The emergence of insulin resistance following a chronic high-fat diet regimen coincides with an increase in the reinforcing effects of nicotine in a sex-dependent manner.

The present study assessed the sex-dependent effects of insulin resistance on the reinforcing effects of nicotine. Female and male rats received a chronic high-fat diet (HFD) or regular diet (RD) for 8 weeks. A subset of rats then received vehicle or a dose of streptozotocin (STZ; 25 mg/kg) that induces insulin resistance. To assess insulin resistance, glucose levels were measured 15, 30, 60, 120, and 180 min after an insulin injection (0.75 U/kg). Nine days later, the rats were given extended access to intravenous self-administration (IVSA) of nicotine (0.015, 0.03, 0.06 mg/kg) in an operant box where they consumed their respective diet ad libitum and performed responses for water deliveries. Each nicotine dose was delivered for 4 days with 3 intermittent days of abstinence in their home cage. The day after the last IVSA session, physical signs were compared following administration of mecamylamine (3.0 mg/kg) to precipitate nicotine withdrawal. The results revealed that there were no changes in insulin resistance or nicotine intake in HFD alone rats regardless of sex. Insulin resistance was observed in HFD-fed rats that received STZ, and the magnitude of this effect was greater in males versus females. Our major finding was that nicotine intake was greater among HFD + STZ female rats as compared to males. Lastly, the physical signs of withdrawal were similar across all groups. Our results suggest that females diagnosed with disorders that disrupt insulin signaling, such as diabetes may be at risk of greater vulnerability to nicotine use due to enhanced reinforcing effects of this drug.

Pain-induced impulsivity is sexually dimorphic and mu-opioid receptor sensitive in rats.

RATIONALE AND OBJECTIVES: Pain sensation can negatively impact cognitive function, including impulsivity. Pain-induced changes in impulsivity can contribute to development of psychiatric comorbidities found in those with chronic pain conditions. The goal of this study was to determine whether complete Freund's adjuvant (CFA)-induced pain manipulation enhances impulsivity in rats. Whether the pain-induced impulsivity is sexually dimorphic, and if mu-opioid receptors play a role in these processes. METHODS: Male and female rats were screened for trait impulsivity and designated as high or low impulsive using a delay discounting task. Rats then received a hind paw injection of CFA, and their impulsivity was assessed for 16 days. The effects of morphine on impulsivity were also examined. In a separate experiment, rats were pretreated with beta-funaltrexamine (ß-FNA) to determine the role of mu-opioid receptors on impulsivity. RESULTS: CFA treatment increased impulsivity in males and females. The onset of CFA-induced impulsivity was faster in high impulsive females than males. Morphine blocked CFA-induced impulsivity in both sexes in a dose- and time-dependent manner. ß-FNA prevented the actions of morphine on CFA-induced impulsivity in high impulsive males, but not high impulsive females. Moreover, ß-FNA increased CFA-induced impulsivity in morphine naïve males, but not females. CONCLUSION: These findings demonstrate unique sex differences in CFA-induced impulsivity, response to morphine, and the impact of mu-opioid receptors. A better understanding of cognitive deficits and their mechanisms can provide insight into the development of substance abuse and psychiatric comorbidities that occur in people with chronic pain.

Factors mediating pain-related risk for opioid use disorder.

Pain is a complex experience with far-reaching organismal influences ranging from biological factors to those that are psychological and social. Such influences can serve as pain-related risk factors that represent susceptibilities to opioid use disorder. This review evaluates various pain-related risk factors to form a consensus on those that facilitate opioid abuse. Epidemiological findings represent a high degree of co-occurrence between chronic pain and opioid use disorder that is, in part, driven by an increase in the availability of opioid analgesics and the diversion of their use in a non-medical context. Brain imaging studies in individuals with chronic pain that use/abuse opioids suggest abuse-related mechanisms that are rooted within mesocorticolimbic processing. Preclinical studies suggest that pain states have a limited impact on increasing the rewarding effects of opioids. Indeed, many findings indicate a reduction in the rewarding and reinforcing effects of opioids during pain states. An increase in opioid use may be facilitated by an increase in the availability of opioids and a decrease in access to non-opioid reinforcers that require mobility or social interaction. Moreover, chronic pain and substance abuse conditions are known to impair cognitive function, resulting in deficits in attention and decision making that may promote opioid abuse. A better understanding of pain-related risk factors can improve our knowledge in the development of OUD in persons with pain conditions and can help identify appropriate treatment strategies. This article is part of the special issue on 'Vulnerabilities to Substance Abuse.'.

