Recent work implicates regulation of neurogenesis as a form of plasticity in the adult rat hippocampus. Given the known effects of opiates such as morphine and heroin on hippocampal function, we examined opiate regulation of neurogenesis in this brain region. Chronic administration of morphine decreased neurogenesis by 42% in the adult rat hippocampal granule cell layer. A similar effect was seen in rats after chronic self-administration of heroin. Opiate regulation of neurogenesis was not mediated by changes in circulating levels of glucocorticoids, because similar effects were seen in rats that received adrenalectomy and corticosterone replacement. These findings suggest that opiate regulation of neurogenesis in the adult rat hippocampus may be one mechanism by which drug exposure influences hippocampal function.
Opiates are among the most commonly abused illegal drugs in the United States (1, 2). Several reports suggest that chronic exposure to opiates, such as morphine and heroin, can result in cognitive deficits (3-5). For example, heroin users have poorer performance on attention, verbal fluency, and memory tasks than controls (3), and rats chronically exposed to morphine show impaired acquisition of reference memory (5). Such findings suggest that long-term opiate use may produce maladaptive plasticity in brain structures involved in learning and memory, such as the hippocampus.One aspect of the mammalian hippocampus that recently has received considerable attention is the birth of new neurons that occurs in the dentate gyrus throughout the lifetime of the animal (6-8). This phenomenon has been described in rodents, nonhuman primates, and, most recently, humans (9-12). Research suggests that cells are born in the subgranular zone of the dentate gyrus, migrate into the granule cell layer and express neuronal markers (8,13,14), extend processes to CA3 pyramidal neurons (15, 16), receive synaptic connections (10, 13, 16), and demonstrate long-term potentiation (17). Although a growing number of pharmacological and environmental manipulations have been shown to influence adult neurogenesis, the functional implication of the newly born neurons remains poorly understood (see Discussion). It has been proposed that the thousands of new neurons born each day in the adult rodent hippocampus may contribute to a variety of hippocampal-related functions, including learning and memory (6, 7).Drugs of abuse, including opiates, can significantly alter the birth of neural progenitors during early stages of development (18)(19)(20), yet it remains unclear what effect drug exposure has on the birth of neural progenitors in the mature brain. Here we examine the consequence of long-term opiate exposure on the birth of new neurons in the adult rat hippocampus.
Materials and MethodsAnimals and Drug Treatment. Adult, male Sprague-Dawley rats (initial weight 275-300 g; Charles River Breeding Laboratories) were used for all experiments. For chronic morphine treatment, rats were given sham surgery (n ϭ 10) or a morphine pellet (75 ...