Environmental regulation of the development of mesolimbic dopamine systems: a neurobiological mechanism for vulnerability to drug abuse?

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1 Psychoneuroendocrinology 27 (2002) Environmental regulation of the development of mesolimbic dopamine systems: a neurobiological mechanism for vulnerability to drug abuse? Michael J. Meaney *, Wayne Brake, Alain Gratton McGill Centre for the Study of Behavior, Genes and Environment, Douglas Hospital Research Centre, McGill University, 6875 Boul LaSalle, Montreal, Que. H4H 1R3, Canada Abstract Repeated periods of maternal separation in the early life of rats decreased dopamine transporter expression and significantly increased dopamine responses to stress, and behavioral responses to either stress or cocaine. As adults, maternal separation animals showed increased sensitivity to the effects of cocaine on locomotor activity and greater sensitivity to stressinduced sensitization to the effects of amphetamine on locomotor activity. These findings raise the possibility that in addition to effects on stress reactivity, early life events might dispose individuals to illness in later life through effects on very specific neurotransmitter systems Published by Elsevier Science Ltd. Keywords: Maternal separation; Dopamine; Dopamine transporter; Cocaine; Stress 1. Introduction The relationship between early life events and health in adulthood appears to be mediated by parental influences on the development of neural systems which underlie the expression of behavioral and endocrine responses to stress (Nemeroff, 1996; Sroufe, 1997; Francis and Meaney, 1999). There are two critical assumptions here; first, that prolonged activation of neural and hormonal responses to stress can pro- * Corresponding author: Tel.: x3938; fax: address: michael.meaney@mcgill.ca (M.J. Meaney) /01/$ - see front matter 2001 Published by Elsevier Science Ltd. PII: S (01)

2 128 M.J. Meaney et al. / Psychoneuroendocrinology 27 (2002) mote illness, and second that early environmental events influence the development of these responses. There is strong evidence in favor of both ideas. While the activation of central corticotropin-releasing factor (CRF), adrenal glucocorticoid and peripheral catecholamine systems is essential for survival under conditions of stress, prolonged exposure to these substances results in decreased sensitivity to insulin and a risk of steroid-induced diabetes, hypertension, hyperlipidemia, arterial disease, and the impairment of growth and tissue repair, and immunosuppression (McEwen, 1998). Chronic activation of central CRF systems also results in persistent activation of central serotonin and noradrenaline systems, and thus an increased risk of anxiety and depression (Nemeroff, 1996). Early life events influence the development of neuroendocrine and behavioral responses to stress, and not surprisingly, central CRF systems are a critical target for these effects. Hypothalamic CRF neurons in the parvocellular region of the paraventricular nucleus of the hypothalamus (PVNh) regulate the release of adrenocorticotropin (ACTH) from the pituitary which, in turn, stimulates the release of adrenal glucocorticoids (Plotsky, 1991). CRF neurons in the central nucleus of the amygdala (CnAmy) project to, and increase the firing rate of, neurons in the locus coeruleus as well as neighboring noradrenergic regions resulting in increased release of noradrenaline. The amygdaloid CRF activation of the noradrenergic neurons of the locus coeruleus is critical for the expression of behavioral responses to stress (Bakshi et al., 2000; Koob et al., 1994; Nemeroff, 1996; Page and Valentino, 1994). Hence, the CRF neurons in the PVNh and the CnAmy serve as important mediators of both behavioral and endocrine responses to stress. In humans, physical and/or sexual abuse in early life, for example, increases endocrine and autonomic responses to stress in adulthood (DeBellis et al., 1994; Heim et al., 1997). These findings suggest that early life events can exert a sustained influence over neural systems that mediated stress reactivity. There is considerable evidence from studies with non-human species in support of this idea. Repeated and prolonged periods of maternal separation in neonatal rats alters the development of central CRF systems. As adults, maternal separation animals show increased fearfulness in the face of novelty (Caldji et al., 2000) and exaggerated HPA responses to stress (Liu et al., 2000; Plotsky and Meaney, 1993). These effects are associated with increased resting-state CRF mrna expression in the PVNh and CnAmy, increased levels of CRF-like immunoreactivity in the locus coeruleus (Ladd et al., 2000; Plotsky and Meaney, 1993; Viau et al., 1993), and increased CRF receptor levels in the locus coeruleus and the raphé nuclei (Ladd et al. 1996, 2000). Maternal separation also alters systems which regulate CRF synthesis. The expression of CRF in PVNh neurons is subject to inhibitory regulation via glucocorticoid negative feedback. Maternal separation rats show decreased negative feedback sensitivity to glucocorticoids (Ladd et al., 2000) that is accompanied by decreased glucocorticoid receptor expression in the hippocampus and frontal cortex, regions which are known to mediate the inhibitory effects of glucocorticoid of CRF synthesis in PVNh neurons (Dallman et al., 1994; DeKloet, 1991; Diorio et al., 1993). Maternal separation rats also show decreased GABAA receptor levels in the noradrenergic cell body regions of the locus coeruleus as well as decreased central benzodiazepine