Insulin restores the neurochemical effects of nicotine in the mesolimbic pathway of diabetic rats.

This study examined whether insulin modulates the neurochemical effects of nicotine in the mesolimbic pathway of diabetic rats. The rats received vehicle or streptozotocin (STZ) to induce hypoinsulinemia. A subset of STZ-treated rats was implanted with insulin pellets that rapidly normalized glucose levels. Two-weeks later, dialysis probes were implanted into the nucleus accumbens (NAc) and ipsilateral ventral tegmental area (VTA). The next day, dialysate samples were collected during baseline and then following systemic administration of nicotine. Samples were also collected following intra-VTA administration of the gamma-aminobutyric acid (GABA)A receptor antagonist, bicuculline. Dopamine, GABA, glutamate, and acetylcholine (ACh) levels were assessed using liquid chromatography/mass spectrometry (LC/MS). The results revealed that vehicle-treated rats displayed a nicotine-induced increase in NAc dopamine levels. In contrast, STZ-treated rats did not display any changes in NAc dopamine following nicotine administration, an effect that was likely related to a concomitant increase in GABA and decrease in glutamate levels in both the NAc and VTA. Intra-VTA administration of bicuculline increased NAc dopamine in vehicle-treated rats, and this effect was absent in STZ-treated rats. Vehicle-treated rats displayed a nicotine-induced increase in ACh levels in the NAc (but not VTA), an effect that was lower in the NAc of STZ-treated rats. Insulin supplementation normalized the neurochemical effects of nicotine in the NAc and VTA of STZ-treated rats, suggesting that insulin modulates the neurochemical effects of nicotine in the mesolimbic pathway of diabetic rats.

Sex differences in nicotine-induced impulsivity and its reversal with bupropion in rats.

BACKGROUND: Enhancement in cognitive impulsivity and the resulting alterations in decision making serve as a contributing factor for the development and maintenance of substance-use disorders. Nicotine-induced increases in impulsivity has been previously reported in male humans and rodents. Although the potential for sex differences in nicotine-induced impulsivity has not been examined. AIMS AND METHODS: In the present study, male and female Sprague Dawley rats were submitted to a delay discounting task, in which several consecutive measures of self-control were taken. Firstly, rats were tested with vehicle, and next with nicotine doses of 0.4 and 0.8 mg/kg. Thereafter, chronic treatment with bupropion started, and the animals were tested again. Half the animals continued to receive 0.8 mg/kg of nicotine, while the rest received nicotine and also a daily dose of 30 mg/kg of bupropion. RESULTS: When the animals were first tested with nicotine, female rats showed a significant nicotine dose dependent increase of impulsive behaviour, whereas male rats only showed a decrease on their elections of the larger but delayed reward under the highest dose of 0.8 mg/kg of nicotine. Treatment with bupropion blocked the effect of nicotine on decision making in female rats, as they showed results close to their baseline levels. On the other hand, bupropion did not affect the nicotine-induced delay discounting in male rats. CONCLUSION: These findings demonstrate sexually dimorphic effects of nicotine on cognitive impulsivity which may help to shed light on nicotine use vulnerabilities observed in women.

Examination of nicotine and saccharin reward in the Goto-Kakizaki diabetic rat model.

Morbidity and mortality attributed to type 2 diabetes have exponentially increased in the US. At exceptionally high risk is a subpopulation of persons with type 2 diabetes who smoke, which are shown to have decreased success rates of smoking cessation than euglycemic smokers. Preclinical research in our laboratory has shown that the rewarding effects of nicotine are enhanced in the streptozotocin and high-fat diet rodent model of diabetes. It is presently unclear whether this enhancement of nicotine reward can be demonstrated in other insulin resistant rat models. This study aimed to determine if a similar increase in nicotine reward is found in Goto-Kakizaki (GK) rats, a model of the spontaneous formation of insulin resistance in an inbred sub-strain of Wistar rat. Nicotine conditioned place preference (CPP) was examined in Sprague-Dawley (SD), Wistar, and GK rats. A robust nicotine CPP was found in SD and Wistar rats, but nicotine CPP was not detected in GK rats. Locomotor activity was also evaluated in all three strains, and GK rats demonstrated significantly less activity as compared to SD and Wistar rats. To further assess reward behavior in GK rats, consumption of saccharin solution was measured over a 48 -h period. GK rats showed a significant increase in saccharin intake compared to SD rats. These findings suggest that GK rats experience an enhanced hedonic processing as compared to SD rats. The lack of nicotine CPP in GK rats may be due to deficits in learning and memory, thus hindering their ability to acquire or express a place preference.

Insulin modulates the strong reinforcing effects of nicotine and changes in insulin biomarkers in a rodent model of diabetes.

This study examined whether the strong reinforcing effects of nicotine and changes in insulin biomarkers observed in diabetic rats are modulated via insulin. A model of diabetes was employed involving administration of streptozotocin (STZ), which produces hypoinsulinemia in rats. The present study included vehicle- or STZ-treated rats that received sham surgery or insulin pellets. Two weeks later, the rats were given extended access to intravenous self-administration (IVSA) of saline or nicotine. Concomitant changes in food intake, water responses, and body weight were assessed during 12 days of IVSA. After the last session, plasma levels of insulin, leptin, amylin, and glucagon-like peptide-1 (GLP-1) were assessed using Luminex® technology. In a separate cohort, phosphorylated insulin receptor substrate-2 (pIRS-2) and insulin growth factor-1 receptor ß (IGF-1Rß) were assessed in the nucleus accumbens (NAc) and ventral tegmental area (VTA) of vehicle- or STZ-treated rats that received sham surgery or an insulin pellet. STZ-treated rats displayed an increase in glucose levels, a decrease in body weight, and an increase in nicotine, food, and water intake relative to controls. STZ-treated rats also displayed a decrease in plasma insulin and leptin levels and an increase in amylin and GLP-1 levels relative to controls. Importantly, all of the STZ-induced changes in behavior and insulin biomarkers were prevented by insulin supplementation. STZ-treated rats also displayed a decrease in pIRS-2 and IGF-1Rß in the NAc (but not VTA), an effect that was also prevented by insulin. These data suggest that insulin systems in the NAc modulate the strong reinforcing effects of nicotine in male diabetic rats.

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

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 (0.2 mg/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 (10 mg/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.

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

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 freund's 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, 12.0 mg/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 12.0 mg/kg produced a CPP in male rats, while female rats exhibited CPP with only the 12.0 mg/kg dose. Seven days after CFA treatment, both male and female rats exhibited a CPP with morphine doses of 4.0 mg/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.

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

RATIONALE: It is presently unclear whether diabetic rats experience greater rewarding effects of nicotine and/or negative affective states produced by nicotine withdrawal. OBJECTIVE: The 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. METHODS: Separate 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. RESULTS: STZ-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. CONCLUSION: The 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.

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.

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.

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.

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.

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.

Progesterone does not affect cocaine-induced conditioned place preference or locomotor activity in male rats.

INTRODUCTION: The present study aimed to determine if, as occurs in female rats, progesterone attenuates cocaine-induced reward and psychomotor responses in male rats. METHODS: The role of progesterone in the acquisition and/or expression of cocaine-induced conditioned place preference (CPP) and locomotor responses of intact male rats was studied. For chronic progesterone treatment, rats received Silastic capsules with either progesterone (100%) or vehicle 1 week prior to conditioning. For acute progesterone treatment, rats received subcutaneous injections of progesterone (500 microg) or vehicle (sesame oil) 4 hours before intraperitoneal injections of saline or cocaine administration (20 mg/kg) on conditioning days (acquisition phase-formation of reward associations) or before testing (expression phase-recall of reward associations). RESULTS: Both progesterone-treatment paradigms produced equivalent progesterone serum levels. Progesterone administered chronically or acutely during the acquisition and expression phases of cocaine conditioning did not block cocaine-induced CPP. Nor did progesterone affect ambulatory or rearing behaviors after cocaine administration. CONCLUSION: These results suggest that, unlike the findings with female rats (in which similar treatment paradigms inhibited the formation and recall of cocaine-induced CPP), progesterone plays a limited role in the cocaine-induced reward or psychomotor responses of male rats.

