Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation
817—Amphetamine and Related Drugs: Neural Mechanisms of Addiction
Wednesday, November 13, 2013, 1:00 pm - 5:00 pm
817.04: Leptin protects striatal neurons from the methamphetamine-induced apoptosis in mice
Location: Halls B-H
*N. H. KUTUB1,3, L. YELIN1, J. LAING1, J. A. ANGULO2; 1Biol. Psychology, 2Biol., Hunter Col., New York, NY; 3Psychology, The Grad. Ctr. of City Univ. of New York, New York, NY
Abstract Body: Methamphetamine (METH) is a highly addictive illicit psychostimulant that is neurotoxic. In the striatum METH neurotoxicity intertwines several factors such as dopamine (DA) overflow causing depletion, glutamate signaling, and free radicals formation causing oxidative stress. In addition, excessive dopaminergic innervation leads to severe reduction in DA terminals which are measured by terminal markers tyrosine hydroxylase (TH) and DA transporters (DAT). The purpose of this study is to identify neuroprotective agents that can inhibit degeneration. Several labs including ours have identified the neuroprotective capacity of endogenous peptides, such as somatostatin (SST) and neuropeptide Y (NPY), upon METH-induced toxicity in striatal neurons. Similarly, leptin is a peripheral hormone produced mainly by adipocytes, which circulates in the plasma, and is found ubiquitously in the central nervous system (CNS). Though leptin is primarily known for its regulation of food intake and energy homeostasis, mediated by its receptors on hypothalamic neurons, it has been shown to serve other functions that deviate from its traditional role. Leptin mainly acts via its long form receptor, ObRb, which are found in hypothalamic and extra hypothalamic areas such as mesolimbic DA pathway, specifically in the ventral tegmental area (VTA), substantia nigra (SN), and nucleus accumbens (NAc) of the ventral striatum. The precise molecular pathway underlying the direct effects of leptin in these regions is mostly unknown. But studies report that leptin administration decreases the firing rate of dopaminergic neurons causing decreased DA release in the VTA. Suggesting that leptin may inhibit dopaminergic neurons in the VTA that may mediate the effects of leptin on the mesolimbic DA system. The exact cellular mechanism for this reduced excitability by leptin remains to be determined. Using the above evidence as a backbone, along with preliminary data, we have evidence that leptin signaling can be neuroprotective in striatal neurons upon METH-induced injury. To measure the role of leptin on the METH-induced apoptosis, a single toxic dose of METH (30mg/kg) and a dose of leptin (1mg/kg) were administered to 10-week old male mice. METH-induced apoptosis was measured 24hr post injections by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) immunofluorescence. Percent cell death was compared to baseline counts done with Neuronal Nuclei (NeuN) marker. There is significant attenuation of apoptosis in mice pre-treated with leptin suggesting that leptin protects striatal neurons from METH-induced apoptosis.
Lay Language Summary: We demonstrate that brain injury that is caused by the use of the drug methamphetamine can be diminished by leptin, a hormone produced by our fat cells. Methamphetamine (METH) is a widely used drug of abuse in the USA. Progressive increase in METH abuse and the brain deficits among users attracted attention from researchers and the government. It’s been recognized for almost 30 years that METH causes permanent damage to brain in animals and humans. Specifically, in the areas that control emotions, motivation, cognition and critical thinking. The immediate effects of METH use are euphoria, increased sexuality, productivity and energy, and decreased anxiety and appetite. Compared to other psychostimulants, METH remains unchanged in the body for a longer period causing a prolonged stimulatory effect and triggering the death of brain cells. Even moderate use of METH can cause permanent brain damage, which presents a serious burden for the user and society. Our findings suggest that brain cells can be protected from METH toxicity by leptin released into the bloodstream by fat cells playing a role in the motivational and rewarding circuitry of the brain to control energy balance and the rewarding properties of food and drug. We now have strong evidence suggesting that the cell death known as apoptosis in the brain area called the striatum can be inhibited. The striatum is mainly linked to mediating goal directed behavior of drug seeking and reward, which is extensively affected by METH. Also, the chemical structure of METH resembles the structure of the natural brain chemical, dopamine, thus allowing it to easily access the brain. The striatum receives most of the dopamine signals in the reward circuitry, making it vulnerable to METH injury. We show that giving a dose of leptin before giving METH to mice can significantly reduce apoptosis in the striatum. To test our hypothesis and measure apoptosis, we divide ten-week old male mice into four groups (saline, leptin alone, leptin + METH, and METH alone). We administered leptin injections thirty minutes prior to a dose of METH and the controls received saline. Twenty-four hours post injections we analyzed striatal brain tissue and counted the number of apoptotic brain cells compared to leptin + METH group. We did not see any apoptosis in the saline or leptin alone groups. Our results suggests that when keeping all other factors constant, we see that leptin is protecting striatal neurons from METH toxicity. There was a significant difference between the group that received leptin+ METH versus METH alone. The METH alone group showed the typical 25% of cell death we have measured and published in the past. But when leptin is administered prior to METH, these cells are protected. In the leptin+ METH group less than 10% of the cells die within 24 hours post injection significantly different from the METH alone group. Damage to the brain as a result of METH resembles degeneration that occurs in various neurodegenerative diseases such as Parkinson’s and Huntington’s disease. Therefore, understanding the mechanism of how METH is causing brain degeneration will provide an avenue towards identifying effective therapeutic targets for treatments of METH abuse and neurological disorders. Leptin is a good candidate as others have shown that leptin can reduce the excitability of brain cells in other brain areas related to motivational aspect of food intake. The exact cellular mechanism of this reduced excitability by leptin remains to be determined. However, our results suggest that leptin signaling can be neuroprotective in striatum upon METH-induced injury. It is significant to note that METH abuse is associated with weight loss and consequently reduced leptin production by the body.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit