In this paper, we will outline the evidence from preclinical and human studies to address the following propositions outlined in Figure ​Figure1:1: (a) addictive processes are a reflection of a dysregulation of the balance between reward systems and the stress response; (b) parenting involves a special adaptation of both reward and stress regulatory neural systems to the relevant cues from offspring that become highly salient for the adult, now a parent; and (c) in the addictive situation, parenting cues are not rewarding but instead stressful. This heightened stress response may promote drug-seeking behaviors rather than parenting behaviors and attending to the infant’s needs. We focus on cocaine addiction to explore the evidence for this model.

In human studies, the consequences of cocaine exposure and administration on parenting have been explored primarily through observations of mother–child interactions. Within 12–48h postpartum, mothers who used cocaine during pregnancy responded more passively and were more disengaged from their newborn compared to mothers who were drug-free (Gottwald and Thurman, 1994). Early work with infants suggested that mothers using cocaine during pregnancy evidence reduced expression of positive affect and sensitivity to infant cues, as well as poorer creativity and resourcefulness during dyadic interactions (Burns et al., 1991, 1997). There is some evidence to suggest that while early impairments (e.g., reduced attention toward the infant, shifts in attention away from the infant) in mother–child interactions appear modulated by prenatal cocaine exposure, follow up assessments have shown either a reduction (Mayes et al., 1997) or absence of these same dysfunctions (Ball et al., 1997) suggesting the effects of cocaine exposure may change over time. This has prompted studies to explore the effects of prenatal cocaine exposure on maternal interactions in toddlers too, evidencing maladaptive and hostile interactions of dyads with cocaine exposure (Johnson et al., 2002; Uhlhorn et al., 2005; Molitor and Mayes, 2010). The consequences of cocaine use during pregnancy have also been explored during feeding episodes. Poorer feeding interactions were reported in mothers who used cocaine during pregnancy and who relapsed postpartum, compared to mothers who had not relapsed (Blackwell et al., 1998). These feeding dyads demonstrated greater conflict (Eiden, 2001) as well as insensitivity (Eiden et al., 2006) between mother and child. It is important to note that impairments in mother–child interactions may also be related to the amount of cocaine consumed during pregnancy (Tronick et al., 2005), as well as postpartum use (Blackwell et al., 1998; Johnson et al., 2002; Eiden et al., 2006). Although to date there are no published neuroimaging studies in cocaine addicted mothers, initial pilot work suggests differential prefrontal cortex (PFC) activation when viewing infant faces in these women compared to mothers with no cocaine use history (Strathearn and Kosten, 2008).

Studies on mother–infant dynamics in the rodent have shown that exposure to cocaine, through acute, intermittent, or chronic treatment regimens, disrupts aspects of MB, with the extent of disruption dependent on dose, duration, time of testing, and treatment regimen (Johns et al., 1994; Nelson et al., 1998). In one commonly used paradigm, dams receive cocaine either chronically on gestation days (GD 1–20; 30mg/kg) or via single injections during the postpartum period, and are then tested for pup-directed MB following separation and reunion with pups. Either regimen can lead to increased latency and decreased duration of nursing, along with disruptions in licking and nest-building. Cocaine treated dams also exhibit maladaptive maternal aggressive behavior, indicating that social behavior deficits may extend past pup relationships (Johns et al., 1997b; McMurray et al., 2008).These disruptions are not caused by hyperactivity or cocaine withdrawal (Johns et al., 1997b), suggesting instead alterations in motivational or social interaction circuitry.

In contrast to treatment during gestation, repeated exposure to cocaine before pregnancy increases retrieval and licking behaviors in rats and mice early postpartum, suggesting that adult cocaine exposure alters motivational salience and behavior toward later, naturally rewarding stimuli, such as pups (Nephew and Febo, 2010). However, although these mothers were quicker to retrieve pups, they took longer to initiate other MBs, suggesting that the salience may be in having the pup nearby but not in the act of caring for it. Functional magnetic resonance imaging (fMRI) in awake animals has allowed investigation of the activation of brain regions following exposure to rewarding stimuli. Indeed, cocaine pre-exposure also diminished the activation to pup suckling in the medial prefrontal cortex (mPFC), striatum, and auditory cortex, but did not affect baseline dopamine (DA) or percent increase of DA upon exposure to pups in the mPFC (Febo and Ferris, 2007), supporting the important roles in MB and addiction processes these regions hold, a point we will return to later in this review.

Taken together, these findings indicate that cocaine use before, during, and/or after pregnancy can significantly alter MB in the postpartum period. Since MB is not entirely abolished, we propose that these behavioral changes may indicate differences in the reward salience of offspring. Additionally, the transition from pregnancy to the postpartum is inherently stressful to mothers; however, the successful adaptation to this new environment may be considered under the control of allostatic mechanisms. Allostasis has been defined as the active process of responding to challenges from the environment to maintain homeostasis, usually through activation of hormonal stress responses. Successful adaptation to this stressful environment and the ability to respond appropriately to an infant’s needs is critical for the infant’s survival and thus has been conserved throughout mammalian evolution. It has been proposed that drug addiction can disrupt typical adaptation to stressful non-parenting environments (Le Moal, 2009); however, whether the same is true for the postpartum period remains unclear and offers a potential explanation for the drug-induced deficits described above. The review presented here considers the involvement of neural structures in both the reward and stress systems in parenting (outlined in Figure ​Figure22).

