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  • Addiction, Drugs
  • Addiction, Drugs

    430 Cocaine Reinforcement II

    430.01 Transient optogenetic inhibition bidirectionally influences dendritic morphology in the nucleus accumbens core while attenuating cocaine-seeking behavior

    November 17, 2014 1:00 PM - November 17, 2014 5:00 PM

    • M. T. STEFANIK $lastName ;
    • Y. M. KUPCHIK $lastName ;
    • P. W. KALIVAS $lastName

    Information from abstracts and lay language summaries is embargoed until the conclusion of the scientific presentation.

    430—Cocaine Reinforcement II

    Monday, November 17, 2014, 1:00 pm - 5:00 pm

    430.01: Transient optogenetic inhibition bidirectionally influences dendritic morphology in the nucleus accumbens core while attenuating cocaine-seeking behavior

    Location: Halls A-C

    *M. T. STEFANIK1, Y. M. KUPCHIK2, P. W. KALIVAS2; 1Dept. of Neurosciences, 2Med. Univ. of South Carolina, Charleston, SC

    Abstract Text: Evidence suggests certain morphological and physiological changes in the nucleus accumbens NAc are important mediators of relapse. We previously demonstrated optogenetic inhibition of the NAc core subcompartment (NAcore) or its afferents from the prelimbic prefrontal cortex (PL) over a 2-hour reinstatement session attenuated cocaine seeking. Recent work suggests dynamic changes in plasticity occur during the first 15 minutes of these sessions, and these adaptations are blocked via pharmacological inhibition of the PL. Current work examined the behavioral and morphological consequences of optically silencing the NAcore, or its afferents in the PL during this first 15
    minutes of cue-induced reinstatement. Male Sprague -Dawley rats underwent surgeries for microinjections of adeno- associated virus (AAV) coding for archaerhodopsin (ArchT) in either the PL or NAcore, implantation of bilateral fiber optics aimed the NAcore, and intra-jugular venous catheters. Studies were designed to assess selective inhibition of either PL terminals or cell bodies within the NAcore. Animals then went through 12 days of cocaine self- administration (FR1) followed by extinction training (2 hr/day). Following extinction, animals underwent cue-
    induced reinstatement along with the presence/absence of optical inhibition. Inhibiting PL-to -NAcore projections during the first 15 minutes sufficiently blocked reinstatement behavior while the laser was on and paralleled a decrease in dendritic spine head diameter relative to controls. In animals receiving NAcore cell body inhibition, behavior was attenuated while the light was being delivered, but lever pressing rebounded when optical inhibition was relieved, and spine head diameter was potentiated. Electrophysiological experiments examined physiological changes resulting from optical inhibition. Results reveal interesting differences between reinstated behavior and spine morphology, suggestive that changes in spine morphology are a requisite antecedent to behavior.

    Lay Language Summary: Experiences affect the function and connectivity of neurons in the brain. Neurons can alter their physiological and structural characteristics in response to changes in synaptic activity, most notably at small protrusions called dendritic spines. The strengthening and weakening on synapses allows the brain to interpret, adapt, and store information for future use.
    Experience with addictive drugs like cocaine has also been shown to change the structure, function, and connectivity of neurons; something that is thought to be responsible, at least in part, for the pathological drug- seeking behaviors seen in addicts. Despite this basic knowledge, structure/function relationships in the brain still remain poorly understood. Gaining a better insight into how neural circuit activity changes neuron morphology and how such changes relate to behavior is critical to furthering our understanding of reward system function and dysfunction.
    In the current study, we show that intervention during a key 15 minute period can not only stop relapse to drug seeking in a rat model, but this intervention can also bi-directionally influence neuronal morphology in a key addiction -related region, the nucleus accumbens. In this model, rats are allowed to self-administer cocaine daily, receiving infusions paired with a light and tone cue each time a lever press is made. The association between the light/tone cue and cocaine delivery that the rat makes allows us to induce relapse -like drug seeking by presenting the cues again in a later session. Then we use an inhibitory optogenetic strategy to selectively turn off critical regions within the brain’s reward circuitry and stop subsequent drug seeking.
    By optically inhibiting the projections into the nucleus accumbens from the prefrontal cortex during the first 15 minutes of a cue-induced reinstatement session, we were able to significantly able to reduce drug-seeking
    behavior. This result was paralleled by a decrease in dendritic spine diameter. Interestingly, optical inhibition of the nucleus accumbens itself also reduced
    behavior while light was being delivered, but lever pressing rebounded when optical inhibition was relieved, and was paralleled by increased spine head diameter.
    These results reveal interesting differences between spine morphology and behavior. They also suggest that spine morphology may be an essential precursor that sets the stage for behavioral responding.

