Chemotherapy is associated with long-term cognitive deficits in breast cancer survivors. Studies suggest that these impairments result in the loss of cognitive reserve and/or induce a premature aging of the brain. This study has been aimed to determine the potential underlying mechanisms that induce cognitive impairments by chemotherapeutic agents commonly used in breast cancer. Intact and ovariectomized (OVX) female rats were treated intravenously with either saline or a combination of cyclophosphamide (40mg/kg) and doxorubicin (4 mg/kg). All subjects were tested for anxiety, locomotor activity, working, visual and spatial memory consecutively. Although anxiety and visual memory were not affected, chemotherapy significantly decreased locomotor activity and impaired working and spatial memory in female rats, independent of their hormonal status. The cognitive deficits observed are hippocampal dependent. Therefore, as a first step to identity the potential signaling pathways involved in this cognitive dysfunction, the protein levels of extracellular signal-regulated kinase 1/2 (Erk1/2), Akt (neuroprotectant) BDNF and (structural protein) PSD95 in hippocampal lysates were measured. Erk1/2 and Akt pathways are known to modulate synaptic plasticity, neuronal survival, aging and cancer. We found an increased activation of Erk1/2 and Akt as well as an increase in the protein levels of PSD95 in OVX female rodents. However, OVX females had a higher overall BDNF level, independent of chemotherapy. These studies provide additional evidence that commonly used chemotherapeutic agents affect cognitive function and impact synaptic plasticity/aging molecules which may be part of the underlying biology explaining cognitive change and can be potential therapeutic targets.

Opiates modulate nociception in vertebrates. This has also been demonstrated in a number of invertebrate models. Herein, the effect of the opiate morphine and opioid neuropeptides Endomorphin 1 and 2 on the thermal avoidance (Tav) behavior of Caenorhabditis elegans is explored. Adult wild-type C. elegans N2 were collected from NGM plates using M9 buffer and exposed to morphine and endomorphine 1 and 2 in concentrations between 10 −8 and 10 −4 M (2.5 pmol/mg to 25 nmol/mg) for 30 min and tested for Tav. The opioid receptor antagonists Naloxone and CTOP were tested in combination with the drugs. Forty-seven percentage of the morphine exposed worms exhibited a class I response versus 76% of the control group (P < 0.001). Endomorphin 1 and 2 also caused a statistically significant reduction in class I responses, 36 and 39%, respectively. These effects were reversed with Naloxone and CTOP. Thermonocifensive behavior in C. elegans is modulated by opioids.

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