Sex differences in basal and cocaine-induced alterations in PKA and CREB proteins in the nucleus accumbens.

INTRODUCTION: Alterations in protein kinase (PKA) protein levels have been implicated in the regulation of responses to and development of cocaine addiction. However, the contribution of differences in PKA intracellular cascade to the known sex differences in responses to cocaine is not well understood. This study examined whether there are intrinsic or cocaine-induced alterations in PKA-mediated responses, such as phosphorylation of cyclic AMP response element binding protein, in male and female rats. MATERIALS AND METHODS: To this end, protein levels of PKA and phosphorylated CREB (pCREB) in the caudate putamen (CPu) and nucleus accumbens (NAc) of male and female rats were measured basally or after acute (one 30-mg/kg intraperitoneal injection) or chronic (twice-daily 15-mg/kg injections for 14 days) cocaine administration. Behavioral responses to both cocaine administration paradigms were also studied. RESULTS: Similar to previous findings, ambulatory, rearing, and stereotypic activities were higher in female rats after acute cocaine administration. Sex differences in cocaine-induced responses were also observed after chronic cocaine administration: While males developed a robust sensitization in ambulatory activities to cocaine, females developed tolerance in cocaine-induced rearing and stereotypic activities. In the basal group, females had significantly higher PKA protein levels in the NAc. Regardless of the cocaine administration paradigm, PKA protein levels in the NAc were higher overall in females than in males. Furthermore, after cocaine administration, while pCREB protein levels in male rats were induced for a longer amount of time than in female rats, the magnitude of change on pCREB levels were higher in female than male rats. However, in the CPu, no sex differences in PKA or pCREB protein levels were observed either in the basal group or after acute or chronic cocaine administration. DISCUSSION: Taken together, these findings suggest that sex differences in basal and cocaine-induced alterations in the PKA signaling regulation in the NAc may contribute to sex differences in the psychomotor responses to cocaine.

Basal and cocaine-induced sex differences in the DARPP-32-mediated signaling pathway.

RATIONALE: Behavioral and dopamine responses to cocaine are sexually dimorphic: Female rats exhibit higher levels of locomotor and reward-associated behaviors after cocaine administration and dopamine release than do males. Activation of the dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa (DARPP-32) intracellular cascade mediates responses to cocaine. OBJECTIVE: To examine the possibility that acute cocaine administration alters the DARPP-32 cascade in a sexually dimorphic pattern. MATERIALS AND METHODS: Male and female rats received either saline or cocaine (30 mg/kg). Protein levels of DARPP-32, phosphorylation of DARPP-32 at the Thr34 site (P-Thr34-DARPP-32), protein phosphatase 1 (PP-1), and protein phosphatase 2B (PP-2B) in nucleus accumbens were measured via Western blot analysis. RESULTS: Females had higher protein levels of DARPP-32, P-Thr34-DARPP-32, calcineurin A (CaN-A; catalytic subunit of PP-2B), and calcineurin B (CaN-B; regulatory subunit of PP-2B) than males 5 min after saline treatment. In females, CaN-A protein levels were also higher at 15 min and PP-1 protein levels were higher 30 min after saline administration than males. In male rats, cocaine significantly increased CaN-A protein levels at 30 min and CaN-B protein levels at 15 min. In females, cocaine administration significantly decreased protein levels of DARPP-32, P-Thr34-DARPP-32, and CaN-A at 45 min but increased PP-1 protein levels at 30 min. Overall, males had higher activation of the DARPP-32 pathway after cocaine administration than did females. CONCLUSION: These novel results show that basal and cocaine-induced sex differences in the DARPP-32/PP-1 cascade may be responsible for the sexual dimorphism in acute cocaine-induced behavioral responses.