventricular nucleus, but not central amygdala or lateral septum in lactating residents and virgin intruders during maternal defence
Neuroscience
(2004)
K.D. Broad et al.
Involvement of the medial prefrontal cortex in mediating behavioural responses to odour cues rather than olfactory recognition memory
Neuroscience
(2002)
S.M. Coyer
Mothers recovering from cocaine addiction: factors affecting parenting skills
J Obstet Gynecol Neonatal Nurs
(2001)
E.H. Ellinwood et al.
Rating the behavioral effects of amphetamine
Eur J Pharmacol
(1974)
C.R. Genovese et al.
Thresholding of statistical maps in functional neuroimaging using the false discovery rate
Neuroimage
(2002)
S. Hansen
Maternal behavior of female rats with 6-OHDA lesions in the ventral striatum: characterization of the pup retrieval deficit
Physiol Behav
(1994)
S. Hansen et al.
Interaction with pups enhances dopamine release in the ventral striatum of maternal rats: a microdialysis study
Pharmacol Biochem Behav
(1993)
A.L. Harmer et al.
Influence of negative childhood experiences on psychological functioning, social support, and parenting for mothers recovering from addiction
Child Abuse Negl
(1999)
M. Hernandez-Gonzalez et al.
Electrical activity of prefrontal cortex and ventral tegmental area during rat maternal behavior
Behav Processes
(2005)

S.E. Keer et al.

Dopamine receptor blockade in the nucleus accumbens inhibits maternal retrieval and licking, but enhances nursing behavior in lactating rats

Physiol Behav

(1999)

J.A. King et al.

Procedure for minimizing stress for fMRI studies in conscious rats

J Neurosci Methods

(2005)

C.H. Kinsley et al.

Cocaine alters the onset and maintenance of maternal behavior in lactating rats

Pharmacol Biochem Behav

(1994)

A. Lee et al.

Mother rats bar-press for pups: effects of lesions of the MPOA and limbic sites on maternal behavior and operant responding for pup-reinforcement

Behav Brain Res

(1999)

J.P. Lorberbaum et al.

A potential role for thalamocingulate circuitry in human maternal behavior

Biol Psychiatry

(2002)

B.J. Mattson et al.

Preference for cocaine- versus pup-associated cues differentially activates neurons expressing either Fos or cocaine- and amphetamine-regulated transcript in lactating, maternal rodents

Neuroscience

(2005)

P. Nair et al.

Risk factors for disruption in primary caregiving among infants of substance abusing women

Child Abuse Negl

(1997)

J.B. Nitschke et al.

Orbitofrontal cortex tracks positive mood in mothers viewing pictures of their newborn infants

Neuroimage

(2004)

M. Numan et al.

Medial preoptic area interactions with the nucleus accumbens-ventral pallidum circuit and maternal behavior in rats

Behav Brain Res

(2005)

R.E. See et al.

Chronic haloperidol-induced changes in regional dopamine release and metabolism and neurotensin content in rats

Brain Res

(1995)

H. Simon et al.

Deficits in spatial-memory tasks following lesions of septal dopaminergic terminals in the rat

Behav Brain Res

(1986)

J.M. Stern et al.

Maternal motivation of lactating rats is disrupted by low dosages of haloperidol

Behav Brain Res

(1999)

J.P. Strupp

Stimulate: A GUI based fMRI analysis software package

Neuroimage

(1996)

J.M. Williams et al.

Time-dependent effects of repeated cocaine administration on dopamine transmission in the medial prefrontal cortex

Neuropharmacology

(2005)

L.H. Amir et al.

Does maternal smoking have a negative physiological effect on breastfeeding?The epidemiological evidence

Birth

(2002)

L.M. Bjursten et al.

Behavioural repertory of cats without cerebral cortex from infancy

Exp Brain Res

(1976)

O.J. Bosch et al.

Brain oxytocin correlates with maternal aggression: link to anxiety

J Neurosci

(2005)

R. Bridges et al.

Differences in maternal responsiveness between lactating and sensitized rats

Dev Psychobiol

(1972)

R.S. Bridges

A quantitative analysis of the roles of dosage, sequence, and duration of estradiol and progesterone exposure in the regulation of maternal behavior in the rat

Endocrinology

(1984)

S.M. Coyer

Women in recovery discuss parenting while addicted to cocaine

MCN Am J Matern Child Nurs

(2003)

A. Devor et al.

Suppressed neuronal activity and concurrent arteriolar vasoconstriction may explain negative blood oxygenation level-dependent signal

J Neurosci

(2007)

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Citation Excerpt :
These cited results, along with our imaging findings cited above point to an interesting relation between prefrontal cortical neurotransmission and maternal behavior. Rats showing high rates of retrieval show low BOLD signal and low basal dopamine in the medial PFC (Febo and Ferris, 2007). Neuronal activity in mPFC is important for maternal retrieval and high GABA receptor stimulation in the mPFC reduces maternal behavior (Febo et al., 2010).
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Behavioural neuroscienceDevelopment of cocaine sensitization before pregnancy affects subsequent maternal retrieval of pups and prefrontal cortical activity during nursing

Abstract

Section snippets

Animals

Cocaine-induced behavioral sensitization

Discussion

Conclusions

Acknowledgments

Brain Res

Neuroscience

Neuroscience

J Obstet Gynecol Neonatal Nurs

Eur J Pharmacol

Neuroimage

Physiol Behav

Pharmacol Biochem Behav

Child Abuse Negl

Behav Processes

Physiol Behav

J Neurosci Methods

Pharmacol Biochem Behav

Behav Brain Res

Biol Psychiatry

Neuroscience

Child Abuse Negl

Neuroimage

Behav Brain Res

Brain Res

Behav Brain Res

Behav Brain Res

Neuroimage

Neuropharmacology

Does maternal smoking have a negative physiological effect on breastfeeding?The epidemiological evidence

Birth

Behavioural repertory of cats without cerebral cortex from infancy

Exp Brain Res

Brain oxytocin correlates with maternal aggression: link to anxiety

J Neurosci

Differences in maternal responsiveness between lactating and sensitized rats

Dev Psychobiol

A quantitative analysis of the roles of dosage, sequence, and duration of estradiol and progesterone exposure in the regulation of maternal behavior in the rat

Endocrinology

Women in recovery discuss parenting while addicted to cocaine

MCN Am J Matern Child Nurs

Suppressed neuronal activity and concurrent arteriolar vasoconstriction may explain negative blood oxygenation level-dependent signal

J Neurosci

Behavioural neuroscience
Development of cocaine sensitization before pregnancy affects subsequent maternal retrieval of pups and prefrontal cortical activity during nursing