    469 Cocaine

    469.04 Longitudinal structural changes following long term cocaine self-administration in rhesus macaques: Relationship with motivation of drug administration

    November 17, 2014 1:00 PM - November 17, 2014 5:00 PM

    • H. P. JEDEMA $lastName ;
    • A. BONNER $lastName ;
    • J. N. PORTER $lastName ;
    • H. J. AIZENSTEIN $lastName ;
    • C. W. BRADBERRY $lastName

    Information from abstracts and lay language summaries is embargoed until the conclusion of the scientific presentation.

    469—Cocaine

    Monday, November 17, 2014, 1:00 pm - 5:00 pm

    469.04: Longitudinal structural changes following long term cocaine self-administration in rhesus macaques: Relationship with motivation of drug administration

    Location: Halls A-C

    *H. P. JEDEMA1, A. BONNER2, J. N. PORTER3, H. J. AIZENSTEIN1, C. W. BRADBERRY1,4; 1Psychiatry, 2Neurosci., 3CNUP, Univ. Pittsburgh, Pittsburgh, PA; 4VA, Pittsburgh Health Services, PA

    Abstract Text: Addiction is a complex neurobiological disorder affecting multiple brain regions. Clinical studies have indicated structural changes in human cocaine users compared to matched control subjects in frontal and temporal cortical regions, as well as the cerebellum. It is unknown whether these differences reflect structural differences induced by chronic (poly) drug use or pre-existing structural differences potentially related to enhanced vulnerability to addiction. Because of the similarity in brain structure and response to drugs of abuse in monkeys, we compared the longitudinal impact of chronic intravenous cocaine self-administration (up to 6 infusions 0.5mg/kg each,
    4days/week for 12 months) in adult rhesus macaques (n=8) with control subjects (N=6) in previously defined volume of interest regions using atlas-based morphometry and MRI (Siemens Allegra 3T). In addition, we examined the correlation between the motivation to self-administer cocaine (average time to self-administer each infusion) and structure at baseline as well as structural changes observed following prolonged cocaine self- administration. We observed significant differences in relative structural changes in gray matter in frontal cortical (BA 45), temporal (amygdala), and cerebellar regions between cocaine self-administering and control subjects. In the cocaine group, we found a significant correlation between the relative size of orbital frontal cortex at baseline and the subsequent time to self-administer cocaine. In addition, we observed significant correlations between structural changes and the time to self-administer cocaine in the ventral prefrontal cortex (BA 25), the pre-
    supplementary motor area, and the cerebellum. These data suggest chronic cocaine self-administration may lead to structural changes in lateral prefrontal, temporal, and cerebellar regions. In addition, pre-existing differences in orbital frontal cortex may result in greater vulnerability to cocaine self-administration in monkeys. These observations provide further support for non-human primate models of cocaine addiction and underscore the importance of frontal cortical and cerebellar brain regions in addiction.
    Our research suggests that some differences in brain structure frequently observed in clinical neuroimaging studies of cocaine users are preexisting, rather than a consequence of cocaine use.
    Human neuroimaging studies of cocaine users have observed reduced gray matter (GM) volume in the orbitofrontal cortex (OFC), an area involved in value assessment of rewards for decision making. However, it is unknown whether these differences in GM volume in humans result from chronic drug use, or alternatively, reflect pre- existing differences which may be related to a vulnerability to develop addiction. Based on the similarity in brain

    Lay Language Summary: structure in monkeys and their response to drugs of abuse, we examined the impact of chronic self-administration of cocaine in rhesus macaques. We obtained magnetic resonance imaging (MRI) data before any drug exposure, enabling our observations to distinguish pre-existing differences from changes induced by chronic cocaine exposure. We observed that the rate of self-administration of cocaine correlated with GM volume in OFC prior to cocaine exposure. After obtaining baseline scans, subjects (n=8) were allowed to intravenously self-administer up to six 0.5 mg/kg infusions of cocaine (4 days each week for 1 year) and the rate of self-administration was calculated as the average time per infusion. Smaller OFC volumes prior to cocaine exposure were associated with faster rates of self- administration. These data further emphasize the long-standing pivotal role of the OFC in drug addiction, but more importantly, they suggest that small OFC volume in humans could mediate a pre-existing vulnerability that could
    be driving an increased rate of cocaine consumption, leading to more severe consequences and addiction. In the same way, a larger OFC volume may be more closely associated with satiety to cocaine, resulting in self-limitation of their exposure and its negative consequences. Further support for a smaller OFC volume as a pre-existing factor rather than a consequence of cocaine use is provided by our longitudinal structural data indicating that OFC GM volume increased rather than decreased with cocaine exposure.
    Future studies will examine the neural correlates of decision making in the OFC to better understand at a cellular level the processes in OFC that may contribute to choices between cocaine and non-drug rewards.

