Arbi Nazarian

Enhanced nicotine self-administration and suppressed dopaminergic systems in a rat model of diabetes

Patients with diabetes display a heightened propensity to use tobacco; however, it is unclear whether they experience enhanced rewarding effects of nicotine. Thus, this study examined the reinforcing effects of nicotine in a rodent model of diabetes involving administration of streptozotocin (STZ), a drug that is toxic to pancreatic insulin‐producing cells. The first study compared STZ‐ and vehicle‐treated rats that had 23‐hour access to intravenous self‐administration (IVSA) of nicotine or saline and concomitant access to food and water. In order to examine the contribution of dopamine to our behavioral effects, dopamine transporter (DAT), D1 and D2 receptor levels were compared in the nucleus accumbens (NAc) following 10 days of nicotine or saline IVSA. Dopamine levels in the NAc were also compared following nicotine administration. Lastly, nicotine metabolism and dose‐dependent effects of nicotine IVSA were assessed. The results revealed that STZ‐treated rats displayed enhanced nicotine intake and a robust increase in food and water intake relative to controls. Protein analysis revealed an increase in DAT and a decrease in D1 receptor levels in the NAc of STZ‐ versus vehicle‐treated rats regardless of IVSA condition. STZ‐treated rats also displayed suppressed NAc dopamine levels during baseline and in response to nicotine. STZ treatment did not alter our assessment of nicotine metabolism. Furthermore, STZ treatment increased nicotine IVSA in a dose‐dependent manner. Our findings suggest that STZ‐treatment increased the rewarding effects of nicotine. This suggests that strong reinforcing effects of nicotine may contribute to greater tobacco use in patients with diabetes.

Insulin resistant rats display enhanced rewarding effects of nicotine

BACKGROUND Tobacco use among persons with Type II diabetes exponentially increases negative health consequences and mortality rates. It is especially troubling that diabetic persons who smoke have a greater difficulty with tobacco cessation as compared to non-diabetic smokers. Diabetes is a metabolic syndrome that consists of insulin resistance due to disruptions in insulin signaling. We have previously shown that insulin depletion enhances the motivational effects of nicotine. METHODS The present study expands our previous work by examining whether insulin resistance, produced by a high-fat diet (HFD) regimen, enhances the rewarding effects of nicotine, as measured by the conditioned place preference (CPP) paradigm. Rats were placed on either a regular diet (RD) or a HFD for 5 weeks, after which they were assessed for insulin resistance via blood glucose measurements after an insulin challenge. Rats then underwent a nicotine CPP study. RESULTS The findings revealed that HFD produced insulin resistant and non-insulin resistant animals. Interestingly, the magnitude of nicotine CPP was larger in insulin resistant rats versus RD rats. Nicotine CPP was absent in non-insulin resistant animals. A similar increase in body weight was observed in insulin resistant and non-insulin resistant rats as compared to RD rats. These findings suggest that neither the increased body weight nor the HFD per se in the insulin resistant rats contributed to the enhanced nicotine reward. CONCLUSION These present study suggests that insulin resistant rats undergo unique neurobiological changes related to a disruption in insulin signaling that promotes the rewarding effects of nicotine.

Sex differences in formalin-evoked primary afferent release of substance P.

Sex differences in pain have been well documented; however, the mechanisms involved remain to be elucidated. The present study examined whether sex differences exist in the functioning of primary afferent fibres by assessing formalin‐evoked release of substance P by way of neurokinin 1 receptor (NK1r) internalization. The study also investigated whether the observed effects would be oestradiol‐sensitive.

Hydrocodone and Morphine Possess Similar Rewarding Effects and Reduce ERK and CREB Phosphorylation in the Nucleus Accumbens

The number of prescriptions for hydrocodone‐containing opioid analgesics has greatly increased over the past decade. This increase has led to an associated enhancement in the nonmedical use of hydrocodone products. There is a lack of evidence to determine the extent of the rewarding effects and signal transduction properties of hydrocodone. Therefore, this study aimed to examine the rewarding properties of hydrocodone (1 and 5 mg/kg) and morphine (1 and 5 mg/kg) using the conditioned place preference paradigm (CPP) in rats. Both hydrocodone and morphine produced a CPP at the 5 mg/kg dose, but not the lower 1 mg/kg dose, suggesting that both drugs possess similar rewarding properties in the CPP paradigm. Moreover, hydrocodone and morphine equally reduced phosphorylation levels of ERK and CREB proteins in the nucleus accumbens, suggesting that both drugs exert their effects through signal transduction pathways known to be involved in drug reward and reinforcement. These findings suggest that hydrocodone should be viewed as similarly capable of producing rewarding and euphoric properties as morphine. Synapse 2012.

