Chronic Morphine Treatment Impaired Hippocampal Long-Term Potentiation and Spatial Memory via Accumulation of Extracellular Adenosine Acting on Adenosine A₁Receptors

Abstract

Chronic exposure to opiates impairs hippocampal long-term potentiation (LTP) and spatial memory, but the underlying mechanisms remain to be elucidated. Given the well known effects of adenosine, an important neuromodulator, on hippocampal neuronal excitability and synaptic plasticity, we investigated the potential effect of changes in adenosine concentrations on chronic morphine treatmentinduced impairment of hippocampal CA1 LTP and spatial memory. We found that chronic treatment in mice with either increasing doses (20 -100 mg/kg) of morphine for 7 d or equal daily dose (20 mg/kg) of morphine for 12 d led to a significant increase of hippocampal extracellular adenosine concentrations. Importantly, we found that accumulated adenosine contributed to the inhibition of the hippocampal CA1 LTP and impairment of spatial memory retrieval measured in the Morris water maze. Adenosine A 1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine significantly reversed chronic morphine-induced impairment of hippocampal CA1 LTP and spatial memory. Likewise, adenosine deaminase, which converts adenosine into the inactive metabolite inosine, restored impaired hippocampal CA1 LTP. We further found that adenosine accumulation was attributable to the alteration of adenosine uptake but not adenosine metabolisms. Bidirectional nucleoside transporters (ENT2) appeared to play a key role in the reduction of adenosine uptake. Changes in PKC-␣/␤ activity were correlated with the attenuation of the ENT2 function in the short-term (2 h) but not in the long-term (7 d) period after the termination of morphine treatment. This study reveals a potential mechanism by which chronic exposure to morphine leads to impairment of both hippocampal LTP and spatial memory.

Protective Role of Taurine Against Morphine-Induced Neurotoxicity in C6 Cells via Inhibition of Oxidative Stress

“…In addition, chronic use of morphine has deleterious physiological effects beyond addiction as well. For example, rats chronically exposed to morphine show a spectrum of symptoms, from drowsiness to hallucinations, delirium, seizures (Smith 2000) and cognitive deficits, such as poorer performance in learning and memory (Lu et al 2010;Eisch et al 2000). Furthermore, the abuse of morphine or heroin during pregnancy can cause human fetal brain developmental abnormalities and induce long-term neurobehavioral damage (Yanai et al 2003).…”

Cognitive Impairments in Drug Addicts

“…Also addicts in methadone maintenance programs or chronic pain patients treated with methadone are shown to display cognitive impairmats (Mitzler and Stitzer, 2002;Soyka et al, 2010). These findings suggest an effect of chronic opiates on brain regions related to learning and memory, such as the frontal cortex (Ornstein et al, 2000;Yang et al, 2009) and the hippocampus (Lu et al, 2010) Regarding the mechanisms by which opioids induce cognitive impairments through action on hippocampal and prefrontal cortex structures it is shown that these drugs may enhance apoptosis and inhibted neurogenesis. An opioid-induced attenuation of neurogenesis in hippocampus was earlier seen in male rats exposed to morphine (Eisch et al, 2000).…”

“…However, at higher doses the stimulant may induce impaired cognitive function (Reske et al, 2010), particularly those mediated by the prefrontal cortex (Xu et al, 2010). Also, chronic use of amphetamine induces significantly impaired performance in cognitive tests (Ornstein et al, 2000).…”

“…Heroin is characterized as one of the most frequently abused illegal drugs, and addiction to this drug is linked to significant attention deficits and inadequate performance on memory tasks (Guerra et al, 1987). Furthermore, chronic exposure to morphine is also shown to cause vigilance and attention impairments in chronic pain patients (Mao et al, 2002) and impairs acquisition of reference memory in rats (Spain and Newsom, 1991;Lu et al, 2010). Also addicts in methadone maintenance programs or chronic pain patients treated with methadone are shown to display cognitive impairmats (Mitzler and Stitzer, 2002;Soyka et al, 2010).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Hippocampal LTP could be restored by re-exposure to opioids, including the m receptor agonist [D-Ala 2 , NMePhe 4 , Gly-ol 5 ]-enkephalin (DAMGO) and inhibitors of PKA, suggesting that upregulation of the cAMP pathway was one of the underlying mechanisms (Pu et al, 2002;Bao et al, 2007). In addition, chronic morphine exposure increased hippocampal extracellular adenosine concentrations, which contributed both to the inhibition of hippocampal LTP and impairment of spatial memory retrieval, and both deficits could be reversed by an adenosine antagonist or adenosine deaminase (Lu et al, 2010a). There is also evidence to suggest that opioid-induced changes in hippocampal synaptic plasticity could have a role in drug-context associations.…”