Multiple reviews of reward circuitry have proposed that DA has a prominent role in drug reward and that the “reward circuit,” as presented in Figure ​Figure4,4, consists of a midbrain–forebrain pathway that connects the VTA with the NAc and mPFC, with information converging in the NAc to drive locomotor responses toward reward seeking (Koob and Volkow, 2010; Sesack and Grace, 2010). Widespread use of fMRI has also enabled reward circuitry in humans to be investigated, with comparable regions identified, including the orbitofrontal cortex (OFC), amygdala, NAc, as well as the PFC and anterior cingulate cortex (ACC; McClure et al., 2004). A growing literature is emerging that dissects reward-seeking behaviors into independent cognitive processes: “wanting,” “liking,” and “learning” (Berridge, 2004; Berridge et al., 2009). Liking is defined as the neural reaction underlying sensory pleasure-triggered by immediate receipt of reward. In contrast, “wanting” is defined as the motivational incentive value of the same reward. It has been postulated that dopaminergic signaling described above (VTA/Nac/mPFC) is most important for the “wanting” aspects of behavior. This theory may help explain why, although certain aspects of maternal care are unlikely to have high hedonic impact (i.e., initial nursing, maternal aggression, sleep interruption), mothers still “want” to provide maternal care.

At a neurobiological level, the relationship between parenting, addiction, and stress is in its infancy. However, substance use has been well associated with stress-related symptomatology (Sinha, 2001), and early on stress has been highlighted as modulating parenting behavior (Webster-Stratton, 1990). Increasing levels of stress in parenting are believed to be related to insufficient resources (e.g., income, emotional stability) to manage the demands of caring for a child, and that this is enhanced in addicted mothers, who report higher levels of stress than non-substance using mothers (Kelley, 1998). This data suggests that addicted mothers may exhibit a maladaptive shift in allostasic control of stress during the postpartum period. Additional research has evidenced parenting stress as an important mediator to maternal risk factors and their impact on parenting behavior (Suchman and Luthar, 2001). These initial studies support the notion of parenting as a stressor, and we will now consider the relationship between stress and craving which is integral to our model.

Accumulating evidence has shown that individuals with more intense craving when exposed to stress are more likely to relapse, and that drug use affords one means of stress regulation, albeit a maladaptive, self-perpetuating one (Sinha and Li, 2007). In these studies, participants are exposed to an interpersonal stressor and changes in the hemodynamic response are then compared to exposure to a neutral non-stressor condition. In non-substance using individuals, exposure to stress has been shown to increase the hemodynamic response in (1) frontal regions, including the right mPFC and ventral ACC; and (2) limbic and midbrain regions, including the posterior cingulate, left striatum, thalamus, bilateral caudate and putamen, and left hippocampal and parahippocampal regions (Sinha et al., 2004). Further work by the same research group (Sinha et al., 2005) demonstrated that while some changes in the hemodynamic response are common in normal individuals and cocaine-dependent subjects, healthy controls show increased activity in the ACC, while cocaine-dependent participants instead have a decrease in activity in this same region that extended into the lateral frontal cortex. The authors interpret this difference in ACC functioning in relation to differences in emotion regulation and cognitive control between the two groups and the relationship of these functions to addictive behaviors. Replicating their earlier finding, stress exposure increased activity in hippocampal and parahippocampal regions in healthy controls, but this response was absent in cocaine-dependent participants, who instead showed an increased response in the bilateral dorsal striatum and caudate region. Activity in this latter region positively correlated with self-report craving scores, consistent with this structure’s role in addiction. Increasing activity in the right dorsolateral PFC, as well as the left posterior insular and superior temporal sulcus, also correlated with increasing scores on self-report of craving and distress in cocaine-dependent participants. The implications of these findings are that, while addiction modulates the stress response, this modulation of activity correlates with self-reports of drug craving, suggesting a putative link between craving, stress, and addiction. This is further emphasized by finding that increasing activity in regions including the medial PFC, following stress induction, predicts time to relapse, correlating with amount of drug use on each occasion, as well as the number of days drug use has occurred following relapse (Sinha and Li, 2007). A wealth of literature, too large to detail here, has begun to discover the molecular mechanisms and brain activation patterns of similar stress-induced relapse behaviors in animal models. Important to our hypotheses are data suggesting that DA and CRF are critical signaling molecules in the VTA, extended amygdala, and PFC (Erb, 2010; Van den Oever et al., 2010; Wise and Morales, 2010), as well as being associated with alterations in allostatic load.