Enhanced vulnerability to tobacco use in persons with diabetes: A behavioral and neurobiological framework

Tobacco use significantly magnifies the negative health complications associated with diabetes. Although tobacco use is strongly discouraged in persons with diabetes, clinical evidence suggests that they often continue to smoke and have more difficulty quitting despite serious contraindications. Here, we suggest that a potential reason for enhanced vulnerability to tobacco use in persons with diabetes is greater rewarding effects of nicotine. This review summarizes pre-clinical evidence indicating that the rewarding effects of nicotine are enhanced in rodent models of type 1 and type 2 diabetes. We also provide a framework of neurobiological mechanisms that are posited to promote tobacco use in persons with diabetes. This framework suggests that diabetes induces a disruption in insulin signaling that leads to a suppression of dopamine systems in the mesolimbic reward pathway. Lastly, we consider the clinical implications of enhanced rewarding effects of nicotine that may promote tobacco use in persons with diabetes. The clinical efficacy of smoking cessation medications that enhance dopamine are important to consider, given that persons with diabetes may display disrupted dopaminergic mechanisms. Future work is needed to better understand the complex interaction of dopamine and insulin in order to develop better smoking cessation medications for persons with diabetes.

Acetaminophen modulation of hydrocodone reward in rats

Abuse of prescription opioid analgesics in non-medical context has been on the rise over the past decade. The most commonly abused analgesic in this drug class consists of a combined formulation of hydrocodone and acetaminophen. The present study was aimed to determine the rewarding effects of hydrocodone, acetaminophen, and their combination using the conditioned place preference (CPP) paradigm. Using a 6-day CPP paradigm, rats were paired with hydrocodone (0.5, 1.0 or 5.0 mg/kg) or acetaminophen (50, 100 or 300 mg/kg) to determine whether the drugs given alone would produce a CPP. Rats conditioned with the highest dose of hydrocodone exhibited place preference, whereas rats conditioned with acetaminophen did not demonstrate place preference. In a second experiment, varying doses of hydrocodone and acetaminophen were combined to determine whether acetaminophen would enhance hydrocodone reward. Acetaminophen (100 mg/kg) enhanced the rewarding effects of hydrocodone (1mg/kg), although the effect was unique to this particular dose combination. Higher or lower doses of acetaminophen combined with hydrocodone did not alter hydrocodone CPP. The present findings suggest that acetaminophen has a limited potential of modulating the rewarding properties of hydrocodone in rats.

Both nicotine reward and withdrawal are enhanced in a rodent model of diabetes

RationaleIt is presently unclear whether diabetic rats experience greater rewarding effects of nicotine and/or negative affective states produced by nicotine withdrawal.ObjectiveThe present study utilized a rodent model of diabetes to examine the rewarding effects of nicotine and negative affective states and physical signs produced by withdrawal.MethodsSeparate groups of rats received systemic administration of either vehicle or streptozotocin (STZ), which destroys insulin-producing beta cells in the pancreas and elevates glucose levels. Place conditioning procedures were utilized to compare the rewarding effects of nicotine (conditioned place preference; CPP) and negative affective states produced by withdrawal (conditioned place aversion; CPA) in vehicle- and STZ-treated rats. CPA and physical signs of withdrawal were compared after administration of the nicotinic receptor antagonist mecamylamine to precipitate withdrawal in nicotine-dependent rats. A subsequent study utilized elevated plus maze (EPM) procedures to compare anxiety-like behavior produced by nicotine withdrawal in vehicle- and STZ-treated rats.ResultsSTZ-treated rats displayed greater rewarding effects of nicotine and a larger magnitude of aversive effects and physical signs produced by withdrawal as compared to vehicle-treated controls. STZ-treated rats also displayed higher levels of anxiety-like behavior on the EPM during nicotine withdrawal as compared to controls.ConclusionThe finding that both nicotine reward and withdrawal are enhanced in a rodent model of diabetes implies that the strong behavioral effects of nicotine promote tobacco use in persons with metabolic disorders, such as diabetes.

Dissociation of morphine analgesic effects in the sensory and affective components of formalin-induced spontaneous pain in male and female rats.

