scholarly journals Shortening time for access to alcohol drives up front-loading behavior, bringing consumption in male rats to the level of females

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Annabelle Flores-Bonilla ◽  
Barbara De Oliveira ◽  
Andrea Silva-Gotay ◽  
Kyle W. Lucier ◽  
Heather N. Richardson
Keyword(s):  
Sex Differences ◽  
Alcohol Drinking ◽  
Fixed Ratio ◽  
Female Rats ◽  
Male Rats ◽  
Drinking Patterns ◽  
Self Administration ◽  
Dark Cycle ◽  
Male And Female ◽  
Schedule Of Reinforcement

Abstract Background Incentives to promote drinking (“happy hour”) can encourage faster rates of alcohol consumption, especially in women. Sex differences in drinking dynamics may underlie differential health vulnerabilities relating to alcohol in women versus men. Herein, we used operant procedures to model the happy hour effect and gain insight into the alcohol drinking dynamics of male and female rats. Methods Adult male and female Wistar rats underwent operant training to promote voluntary drinking of 10% (w/v) alcohol (8 rats/sex). We tested how drinking patterns changed after manipulating the effort required for alcohol (fixed ratio, FR), as well as the length of time in which rats had access to alcohol (self-administration session length). Rats were tested twice within the 12 h of the dark cycle, first at 2 h (early phase of the dark cycle, “early sessions”) and then again at 10 h into the dark cycle (late phase of the dark cycle, “late sessions”) with an 8-h break between the two sessions in the home cage. Results Adult females consumed significantly more alcohol (g/kg) than males in the 30-min sessions with the FR1 schedule of reinforcement when tested late in the dark cycle. Front-loading of alcohol was the primary factor driving higher consumption in females. Changing the schedule of reinforcement from FR1 to FR3 reduced total consumption. Notably, this manipulation had minimal effect on front-loading behavior in females, whereas front-loading behavior was significantly reduced in males when more effort was required to access alcohol. Compressing drinking access to 15 min to model a happy hour drove up front-loading behavior, generating alcohol drinking patterns in males that were similar to patterns in females (faster drinking and higher intake). Conclusions This strategy could be useful for exploring sex differences in the neural mechanisms underlying alcohol drinking and related health vulnerabilities. Our findings also highlight the importance of the time of testing for detecting sex differences in drinking behavior.

scholarly journals SHORTENING TIME FOR ALCOHOL ACCESS DRIVES UP FRONT-LOADING BEHAVIOR, BRINGING CONSUMPTION IN MALE RATS TO THE LEVEL OF FEMALES

2021 ◽  
Author(s):  
Annabelle Flores-Bonilla ◽  
Barbara De Oliveira ◽  
Andrea Silva-Gotay ◽  
Kyle W. Lucier ◽  
Heather N. Richardson
Keyword(s):  
Sex Differences ◽  
Alcohol Drinking ◽  
Drinking Behavior ◽  
Fixed Ratio ◽  
Male Rats ◽  
Drinking Patterns ◽  
Self Administration ◽  
Dark Cycle ◽  
Female Wistar Rats ◽  
Total Alcohol

Alcohol can have more detrimental effects on mental health in women, even when intake is comparable or higher in men. This may relate to a differential pattern of drinking, e.g., how rapidly alcohol is consumed. We used operant procedures to gain insight into sex differences in the drinking dynamics of rats. Adult male and female Wistar rats underwent operant training to promote voluntary drinking of 10% (w/v) alcohol (8 rats/sex). We tested how drinking patterns changed after manipulating the effort required for alcohol (fixed ratio, FR), as well as the length of time in which animals had access to alcohol (self-administration session length). Rats were tested twice within the 12 hours of the dark cycle, at 2 hours (early sessions) and 10 hours into the dark cycle (late sessions). As expected, adult females consumed significantly more alcohol than males in the 30-minute sessions with the FR1 paradigm. Alcohol consumption within females was higher in the late sessions compared to early sessions, whereas this difference was not found within males. Front-loading of alcohol (heavier drinking in the first five minutes of the session) was the primary factor underlying higher consumption in females, and this sex difference was accentuated in the late sessions. Increasing the effort required from FR1 to FR3 reduced alcohol drinking in both sexes. Front-loading behavior remained in females in both early and late sessions, whereas males exhibited minimal front-loading behavior only in the early sessions. Compressing drinking access to 15-minutes drove up front-loading behavior, producing total alcohol intake levels that were comparable in both sexes. This strategy could be useful for exploring sex differences in the effect of voluntary alcohol drinking on the brain. Our findings also highlight the importance of the time of testing for detecting sex differences in drinking behavior.

scholarly journals Sex Differences in Escalated Methamphetamine Self-Administration and Altered Gene Expression Associated With Incubation of Methamphetamine Seeking

2019 ◽  
Vol 22 (11) ◽  
pp. 710-723 ◽  
Author(s):  
Atul P Daiwile ◽  
Subramaniam Jayanthi ◽  
Bruce Ladenheim ◽  
Michael T McCoy ◽  
Christie Brannock ◽  
...  
Keyword(s):  
Sex Differences ◽  
Nucleus Accumbens ◽  
Fixed Ratio ◽  
Female Rats ◽  
Male Rats ◽  
Mrna Levels ◽  
Self Administration ◽  
Male And Female ◽  
Orexin Receptors ◽  
Male And Female Rats

Abstract Background Methamphetamine (METH) use disorder is prevalent worldwide. There are reports of sex differences in quantities of drug used and relapses to drug use among individuals with METH use disorder. However, the molecular neurobiology of these potential sex differences remains unknown. Methods We trained rats to self-administer METH (0. 1 mg/kg/infusion, i.v.) on an fixed-ratio-1 schedule for 20 days using two 3-hour daily METH sessions separated by 30-minute breaks. At the end of self-administration training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 and 30. Twenty-four hours later, nucleus accumbens was dissected and then used to measure neuropeptide mRNA levels. Results Behavioral results show that male rats increased the number of METH infusions earlier during self-administration training and took more METH than females. Both male and female rats could be further divided into 2 phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH self-administration experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin and hypocretin/orexin receptors than males, whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of nucleus accumbens dynorphin after METH self-administration. Moreover, there were significant correlations between nucleus accumbens Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. Conclusion Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.

scholarly journals Analysis of sex differences in dietary copper-fructose interaction-induced alterations of gut microbial activity in relation to hepatic steatosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ming Song ◽  
Fang Yuan ◽  
Xiaohong Li ◽  
Xipeng Ma ◽  
Xinmin Yin ◽  
...  
Keyword(s):  
Sex Differences ◽  
Microbial Activity ◽  
Hepatic Steatosis ◽  
Female Rats ◽  
Male Rats ◽  
Calorie Intake ◽  
Dietary Copper ◽  
Male And Female ◽  
Male And Female Rats ◽  
Rrna Sequencing

Abstract Background Inadequate copper intake and increased fructose consumption represent two important nutritional problems in the USA. Dietary copper-fructose interactions alter gut microbial activity and contribute to the development of nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine whether dietary copper-fructose interactions alter gut microbial activity in a sex-differential manner and whether sex differences in gut microbial activity are associated with sex differences in hepatic steatosis. Methods Male and female weanling Sprague-Dawley (SD) rats were fed ad libitum with an AIN-93G purified rodent diet with defined copper content for 8 weeks. The copper content is 6 mg/kg and 1.5 mg/kg in adequate copper diet (CuA) and marginal copper diet (CuM), respectively. Animals had free access to either deionized water or deionized water containing 10% fructose (F) (w/v) as the only drink during the experiment. Body weight, calorie intake, plasma alanine aminotransferase, aspartate aminotransferase, and liver histology as well as liver triglyceride were evaluated. Fecal microbial contents were analyzed by 16S ribosomal RNA (16S rRNA) sequencing. Fecal and cecal short-chain fatty acids (SCFAs) were determined by gas chromatography-mass spectrometry (GC-MS). Results Male and female rats exhibit similar trends of changes in the body weight gain and calorie intake in response to dietary copper and fructose, with a generally higher level in male rats. Several female rats in the CuAF group developed mild steatosis, while no obvious steatosis was observed in male rats fed with CuAF or CuMF diets. Fecal 16S rRNA sequencing analysis revealed distinct alterations of the gut microbiome in male and female rats. Linear discriminant analysis (LDA) effect size (LEfSe) identified sex-specific abundant taxa in different groups. Further, total SCFAs, as well as, butyrate were decreased in a more pronounced manner in female CuMF rats than in male rats. Of note, the decreased SCFAs are concomitant with the reduced SCFA producers, but not correlated to hepatic steatosis. Conclusions Our data demonstrated sex differences in the alterations of gut microbial abundance, activities, and hepatic steatosis in response to dietary copper-fructose interaction in rats. The correlation between sex differences in metabolic phenotypes and alterations of gut microbial activities remains elusive.

scholarly journals Functional implications of the sex differences in transporter abundance along the rat nephron: modeling and analysis

2019 ◽  
Vol 317 (6) ◽  
pp. F1462-F1474 ◽  
Author(s):  
Rui Hu ◽  
Alicia A. McDonough ◽  
Anita T. Layton
Keyword(s):  
Sex Differences ◽  
Computational Models ◽  
Female Rats ◽  
Male Rats ◽  
Female Rat ◽  
Distal Nephron ◽  
Male And Female ◽  
Modeling And Analysis ◽  
Functional Implications ◽  
Rat Kidneys

The goal of the present study was to investigate the functional implications of sexual dimorphism in the pattern of transporters along the rodent nephron as reported by Veiras et al. ( J Am Soc Nephrol 28: 3504–3517, 2017). To do so, we developed sex-specific computational models of water and solute transport along the superficial nephrons from male and female rat kidneys. The models account for the sex differences in the abundance of apical and basolateral transporters, single nephron glomerular filtration rate, and tubular dimensions. Model simulations predict that ~70% and 60% of filtered Na+ is reabsorbed by the proximal tubule of male and female rat kidneys, respectively. The lower fractional Na+ reabsorption in female kidneys is due primarily to their smaller transport area, lower Na+/H+ exchanger activity, and lower claudin-2 abundance, culminating in significantly larger fractional delivery of water and Na+ to the downstream nephron segments in female kidneys. Conversely, the female distal nephron exhibits a higher abundance of key Na+ transporters, including Na+-K+-Cl− cotransporters, Na+-Cl− cotransporters, and epithelial Na+ channels. The higher abundance of transporters accounts for the enhanced water and Na+ transport along the female, relative to male, distal nephron, resulting in similar urine excretion between the sexes. Consequently, in response to a saline load, the Na+ load delivered distally is greater in female rats than male rats, overwhelming transport capacity and resulting in higher natriuresis in female rats.

scholarly journals Sex differences in ET-1 receptor expression and Ca2+ signaling in the IMCD

2013 ◽  
Vol 305 (8) ◽  
pp. F1099-F1104 ◽  
Author(s):  
Chunhua Jin ◽  
Joshua S. Speed ◽  
Kelly A. Hyndman ◽  
Paul M. O'Connor ◽  
David M. Pollock
Keyword(s):  
Sex Differences ◽  
Radioligand Binding ◽  
Collecting Duct ◽  
Receptor Activation ◽  
Receptor Expression ◽  
Female Rats ◽  
Male Rats ◽  
Male And Female ◽  
Male And Female Rats ◽  
Intracellular Ca

The inner medullary collecting duct (IMCD) is the nephron segment with the highest production of endothelin-1 (ET-1) and the greatest expression of ET-1 receptors that function to adjust Na+ and water balance. We have reported that male rats have reduced natriuresis in response to direct intramedullary infusion of ET-1 compared with female rats. Our aim was to determine whether alterations of ET-1 receptor expression and downstream intracellular Ca2+ signaling within the IMCD could account for these sex differences. IMCDs from male and female rats were isolated for radioligand binding or microdissected for intracellular Ca2+ ([Ca2+]i) measurement by fluorescence imaging of fura-2 AM. IMCD from male and female rats had similar ETB expression (655 ± 201 vs. 567 ± 39 fmol/mg protein, respectively), whereas male rats had significantly higher ETA expression (436 ± 162 vs. 47 ± 29 fmol/mg protein, respectively; P < 0.05). The [Ca2+]i response to ET-1 was significantly greater in IMCDs from male compared with female rats (288 ± 52 vs. 118 ± 32 AUC, nM × 3 min, respectively; P < 0.05). In IMCDs from male rats, the [Ca2+]i response to ET-1 was significantly blunted by the ETA antagonist BQ-123 but not by the ETB antagonist BQ-788 (control: 137 ± 27; BQ-123: 53 ± 11; BQ-788: 84 ± 25 AUC, nM × 3 min; P < 0.05), consistent with greater ETA receptor function in male rats. These data demonstrate a sex difference in ETA receptor expression that results in differences in ET-1 Ca2+ signaling in IMCD. Since activation of ETA receptors is thought to oppose ETB receptor activation, enhanced ETA function in male rats could limit the natriuretic effects of ETB receptor activation.

Gonadal and sex steroid feedback regulation of gonadotrophin mRNA levels and secretion in neonatal male and female rats

1989 ◽  
Vol 3 (2) ◽  
pp. 139-144 ◽  
Author(s):  
P. Pakarinen ◽  
I. Huhtaniemi
Keyword(s):  
Sex Differences ◽  
Feedback Regulation ◽  
Female Rats ◽  
Male Rats ◽  
Sex Steroid ◽  
Mrna Levels ◽  
Negative Feedback Regulation ◽  
Α Subunit ◽  
Male And Female ◽  
Male And Female Rats

ABSTRACT Serum and pituitary LH and FSH, and their pituitary mRNA levels, were measured in neonatal male and female rats after gonadectomy and after gonadectomy with sex steroid replacement. The animals were gonadectomized on day 3 of life, and those given sex steroid replacement were implanted with silicone elastomer capsules containing testosterone for males and diethylstilboestrol for females. Shamoperated rats served as controls. The animals were killed 4 or 8 days later and the sera and pituitaries collected. Pituitary contents of mRNAs for the α subunit, FSH-β and LH-β were determined by blot hybridization using corresponding cDNAs. Distinct sex differences were found in the mRNA responses to gonadectomy and steroid replacement. In the males, gonadectomy increased all mRNA levels at 7 days of age. In the females, a rise on day 7 was detected only for FSH-β; the other mRNAs were increased on day 11 of age. The steroid replacements reversed all the post-gonadectomy increases of mRNAs in both sexes. Moreover, the common α and LH-β mRNAs of the male animals were consistently suppressed below control levels. The serum concentrations of gonadotrophins increased after gonadectomy on day 7 in the males but only on day 11 in the females. The steroid replacements also suppressed the post-gonadectomy increases in serum gonadotrophins, but only the serum concentration of FSH in the females was reduced below controls. Pituitary gonadotrophin concentrations were not affected by gonadectomy, but the steroids suppressed LH in the males and FSH in the females. It is concluded that the onset of negative-feedback regulation of gonadotrophin synthesis by gonads and/or gonadal steroids starts earlier in male rats, before 7 days of age. In female rats these responses appear between 7 and 11 days of age. Clear sex differences were observed in how gonadotrophin mRNAs and pituitary and serum hormone levels responded to gonadectomy and steroid replacement in the neonatal period. Some of the responses differed from those previously reported in adult animals.

scholarly journals Sex Differences in the Effect of Alcohol Drinking on Myelinated Axons in the Anterior Cingulate Cortex of Adolescent Rats

2019 ◽  
Vol 9 (7) ◽  
pp. 167
Author(s):  
Tavares ◽  
Silva-Gotay ◽  
Riad ◽  
Bengston ◽  
Richardson
Keyword(s):  
Sex Differences ◽  
Alcohol Drinking ◽  
Alcohol Exposure ◽  
Anterior Cingulate ◽  
Myelinated Fiber ◽  
Drinking Patterns ◽  
Self Administration ◽  
Fiber Density ◽  
Myelinated Axons ◽  
Nodal Domains