    526 Opiate Reinforcement

    526.01 Transgenerational effects of female adolescent morphine exposure on offspring morphine self-administration, reinstatement, and gene expression

    November 18, 2014 8:00 AM - November 18, 2014 12:00 PM

    • F. M. VASSOLER $lastName ;
    • E. M. BYRNES $lastName

    Information from abstracts and lay language summaries is embargoed until the conclusion of the scientific presentation.

    526—Opiate Reinforcement

    Tuesday, November 18, 2014, 8:00 am - 12:00 noon

    526.01: Transgenerational effects of female adolescent morphine exposure on offspring morphine self-administration, reinstatement, and gene expression

    Location: Halls A-C

    *F. M. VASSOLER , E. M. BYRNES; Dept. of Biomed. Sci., Tufts Univ. Cummings Sch. of Vet. Med., North Grafton, MA

    Abstract Text: The prescription of opiates has escalated dramatically over the past decade, resulting in increased access and misuse of these highly addictive medications. The use in adolescent populations, and in particular adolescent female populations, is particularly concerning because opioids play a significant role in neuroendocrine function and development. Thus, exposure to opioids during this critical developmental period could have significant consequences for the female, as well as her future offspring. Here we utilize a rat model established in the laboratory to examine the influence of adolescent morphine exposure, followed by prolonged abstinence on the behavior of the progeny. Female Sprague dawley rats were administered daily subcutaneous (s.c.) injections of morphine sulphate for 10 days using an increasing dosing regimen and beginning at postnatal day 30 (P30). The dose started at 5 mg/kg and increased every other day by 5 mg/kg. Therefore, on P30 and P31 the animals received 5 mg/kg, on P32 and P33 10 mg/kg and so forth until P40 when they received 25 mg/kg. Age-matched control animals received saline injections. A minimum of 20 days later (on or after P60) the females were mated with naïve males. Morphine self-administration, extinction and reinstatement in the offspring were examined during adulthood (P60). The acquisition of morphine self-administration was examined at two doses: 0.25 or 0.75 mg/kg/infusion. At the low dose, a main effect of maternal treatment was observed demonstrating that MorF1 animals self-administered significantly more morphine than the SalF1 animals. This effect appeared to be driven by the MorF1 males, who took significantly more morphine than the SalF1 males (p<0.05). In contrast, at the higher dose, there was no difference in the acquisition between the male animals but the MorF1 females took significantly less morphine than the SalF1 females (p<0.05). Following extinction, reinstatement was induced with a 1 mg/kg intraperitoneal (i.p.) priming injection. We found significant attenuation of reinstatement in both male and female MorF1 animals (following high dose self-administration). This suggests that female adolescent exposure to opioids, even following prolonged abstinence, affects the offspring’s response to morphine. Experiments examining the transcriptome of the nucleus accumbens at baseline and in response to a morphine injection using RNA deep sequencing are ongoing.

    Lay Language Summary: Opiate addiction runs in families. While it is known that genetics may play a role in developing addictive behaviors, it does not fully explain why children of addicts often become addicts themselves. Certainly the home environment may play a role, but does drug use itself increase the risk for addiction in future offspring? Opiates are being prescribed at increasing rates. In the past decade, increased access and misuse of these highly addictive medications is creating a public health crisis. The use in adolescent populations, and in particular adolescent female populations, is particularly concerning because opioids play a significant role in the development of reproductive systems. Therefore, exposure to opiates during adolescence may have significant consequences for the female that may impact her future offspring. Here we utilize a rat model to examine the effect of adolescent morphine
    exposure in females on their subsequent offspring. It is important to note that offspring are never directly exposed to morphine. We then tested the likelihood that offspring would become addicted to opiates. We found that maternal exposure prior to pregnancy had an impact on the motivation to self-administer opiates in this model. These findings varied by sex. We also found changes in the expression of proteins in brain regions critical for addictive behavior. Together these data suggest that maternal opiate use prior to pregnancy can influence addiction vulnerability in the next generation likely by epigenetic mechanisms.

    231 Nicotine: Reward and Seeking

    231.29 A chilling connection; menthol’s effect on nicotinic acetylcholine receptor expression and synaptic structure in the rodent brain

    November 16, 2014 1:00 PM - November 16, 2014 5:00 PM

    • S. P. BRIDGES $lastName ;
    • J. R. KING $lastName ;
    • J. C. NORDMAN $lastName ;
    • P. MULDOON $lastName ;
    • M. LIZARRAGA $lastName ;
    • I. DAMAJ $lastName ;
    • N. KABBANI $lastName

    Information from abstracts and lay language summaries is embargoed until the conclusion of the scientific presentation.

    231—Nicotine: Reward and Seeking

    Sunday, November 16, 2014, 1:00 pm - 5:00 pm

    231.29: A chilling connection; menthol’s effect on nicotinic acetylcholine receptor expression and synaptic structure in the rodent brain

    Location: Halls A-C

    *S. P. BRIDGES1, J. R. KING 1, J. C. NORDMAN 1, P. MULDOON2, M. LIZARRAGA1, I. DAMAJ2, N. KABBANI1; 1Dept. of Mol. Neurosci., George Mason Univ., Fairfax, VA; 2Dept. of Pharmacol., Virginia Commonwealth Univ., Richmond, VA

    Abstract Text: Although menthol, a common flavoring additive to cigarettes, has been found to impact the addictive properties of nicotine cigarettes in smokers, little is known about its molecular actions in the brain. To test the involvement of nicotinic acetylcholine receptors (nAChR) in menthol associated nicotine addiction, we examined proteomic and structural changes in the brain of rodents exposed to nicotine with and without menthol. Western blot analysis of a7, a4, and ß2 nAChR subunit expression suggests that menthol impacts the levels and distribution of several nAChRs in various brain regions. In particular, co-administration of menthol and nicotine appears to promote significant alterations in ß2 and a7 nAChR subunit expression in the hippocampus, amygdala, and striatum of mice. Immunohistochemical analysis of a7 nAChR and synaptic marker protein expression reveals dynamic alterations in post-synaptic structures within hippocampal neurons in response to menthol administration. Because the addition of menthol to tobacco products has been suggested to augment their addictive potential, the current findings reveal several new molecular adaptations that may contribute to its unique addictive profile.

    Lay Language Summary: Recent research out of this lab indicates menthol may increase the addictiveness of nicotine, raising public concern over tobacco products containing menthol.
    Nicotine cigarettes and related tobacco products are major public health burdens, with recent reports from the CDC and Surgeon General attributing over 16 million preventable diseases and 20% of all deaths in the USA to tobacco products in 2013. Directed efforts to understand individual reliance on tobacco are essential. The rise in popularity of menthol flavored nicotine products, especially in young smokers is alarming. Menthol cigarettes, which are marketed as having a milder taste, are associated with increased difficulty in quitting and greater relapse rates, for reasons still unclear
    Research into the molecular mechanisms of substance abuse and drug addiction is still in its infancy, and little is known on the mechanisms by which compounds such as nicotine foster an addiction. Brain regions involving reward and memory formation appear to play an important role in dependence and can contribute to relapse. To date, nicotine is considered the major compound associated with addiction to tobacco products, as it activates pathways
    in the brain associated with reward and pleasure. Nicotine’s major target in the brain is a specialized subset of receptors called nicotinic receptors, whose activation can have far reaching effects.
    A problem commonly associated with tobacco use is the irritation caused by cigarette smoke. Menthol cigarettes were developed and marketed as an alternative with decreased irritation, due to menthol’s ability to produce a cooling sensation. Recent research into menthol, however, shows that menthol acts on the body’s ability to break down nicotine thereby possibly prolonging its effect on nicotinic receptors. Given the widespread distribution of these receptors in the brain, menthol may contribute to changes in nicotinic receptor function in the reward pathway
    In a new study, we examined the effects of chronic menthol and nicotine in adult mice. We explored the effects of nicotine alone and nicotine in conjunction with menthol on the levels and distribution of nicotinic receptors and key synaptic proteins associated with memory formation, decision-making, and impulse control. We report that the combination of nicotine and menthol produced an increase in nicotinic receptor in the brain. Interestingly, we also note that menthol alone was found to impact the expression of several nicotinic receptors and synaptic proteins. How could menthol contribute to nicotine addiction ? In one scenario, it is plausible that menthol can potentiate changes in nicotinic receptors and synaptic proteins that play a role in memory associated mechanisms of tobacco addiction. If true, then menthol and nicotine induced molecular changes could underlie important shifts in neural network activity in brain areas of pleasure such as the limbic system, resulting in an enhanced “feel good” sensation in smokers of menthol cigarettes. Additionally, similar molecular changes in brain centers of memory and emotion could contribute to a higher relapse rates in smokers of menthol cigarettes under times of stress. Finally, early exposure to menthol cigarettes could have long lasting impact on neural activity and regulation, thereby pre- disposing smokers to a life-long struggle with nicotine addiction. Taken together, the combination of menthol with nicotine could induce a state of addiction sooner, increase the difficulty associated with tobacco use cessation, and increase the likelihood of relapse, highlighting the need for a more complete understanding of mechanisms underlying substance addiction.