Prenatal Cocaine Disrupts Serotonin Signaling-Dependent Behaviors: Implications for Sex Differences, Early Stress and Prenatal SSRI Exposure

Abstract

Prenatal cocaine (PC) exposure negatively impacts the developing nervous system, including numerous changes in serotonergic signaling. Cocaine, a competitive antagonist of the serotonin transporter, similar to selective serotonin reuptake inhibitors (SSRIs), also blocks dopamine and norepinephrine transporters, leaving the direct mechanism through which cocaine disrupts the developing serotonin system unclear. In order to understand the role of the serotonin transporter in cocaine's effect on the serotonergic system, we compare reports concerning PC and prenatal antidepressant exposure and conclude that PC exposure affects many facets of serotonergic signaling (serotonin levels, receptors, transporters) and that these effects differ significantly from what is observed following prenatal SSRI exposure. Alterations in serotonergic signaling are dependent on timing of exposure, test regimens, and sex. Following PC exposure, behavioral disturbances are observed in attention, emotional behavior and stress response, aggression, social behavior, communication, and like changes in serotonergic signaling, these effects depend on sex, age and developmental exposure. Vulnerability to the effects of PC exposure can be mediated by several factors, including allelic variance in serotonergic signaling genes, being male (although fewer studies have investigated female offspring), and experiencing the adverse early environments that are commonly coincident with maternal drug use. Early environmental stress results in disruptions in serotonergic signaling analogous to those observed with PC exposure and these may interact to produce greater behavioral effects observed in children of drug-abusing mothers. We conclude that based on past evidence, future studies should put a greater emphasis on including females and monitoring environmental factors when studying the impact of PC exposure.

Keywords: Aggression; depression; development; early environmental stress; prenatal antidepressants; prenatal cocaine; serotonin; sex differences..

Fig. (1)

Serotonergic Synapse. This diagram shows a serotonergic presynaptic neuron on the left. This presynpatic neuron is drawn to show release of 5-HT (rectangles) into the synapse. The released 5-HT can act on many substrates. 5-HT can bind to postsynaptic receptors (on right of figure) including g-protein coupled receptors 5-HT_1A and 5-HT_2A (solid circles) and ionotropic receptors like 5-HT₃ (hollow circle). 5-HT can act on presynaptic neurons through inhibitory autoreceptors (5-HT_1A; solid circle in perisynaptic region) and 5-HT transporters. The 5-HT transporter (SERT: arrow box), brings 5-HT back into the axonal bouton. 5-HT is removed from the synapse through metabolic enzymes MAO and COM-T. 5-HT neurons receive trophic signals from astroglial cells during development and possibly throughout life via S100β (rectangle in astroglial cell). This diagram also includes other transporters for comparison. The dopamine transporter (DAT: arrowed box) is responsible for removing dopamine from synapses. The norepinephrine transporter (NET: arrowed box) is responsible for removing norepinephrine from the synapse. All three transporters are blocked by cocaine and to some extent antidepressants. Black arrows represent the relative ability of each compound to affect the transporters (binding affinities can be found in Table 1).

Fig. (2)

The Impact of Prenatal Cocaine Exposure on 5-HT_1A Receptors is Region-Specific. Immunobinding data are represented as percent control means ± SEM (i.e. PC exposed males compared to Control Males). Asterisks (*) represent that PC exposed males differed significantly from control males (p ≤ 0.05). Pound signs (#) represent that PC exposed females differed significantly from control females (p ≤ 0.05). Infancy: PND 1, Adolescence: PND 30, Early Adult: PND 60, Late Adult: PND 120. Insets display representative anatomical sections from which immunobinding data was collected. PND: postnatal day.

Fig. (3)

Whole brain 5-HT_1A receptor immunobinding. Represented as percent control means ± SEM (i.e. PC exposed males compared to control males) for each sex. Asterisks (*) represent that PC exposed males differed significantly from control males (p ≤ 0.05). Pound signs (#) represent that PC exposed females differed significantly from control females (p ≤ 0.05). Infancy: PND1, Adolescence: PND 30, Early Adult: PND 60, Late Adult: PND 120 PND: postnatal day.

Fig. (4)

PC exposure results in increased aggression through both serotonergic and non-serotonergic neurobiological changes as indicated by the solid lines. Early life stress can also increase aggression through changes in both serotonergic and non-serotonergic signaling components as indicated by the dotted lines. If an animal experiences both PC exposure and early life stress, the impact of low SERT, low 5-HT and high cortical 5-HT_1A may be even greater than either insult alone contributing to a greater behavioral impact as indicated by the thicker arrows. It is likely that PC exposure offspring would experience early life stress through parental neglect induced by drug use by the parents as indicated by the blue arrows.

Fig. (5)

Developmental Effects of Serotonin Deficits. PC exposure can cause a variety of serotonergic changes during infancy that culminate in low serotonergic tone (Box A.) PC exposure causes deficits in adult 5-HT signaling, which may be developmental compensations for early disruptions (Box B). The sum of the 5-HT signaling deficits accrued by adulthood lead to a number of interacting behavioral problems and overall poor behavioral outcomes (Box C).