Overinhibition of corticostriatal activity following prenatal cocaine exposure

Abstract

Objective-Prenatal cocaine exposure (PCE) can cause persistent neuropsychological and motor abnormalities in affected children, but the physiological consequences of PCE remain unclear. Conclusions drawn from clinical studies can sometimes be confounded by poly-substance abuse and nutritional deprivation. However, existing observations suggest that cocaine exposure in utero, as in adults, increases synaptic dopamine and promotes enduring dopamine-dependent plasticity at striatal synapses, altering behaviors and basal ganglia function.Methods-We used a combination of behavioral measures, electrophysiology, optical imaging, and biochemical and electrochemical recordings to examine corticostriatal activity in adolescent mice exposed to cocaine in utero.Results-We show that PCE caused abnormal dopamine-dependent behaviors, including heightened excitation following stress and blunted locomotor augmentation to repeated treatment with amphetamine. These abnormal behaviors were consistent with abnormal GABA interneuron function, which promoted a reversible depression in corticostriatal activity. PCE hyperpolarized and reduced tonic GABA currents in both fast-spiking and PLTS-type GABA interneurons to increase tonic inhibition at GABA B receptors on presynaptic corticostriatal terminals. While D2 receptors paradoxically increased glutamate release following PCE, normal corticostriatal modulation by dopamine was reestablished with a GABA A R antagonist.Interpretation-The dynamic alterations at corticostriatal synapses that occur in response to PCE parallel the reported effects of repeated psychostimulants in mature animals, but differ in being specifically generated through GABA. Our results indicate that approaches which normalize GABA and D2 receptor-dependent synaptic plasticity may be useful for treating the behavioral effects of PCE and other developmental disorders that are generated through abnormal GABAergic signaling.

Models of Intergenerational and Transgenerational Transmission of Risk for Psychopathology in Mice

“…Accompanying this behavioral preference was increased volumes in the olfactory bulbs of the glomeruli that process cherry (M71-expressing olfactory sensory neurons and glomeruli) and mint (M72-expressing cells and glomeruli) (Todrank et al, 2011). In other studies, prenatal exposure to cocaine affected the F1 generation's behavior toward cocaine, as well as dopaminergic neurotransmission and stress responsiveness (Malanga et al, 2007;Wang et al, 2013). Additionally, exposure of pregnant rat dams to a fungicide, Vinclozolin, has been shown to affect reproductive and behavioral endpoints in several generations removed from this F0 exposure (Crews et al, 2007;Skinner et al, 2008;Gillette et al, 2014).…”

Acetylcholine Encodes Long-Lasting Presynaptic Plasticity at Glutamatergic Synapses in the Dorsal Striatum after Repeated Amphetamine Exposure

“…mEPSCs were recorded in gap-free mode both before and 10 min after beginning bath application of a receptor ligand (Wang et al, 2013). The Na ϩ channel antagonist TTX (1 M) was added to block spontaneous cortically derived action potentials and to isolate presynaptic terminal activity.…”

“…9D-F ). The increase in firing frequency during withdrawal was dependent on dopamine release, because it was blocked (17 Ϯ 10%; 2.06 Ϯ 0.21 Hz in aCSF Wang et al, 2013). D, Representative traces from experimental results in E showing cell-attached recordings in saline-and amphetamine-treated TANs.…”

“…Peak AMPAR-mediated currents were measured by averaging a 5 ms window around the eEPSC peak in the presence of APV; peak NMDAR-mediated currents were measured from a 5 ms window around the peak of the resulting trace created by subtracting the eEPSC in the presence of APV from the eEPSC without APV. Amplitudes were normalized by the peak NMDAR value for each respective pair of traces.mEPSCs were recorded in gap-free mode both before and 10 min after beginning bath application of a receptor ligand (Wang et al, 2013). The Na ϩ channel antagonist TTX (1 M) was added to block spontaneous cortically derived action potentials and to isolate presynaptic terminal activity.…”

Prenatal Cocaine Exposure and Adolescent Neural Responses to Appetitive and Stressful Stimuli

“…Preclinical research has demonstrated significant effects of PCE on brain regions involved in emotional regulation, motivational control, and addiction vulnerability during adolescence (Chambers and Potenza, 2003)-eg, anterior cingulate (ACC) (Harvey, 2004), prefrontal cortex (PFC) (McCarthy and Bhide, 2012), and ventral striatum (VS) (Harvey et al, 2001;Wang et al, 2013). In humans, neurostructural (Rando et al, 2013) and neurofunctional (Li et al, 2009;Sheinkopf et al, 2009;Li et al, 2011) alterations (eg, during response inhibition, resting state alterations) in regions of the VS and PFC have also been reported among adolescents with PCE.…”