Prenatal exposure to a cannabinoid agonist produces memory deficits linked to dysfunction in hippocampal long-term potentiation and glutamate release

Abstract

To investigate the possible long-term consequences of gestational exposure to cannabinoids on cognitive functions, pregnant rats were administered with the CB1 receptor agonist WIN 55,212-2 (WIN), at a dose (0.5 mg͞kg) that causes neither malformations nor overt signs of toxicity. Prenatal WIN exposure induced a disruption of memory retention in 40-and 80-day-old offspring subjected to a passive avoidance task. A hyperactive behavior at the ages of 12 and 40 days was also found. The memory impairment caused by the gestational exposure to WIN was correlated with alterations of hippocampal long-term potentiation (LTP) and glutamate release. LTP induced in CA3-CA1 synapses decayed faster in brain slices of rats born from WIN-treated dams, whereas posttetanic and shortterm potentiation were similar to the control group. In line with LTP shortening, in vivo microdialysis showed a significant decrease in basal and K ؉ -evoked extracellular glutamate levels in the hippocampus of juvenile and adult rats born from WIN-treated dams. A similar reduction in glutamate outflow was also observed in primary cell cultures of hippocampus obtained from pups born from mothers exposed to WIN. The decrease in hippocampal glutamate outflow appears to be the cause of LTP disruption, which in turn might underlie, at least in part, the long-lasting impairment of cognitive functions caused by the gestational exposure to this cannabinoid agonist. These findings could provide an explanation of cognitive alterations observed in children born from women who use marijuana during pregnancy. E ven though marijuana is the most widely used illegal drug among women at reproductive age, reports dealing with the effects of prenatal exposure to this substance of abuse on the length of gestation, fetal growth, and offspring behavior are still controversial (1-4). Confounding factors, such as possible impurities in the drug and concomitant tobacco smoking, may be responsible for inconsistencies in the results reported in studies to date (4, 5). It is likely that many of these conflicting results are due to methodological problems such as the measurement of neonatal outcomes and the context in which the research is conducted. More complex and less understood is the scenario concerning the possible long-term consequences of in utero exposure to cannabis derivatives on cognitive functions. In fact, data on this issue are sparse, and the identification of alterations in brain development and adult expression of cognitive and behavioral functions is far from definitive. These inconclusive results may depend on ethical, practical, and interpretative difficulties surrounding research with human subjects (4). In this regard, animal models provide a useful tool for examining the possible developmental and long-term effects of prenatal exposure to cannabinoids (CBs).Studies performed in adult rats have demonstrated the involvement of a specific CB receptor (CB1) highly expressed in many brain regions (6) in the reinforcing effects of CBs (7) and also in the disru...

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