Chronic cocaine exposure impairs progenitor proliferation but spares survival and maturation of neural precursors in adult rat dentate gyrus

Abstract

Recent observations indicate that drugs of abuse, including alcohol and opiates, impair adult neurogenesis in the hippocampus. We have studied in rats the impact of cocaine treatment (20 mg/kg, daily, i.p.) on cell proliferation, survival and maturation following short-term (8-day) and long-term (24-day) exposure. Using 5'-bromo-2-deoxyuridine (BrdU) and Ki-67 as mitotic markers at the end of the drug treatments, we found that both short- and long-term cocaine exposures significantly reduced cell proliferation in the dentate gyrus (DG) of the hippocampus. By labelling mitotic cells with BrdU pulses before or during the early stages of the drug treatment, we determined that long-term cocaine exposure did not affect the survival of newly generated cells. In register with this finding, cocaine chronic exposure did not increase the number of apoptotic cells labelled by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling). Using doublecortin (DCX) immunocytochemistry and electron microscopy, we next examined the effects of cocaine exposure on the maturation of the neural precursors and on synaptic output to CA3. DCX immunocytochemistry showed that immature hippocampal cells of rats exposed to cocaine displayed normal arborization patterns and similar degrees of colocalization with BrdU at two different developmental stages. Moreover, cocaine did not produce significant morphological alterations of the mossy fibre projection system to stratum lucidum in the CA3 area of the hippocampus. The results presented demonstrate that chronic cocaine exposure impairs proliferation dynamics in the DG without significantly altering either the survival and growth of immature cells or the structural features of terminal projections to CA3.

Withdrawal from Cocaine Self-Administration Normalizes Deficits in Proliferation and Enhances Maturity of Adult-Generated Hippocampal Neurons

“…We further show the CSA-induced decrease in proliferation is not attributable to decreased BrdU bioavailability, an important concern given the action of cocaine on the vasculature. This decrease is likely not caused by cell death, an interpretation supported by previous cocaine work ( Dominguez-Escriba et al, 2006). However, the trend in and high variability of the AC-3 data encourage future examination of additional time points after cocaine selfadministration.…”

“…As detailed previously (Powrozek et al, 2004;Eisch and Harburg, 2006), mounting evidence suggests adult neurogenesis plays a role in addiction. Briefly, experimenter-delivered intraperitoneal cocaine decreases SGZ proliferation (Yamaguchi et al, 2005;Dominguez-Escriba et al, 2006) in a dose-and time-dependent manner (Eisch, 2002). Also, the hippocampus is implicated in cocaine addiction and relapse (Canales, 2007), perhaps via drug-specific contextual memory formation.…”

Adult Neurogenesis and Psychiatric Disorders

“…Likewise, cocaine abuse is also negatively associated with some facets of adult hippocampal neurogenesis. Both short-and longterm treatment of cocaine reduces proliferation in the dentate gyrus, but the effect on survival and dendritic maturation is not always consistent, possibly caused by the use of different animal strains and various drug administration protocols (Eisch 2002;Yamaguchi et al 2004;Dominguez-Escriba et al 2006;Noonan et al 2008;Mustroph et al 2011). Negative effects of cocaine on cell proliferation were concomitant with impairments in working memory, even during abstinence from high dosage cocaine self-administration (Sudai et al 2011).…”

Regulation of Adult Neurogenesis and Plasticity by (Early) Stress, Glucocorticoids, and Inflammation

“…Stress further affects various neurotransmitters implicated in the regulation of neurogenesis: g-aminobutyric acid (GABA) (Ge et al 2007), serotonin (Djavadian 2004), noradrenalin (Joca et al 2007), acetylcholine (BruelJungerman et al 2011), and dopamine (e.g., Domínguez-Escribà et al 2006;Takamura et al 2014). Other neurotransmitter systems, such as the cannabinoids, opioids, nitric oxide, various neuropeptides, and gonadal steroids, may also contribute (e.g., see Galea 2008;Balu and Lucki 2009).…”