Sex differences in the analgesic effects of morphine have been previously reported in various models that represent the sensory component of pain. However, pain sensation is a complex process that consists of both sensory and affective components. It is presently unclear whether the analgesic effects of morphine between the sensory and affective components of pain are sexually dimorphic. Moreover, differences in morphine dose-response in the two components of pain have not been examined in male and female rats. Therefore, we examined the analgesic effects of morphine on the sensory and affective components of formalin-induced pain behaviors in male and female rats. To discern the sensory component, rats were pretreated with varying doses of morphine and then intraplantar formalin-induced paw flinches were measured. Morphine reduced the number of formalin-induced paw flinches at a treatment dose of 4.0mg/kg. Morphine analgesia was similar across the sexes in the early (phase 1) and late phase (phase 2) of the formalin test. To examine the affective component, rats were pretreated with varying doses of morphine, and then intraplantar formalin-induced conditioned place aversion (CPA) was examined. Formalin produced CPA, which was blocked by morphine at doses of 1.0mg/kg and higher in male and female rats. Lastly, formalin-induced cFos expression and the effects of systemic morphine were examined in the superficial dorsal horn of the spinal cord. Intraplantar formalin produced robust expression of cFos; however, morphine did not attenuate the cFos expression. These results demonstrate a notable dissociation of the analgesic effects of morphine by detecting a fourfold shift in the minimum effective dose between the sensory and affective components of formalin-induced spontaneous pain, that were similar between male and female rats. The findings further suggest disparate mechanisms involved in systemic morphine-induced analgesia in the two components of formalin-induced pain.

Morphine antinociception on thermal sensitivity and place conditioning in male and female rats treated with intraplantar complete freund’s adjuvant

HIGHLIGHTSMorphine antinociception is sexually dimorphic one day after CFA‐induced persistent nociception.Sex differences in morphine antinociception were resolved seven days after CFA treatment.Morphine conditioned place preference in CFA treated rats was enhanced over time.Sexually dimorphic morphine antinociception is impacted by the chronicity of pain. ABSTRACT The experience of pain is characterized by the presence of a noxious sensory stimulus combined with negative affect, which is often treated clinically through administration of drugs such as morphine or other opioids. This study investigated the effects of morphine one and seven days after intraplantar administration of complete freunds adjuvant (CFA) in male and female rats. Hargreaves test for thermal nociception and conditioned place preference (CPP) were performed following subcutaneous administration of saline or morphine (1.0, 4.0, 8.0, 12.0mg/kg). Hargreaves test results revealed that male rats were more sensitive to morphine antinociceptive actions as compared to female rats one day after CFA treatment; however, this sex difference was not detected seven days after CFA treatment. One day after CFA treatment, morphine doses of 8.0 and 12.0mg/kg produced a CPP in male rats, while female rats exhibited CPP with only the 12.0mg/kg dose. Seven days after CFA treatment, both male and female rats exhibited a CPP with morphine doses of 4.0mg/kg and higher. These results reveal sexually dimorphic properties of morphine in the paw withdrawal latencies and conditioned place preference models, representing reflexive and non‐reflexive behavioral assays employed to examine inflammatory nociception. Our findings also suggest that antinociceptive effects of morphine are dynamic across early and later periods of CFA‐induced inflammatory pain.

Insulin dependent and independent normalization of blood glucose levels reduces the enhanced rewarding effects of nicotine in a rodent model of diabetes

ABSTRACT The rewarding effects of nicotine have been previously shown to be enhanced in rodent models of diabetes. It is presently unclear whether the enhanced nicotine reward observed in the diabetes models are mediated via an insulin or glucose mechanism. This study examined whether the enhanced rewarding effects of nicotine observed in streptozotocin (STZ)‐treated rats are insulin‐mediated. Male and female rats were treated with STZ and the rewarding effects of nicotine (0.2mg/kg) were measured using the conditioned place preference (CPP) procedure. Some STZ‐treated animals received insulin supplementation via subcutaneous pellets immediately after STZ administration, while other rats received daily injections of dapagliflozin (10mg/kg), a sodium‐glucose cotransporter‐2 inhibitor. Both male and female STZ‐treated rats displayed hyperglycemia, and their blood glucose levels (BGLs) were normalized to control levels following insulin supplementation or dapagliflozin administration. STZ‐treated male rats displayed higher nicotine CPP relative to vehicle‐treated controls. This effect was abolished in rats that received insulin supplementation or dapagliflozin administration. STZ‐treated female rats displayed reduced levels of nicotine CPP as compared to male rats, regardless of treatment condition. These results suggest that glucose plays a major role in modulating the rewarding effects of nicotine in male rats treated with STZ. HIGHLIGHTSSTZ‐treated male rats show an enhancement in nicotine CPP more so than control rats.Insulin and dapagliflozin normalize blood glucose level of STZ‐treated rats.Insulin and dapagliflozin reduce the enhanced nicotine CPP of STZ‐treated rats.Enhanced nicotine CPP of STZ‐treated rats is due to an increase in glucose levels.