3 M.J. Meaney et al. / Psychoneuroendocrinology 27 (2002) (CBZ) receptor levels in the lateral and central nucleus of the amygdala, and in the locus coeruleus (Caldji et al., 2000). The GABA/BZ system serves to inhibit CRF synthesis in the CnAmy and to reduce noradrenergic responses to stress. Interestingly, postnatal handling produces exactly the opposite effects on behavioral and endocrine responses to stress and the effect of handling on each of the measures listed above is, likewise, the opposite to that of maternal separation. These findings provide models for the study of the early environmental regulation of individual differences in stress reactivity. More recent findings suggest that there may also be effects on selected neurotransmitter systems. 2. The effects of maternal separation 2.1. Locomotor activity Perhaps the most reliable measure of behavioral differences associated with rearing condition is that of behavior under conditions of novelty. In the open-field test, where behavior is usually studied for only 5 10 min, handled (H) animals are generally more active within the first minutes of the test. During this time H animals actively explore, whereas nonhandled (NH) or MS rats often either freeze, or scurry about the walls. After about 5 min, the NH and MS rats become more active and thus if the test is run for about 20 min or more, the overall level of locomotor activity is significantly higher in the NH and MS rats. Thus, NH and MS rats are significantly more active than H animals when confined within a novel environment for an extended period. Among adult rats, animals which show the highest level of locomotor activity over longer periods of time in a novel test setting (so-called high responders, HR) also show the highest propensity for amphetamine self-administration (Piazza et al., 1989). The HR animals show a faster acquisition of drug self-administration and an upward shift of the dose response curve, suggesting greater sensitivity to psychostimulants (Piazza et al., 1989; Piazza and LeMoal, 1996). Indeed, HR also show a higher level of nucleus accumbens (NAcc) dopamine (DA) levels in response to amphetamine (Hooks et al., 1992). Thus, variations in activity levels under conditions of novelty have been found to predict individual differences in behavioral responses to psychostimulants. Animals showing increased novelty-induced total locomotor activity, like that seen in NH and MS rats, exhibit increased NAcc DA responses to amphetamine (Piazza et al., 1991) Stress-induced sensitization One of the most insidious features of chronic stress is that it tends to enhance the magnitude of responses to subsequent presentations of either the same (Kalivas and Stewart, 1991) or novel stressors (Dallman et al., 1994). In the HPA literature this effect is referred to as facilitation while a comparable process in neurochemical studies is called sensitization (Kalivas and Stewart, 1991). In both areas there is