Cognitive deficits associated with teenage drinking may be due to disrupted myelination of prefrontal circuits. To better understand how alcohol affects myelination, male and female Wistar rats (n = 7–9/sex/treatment) underwent two weeks of intermittent operant self-administration of sweetened alcohol or sweetened water early in adolescence (postnatal days 28–42) and we tested for macro- and microstructural changes to myelin. We previously reported data from the males of this study showing that alcohol drinking reduced myelinated fiber density in layers II–V of the anterior cingulate division of the medial prefrontal cortex (Cg1); herein, we show that myelinated fiber density was not significantly altered by alcohol in females. Alcohol drinking patterns were similar in both sexes, but males were in a pre-pubertal state for a larger proportion of the alcohol exposure period, which may have contributed to the differential effects on myelinated fiber density. To gain more insight into how alcohol impacts myelinated axons, brain sections from a subset of these animals (n = 6/sex/treatment) were used for microstructural analyses of the nodes of Ranvier. Confocal analysis of nodal domains, flanked by immunofluorescent-labeled contactin-associated protein (Caspr) clusters, indicated that alcohol drinking reduced nodal length-to-width ratios in layers II/III of the Cg1 in both sexes. Despite sex differences in the underlying cause (larger diameter axons after alcohol in males vs. shorter nodal lengths after alcohol in females), reduced nodal ratios could have important implications for the speed and integrity of neural transmission along these axons in both males and females. Alcohol-induced changes to myelinated axonal populations in the Cg1 may contribute to long-lasting changes in prefrontal function associated with early onset drinking.

scholarly journals Lasting effects of repeated Δ9-tetrahydrocannabinol (THC) vapor inhalation during adolescence in male and female rats

2018 ◽  
Author(s):  
Jacques D. Nguyen ◽  
K. M. Creehan ◽  
Tony M. Kerr ◽  
Michael A. Taffe
Keyword(s):  
Propylene Glycol ◽  
Radio Telemetry ◽  
Female Rats ◽  
Male Rats ◽  
Control Group ◽  
Self Administration ◽  
Male And Female ◽  
Male Adolescents ◽  
Male And Female Rats ◽  
Adolescent Groups

AbstractAdolescents are regularly exposed to Δ9-tetrahydrocannabinol (THC) via smoking, and, more recently, vaping, cannabis / extracts. Growing legalization of cannabis for medical and recreational purposes, combined with decreasing perceptions of harm, makes it increasingly important to determine the consequences of frequent adolescent exposure for motivated behavior and lasting tolerance in response to THC. Male and female rats inhaled THC vapor, or that from the propylene glycol (PG) vehicle, twice daily for 30 minutes from postnatal day (PND) 35-39 and PND 42-45 using an e-cigarette system. Thermoregulatory responses to vapor inhalation were assessed by radio-telemetry during adolescence and from PND 86-94; chow intake was assessed in adulthood. Blood samples were obtained from additional adolescent groups following initial THC inhalation and after four days of twice daily exposure. Additional groups exposed repeatedly to THC or PG during adolescence were evaluated for intravenous self-administration of oxycodone as adults. Female, not male, adolescents developed tolerance to the hypothermic effects of THC inhalation in the first week of repeated exposure despite similar plasma THC levels. Each sex exhibited tolerance to THC hypothermia in adulthood after repeated adolescent THC with THC greater potency exhibited in females. Repeated-THC male rats consumed more food than their PG treated control group, in the absence of a significant bodyweight difference. Adolescent THC did not alter oxycodone self-administration in either sex, but increased fentanyl self-administration in females. Repeated THC vapor inhalation in adolescent rats results in lasting consequences observable in adulthood.AbbreviationsPG, propylene glycol; THC, Δ9tetrahydrocannabinol;

scholarly journals Sex Differences in a Rat Model of Peripheral Neuropathic Pain and Associated Levels of Endogenous Cannabinoid Ligands

2021 ◽  
Vol 2 ◽  
Author(s):  
Laura Boullon ◽  
David P. Finn ◽  
Álvaro Llorente-Berzal
Keyword(s):  
Sex Differences ◽  
Neuropathic Pain ◽  
Sexual Dimorphism ◽  
Female Rats ◽  
Male Rats ◽  
World Population ◽  
Chronic Neuropathic Pain ◽  
Peripheral Neuropathic Pain ◽  
Male And Female ◽  
Endogenous Cannabinoid

