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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    546—Cocaine: Neural Mechanisms of Addiction IV

    Tuesday, November 12, 2013, 8:00 am - 12:00 noon

    546.02: Cocaine affects acoustic startle in concert with estrus cycle stages

    Location: Halls B-H

    *L. B. MALAVE1,2,3, P. A. BRODERICK1,2,3,4;
    1Dept. of Physiology, Pharmacol. and Neurosci., Sophie Davis Sch. CCNY, New York, NY; 2Biol., CUNY Grad. Ctr., New York, NY; 3Ctr. for Advanced Technol. (CAT) CUNY, New York, NY; 4Neurol., NYU Langone Med. Ctr., New York, NY

    Abstract Body: Startle response to auditory stimuli via prepulse inhibition (PPI) examines the ability to neuronally gate the sensory/motor network to heed warning signals. PPI refers to the process in which a weaker prestimulus (prepulse) impedes the reaction of a subject to a subsequent strong startling stimulus (pulse). PPI is significantly decreased in cocaine-administered human subjects (Geyer; Braff, 1987). Moreover, we reported sex differences to acoustic startle response during cocaine-administration (Broderick and Rosenbaum, 2013). There are many studies showing that sensitivity to cocaine reward varies during the estrous cycle (Zakharova et al., 2009; Kippin et al., 2005; Feltenstein et al., 2009). Furthermore, we have published a body of evidence on cocaine induced estrus cycle changes. Thus, these changes in estrus cycle may be the underlying cause of the sex differences in acoustic startle response for cocaine-administered animals. In addition, caffeine did not affect estrus cycle nor does the combination of cocaine and caffeine. We observed that caffeine blocks the cocaine induced estrus cycle changes and may neuro-protect against the decrease in PPI when administered in concert with cocaine (Broderick et al., 2012). In the present study we set out to correlate estrus cycle stages with acoustic startle responses on varying doses of cocaine, caffeine and combination of both.

    Lay Language Summary: Our research shows that cocaine causes rapid changes in estrogen levels for females affecting their sensitivity and sensorimotor gating. Whereas, caffeine, found in coffee, did not cause such changes and blocked the negative effects of cocaine when taken together. Accordingly, estrogen and caffeine play a role in cocaine abuse causing sex differences in sensitivity and acoustic startle response.
    Cocaine abuse is seen in over 1.8 million Americans and the number of women users is increasing at an alarming rate. Given the highly addictive properties of cocaine this phenomenon has become a public health concern. Cocaine significantly increases neurotransmitters, such as dopamine and serotonin, in the reward areas of the brain. More and more evidence is pointing to the increased vulnerability of cocaine abuse in women compared to men. In laboratory animals, females self-administer cocaine more rapidly, become dependent earlier, and relapse faster compared to males. However, the reason for these sex differences remains unclear.
    Sex hormones, such as estrogen, may be the underlying cause. Estrogen levels fluctuate throughout the four stages of the estrus cycle. Laboratory animals with higher estrogen levels also have higher sensitivity to cocaine. Thus, during the estrus cycle stages when estrogen levels peak, females are more susceptible to cocaine. For instance, females show higher response to lower doses of cocaine compared to males.
    We have found that females were in different stages before and after cocaine administration on the same day. Such changes in the estrus cycle may be the primary cause of sex differences in cocaine sensitivity. On the other hand, females were in the same stage prior to and following administration of caffeine on the same day. Cocaine and caffeine administered together also did not change the estrus cycle, indicating that caffeine played a role in blocking the change induced by cocaine alone.
    Studies in our lab using the BRODERICK PROBE® biosensor showed that caffeine combined with cocaine reduced the significant increase of dopamine that is associated with cocaine. The biosensors were surgically implanted in the limbic system, which involves the reward areas of the brain. Dopamine is a key factor in cocaine-seeking behavior causing the euphoric feeling of reward. This effect was seen in females directly compared to males, supporting the increased vulnerability connected to females. These findings show that caffeine may protect the limbic neurons from the addictive properties of cocaine. Since caffeine acts on adenosine receptors in the brain, this suggests a role for drug therapies that target adenosine receptors for treating cocaine addiction.
    In addition, a valuable behavior model to evaluate drug effects on attention and response processing in the central nervous system is the acoustic startle response. We found that females exhibited more sensitivity to auditory stimuli than males in cocaine studies. Cocaine disrupted sensorimotor gating, the ability to filter stimuli when startled by a sudden noise in acoustic startle response. However, caffeine alone and a combination of both cocaine and caffeine did not affect sensorimotor gating. Interestingly, these findings mimicked cocaine and caffeine’s actions on the estrus cycle changes.
    These results have important clinical relevance in the treatment of cocaine addiction for females. Cocaine addiction is a growing complex issue, encompassing biological, psychological, economical and social concerns. Our work strives to determine how pharmacological therapies can best serve to treat cocaine addiction. As there is not one definitive treatment, a better understanding of the contributing factors to cocaine abuse in a pharmacological manner will be a key step towards finding an answer.