4 130 M.J. Meaney et al. / Psychoneuroendocrinology 27 (2002) evidence that exposure to a stressor potently enhances responses to a novel form of stress. These effects appear to mimic processes involved in drug-induced sensitization, where repeated administration of a psychostimulant, such as amphetamine, enhances the drug s stimulant action on locomotor activity as well as on NAcc DA transmission (Robinson and Becker, 1986). Cross-sensitization occurs between stress and drugs; repeated exposure to stress enhances behavioral responses not only to subsequent stress but also to drugs of abuse (Robinson and Becker, 1986; Sorg and Kalivas, 1991; Stewart and Badiani, 1993). Furthermore, behavioral sensitization to stress and drugs is associated with augmented NAcc DA release (Doherty and Gratton, 1992; Kalivas and Stewart, 1991). We examined sensitization of locomotor activity to repeated, once daily, amphetamine administration in H, NH and MS animals. Animals from each group were injected at the beginning of each of five daily sessions either with d-amphetamine sulfate or saline vehicle, while another group was simply placed in the locomotor chambers for 3 h on each of the five test days. One week after the 5th pretreatment day, the spontaneous locomotor activity of all animals was monitored for 3 h before receiving a challenge drug injection (d-amphetamine, 0.5 mg/kg IP) on the following day after which locomotor activity was monitored for 3 h. The difference in locomotor activity in response to the amphetamine challenge between the amphetamineand saline-pretreatment groups defines the sensitization effect. There were no differences in the acute locomotor response to amphetamine challenge of H, NH and MS animals pre-treated with amphetamine. Likewise, levels of locomotor activity among groups were comparable in the no-pretreatment condition. However, the locomotor activity of the saline-treated, MS animals was significantly elevated following the amphetamine challenge (P 0.001) (Fig. 1). All these animals had been habituated to the testing environment such that on the final two days of habituation there were no group differences in locomotor activity. These findings suggest that the MS animals were more sensitive to the stress of an IP saline injection. The amphetamine challenge test provided evidence for this idea. The locomotor response to the amphetamine challenge injection did not differ across the H, NH and MS groups of amphetamine-pretreated animals suggesting that animals from all three rearing conditions had sensitized to the drug (i.e. the difference in locomotor activity between the amphetamine-pretreatment group and the no-pretreatment group was comparable for H, NH and MS animals). However, the locomotor response of saline-treated MS animals to amphetamine was actually comparable to that of animals that had received repeated amphetamine injection. Among H and NH rats, there was no difference in the locomotor activity of saline-pretreatment and no-pretreatment groups. Thus, MS animals became sensitized to amphetamine following repeated saline administration. The most obvious explanation for this finding is that the stress associated with each saline injection was sufficient to sensitize MS animals to the effects of the amphetamine challenge. This conclusion is supported by the fact that none of the three groups of animals with no pretreatment history differed in their response to the amphetamine challenge. Also, a large body of evidence shows that the behavioral effects of stress will cross-sensitize with those of stimulants. These find-

5 M.J. Meaney et al. / Psychoneuroendocrinology 27 (2002) Fig. 1. The bars represent locomotor activity, measured by photobeam interruptions (mean+sem), following an amphetamine challenge 1 week after pretreatment with either amphetamine, saline, or no treatment in rats that were maternally separated (MS), handled (H), or non-handled (NH). **P 0.001, saline pre-treatment, MS vs. H and NH. ings are also consistent with the increased stress reactivity previously observed in adult, MS animals Development of mesencephalic DA systems Stress- and amphetamine-induced sensitization of locomotor behavior is associated with activation of the mesocorticolimbic DA systems (Kalivas, 1993). Acute stress or psychostimulant drug administration increases extracellular DA levels in the NAcc. Repeated exposure to the stressor or drug, increases both the magnitude and the duration of NAcc DA responses to psychostimulants (Doherty and Gratton, 1992; Kalivas, 1993; Kalivas and Stewart, 1991), reflecting cross-sensitization within the mesolimbic DA system. Hence, the sensitization of mesolimbic DA responses maps onto changes observed for locomotor activity. D 1 receptors appear to be involved in the development of sensitization (Stewart and Vezina, 1989). However, we found no group differences in D 1 receptor binding in the medial prefrontal cortex (PFC) or the NAcc, nor in D 2 receptor binding in corticolimbic structures known to mediate the effects of stress or psychostimulants on locomotor activity. Likewise, Mathews et al. (1999) found no effects of repeated maternal separation on either D 1 or D 2 receptor sensitivity. In contrast with these findings, we found a striking difference in levels of DA transporter binding in receptor autoradiography studies (with either [3H]BTCP or [3H]WIN as radioligands). DA transporter levels in the NAcc were 250% higher in both H and NH than MS