Chronic neuropathic pain is a major unmet clinical need affecting 10% of the world population, the majority of whom suffer from co-morbid mood disorders. Sex differences have been reported in pain prevalence, perception and response to analgesics. However, sexual dimorphism in chronic neuropathic pain and the associated neurobiology, are still poorly understood. The lack of efficacy and the adverse effects associated with current pharmacological treatments, further underline the need for new therapeutic targets. The endocannabinoid system (ECS) is a lipid signalling system which regulates a large number of physiological processes, including pain. The aim of this study was to investigate sexual dimorphism in pain-, anxiety- and depression-related behaviours, and concomitant alterations in supraspinal and spinal endocannabinoid levels in the spared nerve injury (SNI) animal model of peripheral neuropathic pain. Sham or SNI surgery was performed in adult male and female Sprague-Dawley rats. Mechanical and cold allodynia was tested weekly using von Frey and acetone drop tests, respectively. Development of depression-related behaviours was analysed using sucrose splash and sucrose preference tests. Locomotor activity and anxiety-related behaviours were assessed with open field and elevated plus maze tests. Levels of endocannabinoid ligands and related N-acylethanolamines in supraspinal regions of the descending inhibitory pain pathway, and spinal cord, were analysed 42 days post-surgery. SNI surgery induced allodynia in rats of both sexes. Female-SNI rats exhibited earlier onset and greater sensitivity to cold and mechanical allodynia than their male counterparts. In male rats, SNI induced a significant reduction of rearing, compared to sham controls. Trends for depressive-like behaviours in females and for anxiety-like behaviours in males were observed after SNI surgery but did not reach statistical significance. No concomitant alterations in levels of endogenous cannabinoid ligands and related N-acylethanolamines were observed in the regions analysed. Our results demonstrate differential development of SNI-induced nociceptive behaviour between male and female rats suggesting important sexually dimorphic modifications in pain pathways. SNI had no effect on depression- or anxiety-related behaviours in animals of either sex, or on levels of endocannabinoid ligands and related N-acylethanolamines across the regions involved in the descending modulation of nociception at the time points investigated.

scholarly journals Relapse to cotinine seeking in rats: Differential effects of sex

2021 ◽  
Author(s):  
Xiaoying Tan ◽  
Elizabeth Neslund ◽  
Zheng-Ming Ding
Keyword(s):  
Female Rats ◽  
Male Rats ◽  
Potential Mechanism ◽  
Self Administration ◽  
Drug Seeking ◽  
Male And Female ◽  
Rat Models ◽  
Significant Challenge ◽  
Male And Female Rats ◽  
Future Treatments

Relapse is a defining feature of smoking and a significant challenge in cessation management. Elucidation of novel mechanisms underlying relapse may inform future treatments. Cotinine, the major metabolite of nicotine, has been shown to support intravenous self-administration in rats, suggesting it as one potential mechanism contributing to nicotine reinforcement. However, it remains unknown whether cotinine would induce relapse-like behaviors. The current study investigated relapse to cotinine seeking in two relapse models, the reinstatement of drug seeking and incubation of drug craving models. In the reinstatement model, rats were trained to self-administer cotinine, extinguished cotinine-associated responses, and underwent cue-, drug-, or stress-induced reinstatement. Conditioned cues associated with cotinine self-administration, cotinine (1-2 mg/kg), or the pharmacological stressor yohimbine (1.25-2.5 mg/kg) reinstated cotinine seeking. Female rats displayed more pronounced cue-induced, but not drug- or stress-induced reinstatement than male rats. In addition, an overall analysis revealed that female rats exhibited greater cotinine self-administration, but less extinction than male rats. In the incubation model, rats were trained to self-administer cotinine, and underwent forced withdrawal in home cages. Rats were tested for cue-induced cotinine seeking on both withdrawal day 1 and withdrawal day 18. Rats exhibited greater cotinine-seeking on withdrawal day 18 compared to withdrawal day 1, with no difference between male and female rats. These findings indicate that cotinine induces sex-dependent relapse to cotinine seeking in rats, suggesting that cotinine may be a novel mechanism contributing to relapse. These rat models are valuable preclinical tools for interrogation of neurobiological underpinnings of relapse to cotinine seeking.

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