6 132 M.J. Meaney et al. / Psychoneuroendocrinology 27 (2002) animals in NAcc (P 0.001) and almost twice as great in the caudate/putamen (P 0.01) (Fig. 2). There were no differences among the groups in DA transporter mrna in the frontal cortex or ventral tegmental area (VTA). DA transmission is regulated by the clearance of DA from the synapse through reuptake and degradation. DA reuptake occurs via the DA transporter system. Thus, DA transmission is highly sensitive to changes in DA transporter density or kinetics. Cocaine and amphetamine act on the transporter mechanism responsible for the release of DA and its subsequent reuptake, producing elevations in extracellular DA by inhibiting DA reuptake. In fact, cocaine causes reductions in spontaneous DA cell firing partly as a result of elevating DA levels at somatodendritic impulse-regulating autoreceptors (Bradberry and Roth, 1989; Kalivas and Duffy, 1991). One consequence of this action would be decreased DA efflux from terminals. Thus, the main effect of cocaine is to prolong the extrasynaptic life of whatever DA was released by another source of activation. Thus, we found that DA responses in the NAcc to acute stress (tail pinch) were significantly elevated in the MS rats. This finding is consistent with a previous microdialysis study (Hall et al., 1990) showing increased DA responses in the NAcc in MS rats in response to either amphetamine or K+ administration Responses to psychostimulants The next question concerns the functional significance of these differences. The decrease in NAcc DA transporter levels of MS rats suggests a greater responsivity Fig. 2. Mean±SEM levels of the dopamine transporter in adult handled (H), nonhandled (NH) and maternal separation (MS) animals measured using in vitro receptor autoradiography with [3H]BTCP as the radioligand in various brain regions. VTA, ventral tegmental area. *P 0.01, **P

7 M.J. Meaney et al. / Psychoneuroendocrinology 27 (2002) to transporter blockers, such as cocaine. The logic here is simply that higher concentrations of the blocker would be required to affect extracellular DA levels in H animals, endowed with a greater density of transporter sites. Conversely the lower levels of DA transporter in the MS and NH rats suggest that the effects of cocaine on DA transmission should occur at lower doses. In order to test this idea we performed a dose response study using cocaine (0 to 20 mg/kg) and examined locomotor activity. In NH and MS rats, 50% maximal responses (as defined by the effect of the 20 mg/kg dose on locomotor activity) were achieved at doses between 5 and 10 mg/kg. In contrast, even the 10 mg/kg dose of cocaine had no effect on locomotor activity on the H rats, where significant increases in activity were observed only at the 20 mg/kg dose. These findings suggest a dose response shift to the left in the NH and MS rats, consistent with the reduced level of DA transporter binding. Indeed, even at the 20 mg/kg dose, the maximal response level, the effect on the H animals was significantly reduced (in post-hoc analysis, P 0.05) by comparison to both the NH and MS rats. These data are consistent with the idea that the lower density of NAcc DA transporter sites renders the NH and MS rats hypersensitive to the effects of cocaine. Taken together, these findings suggest that early life events can permanently alter mesolimbic DA responses to stress as well as to psychostimulant drugs. These findings might serve to contribute to our understanding of the neurobiological basis for individual differences in vulnerability to drug abuse (Fig. 3). Fig. 3. Mean±SEM level of locomotor activity following the administration of one of various doses of cocaine in adult handled (H), nonhandled (NH), and maternal separation (MS) animals. The data are plotted as a function of the percent of baseline activity. Note, in particular, the absence of any increase in locomotor activity in the H animals at the 10 mg/kg dose.

8 134 M.J. Meaney et al. / Psychoneuroendocrinology 27 (2002) Conclusions 3.1. Neurophysiological model We propose that these effects occur as a result of both specific and non-specific mechanisms (see Fig. 4). Specific mechanisms involve the development of the DA transporter system as well as interactions between mesolimbic and mesocortical DA systems. Nonsspecific mechanisms affect the HPA axis. Another focus here is on the inhibitory role of the medial prefrontal cortex (PFC) over DA responses at the level of the NAcc. The indirect effects focus on MS-induced changes in the development of HPA responses to stress. Maternal separation results in increased HPA responsivity to stress, and thus increased adrenal glucocorticoid release during stress and, in turn, glucocorticoids seem to regulate mesolimbic DA systems. Psychostimulant self-administration has been linked to DA release in the NAcc. Both acute and repeated stress increase DA release in the NAcc. These effects are dependent upon adrenal glucocorticoid levels (Piazza and LeMoal, 1996). Glucocorticoid administration increases DA release in the NAcc, while adrenalectomy has the opposite effect. Moreover, adrenalectomy reduces stress-induced increases in NAcc DA levels. Precisely the same findings emerge using measures of stress-induced sensitization of locomotor responses. These glucocorticoid DA interactions are functionally sig- Fig. 4. A schema outlining the relevant targets for the effects of neonatal maternal separation on dopamine release at the level of the nucleus accumbens (NAcc) involving mesolimbic projections from the ventral tegmental area (VTA). The effects of maternal separation are both specific to the ascending dopamine systems (the effect of dopamine transporter (DAT) levels) and non-specific, involving alterations in CRF expression at the level of the paraventricular nucleus of the hypothalamus and subsequent differences in pituitary ACTH and adrenal glucocorticoid (GC) release. It is assumed that this very simple model will become substantially more complex and sophisticated as further studies on mechanisms are completed. One particular focus is that of the mechanisms by which GCs alter extracellular dopamine levels in the NAcc. Since mesencephalic dopamine neurons express GC receptors (Harfstrand et al., 1986), there exists the possibility that glucocorticoids may directly effect VTA neurons.

9 M.J. Meaney et al. / Psychoneuroendocrinology 27 (2002) nificant. Repeated exposure to stress or to psychostimulant drugs produces a sensitization of mesolimbic DA neurons. Adrenalectomy serves to greatly reduce stressinduced sensitization of DA neurons and locomotor activity. Predictably, HPA activity also influences responses to psychostimulants. Glucocorticoids administered in the range normally occurring in response to stress increase the propensity to selfadminister amphetamine. Moreover, adrenalectomy induces a decrease in the dose response curve for for cocaine self-administration. Thus, we propose that the increased responsivity of the MS animals to amphetamine derives from specific effects on the development of DA receptor systems, notably effects on DA transporter levels, as well as non-specific effects on HPA development. The influence of the HPA axis is related to the effects of adrenal glucocorticoids, and perhaps central corticotropin-releasing factor (CRF), on mesolimbic DA neurons. Shaham et al. (1997), for example, found that the priming effect of stress on the re-establishment of cocaine self-administration in rats was mediated by CRF. As further evidence for this idea, we found that postnatal handling produces exactly the opposite effects on both DA transporter levels in the NAcc as well as on HPA responsivity to stress. It should be noted that H animals show reduced CRF mrna expression in both the PVNh, the CnAmy as well as the bed nucleus of the stria terminalis. As expected, the H animals show a significantly more modest DA response to stress in the NAcc. In addition to these effects on stress mediators the studies summarized here suggest more specific effects on neurotransmitter systems involved in the activation of incentive motivational states. These findings raise the possibility that in addition to effects on stress reactivity, early life events might predispose individuals to illness in later life through effects on very specific neurotransmitters systems, notably the mesocorticolimbic dopamine system. It is also important to note that in nonhuman primate models of early environmental adversity, there are pronounced effects on the development of both serotonin and noradrenaline systems as well as on CRF systems (Kraemer et al., 1989; Coplan et al. 1996, 1998). The studies of Higley, Suomi and colleagues provide an impressive metaphor. Higley et al. (1991) found that adult rhesus monkeys raised in peer groups, without the benefit of maternal care, showed increased pituitary adrenal responses to stress and, during periods of stress, increased alcohol consumption. Morever, alcohol consumption was strongly correlated to the magnitude of the HPA response to stress. This finding is reminiscent of the Piazza et al. (1991) report showing that corticosterone responses to stress predict amphetamine self-administration in rats Potential clinical relevance Early family adversity, including abuse, emotional neglect, and harsh, inconsistent punishment is a risk factor for multiple forms of mental health disorders, including drug abuse (e.g. Zoccolillo et al., 1999). Interestingly, in rodents, maternal separation during early postnatal life alters the development of the ascending mesocorticolimbic dopamine system. As adults, animals reared under conditions of prolonged maternal separation showed decreased dopamine transporter binding in the NAcc, increased

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