Sex Differences in the Reward-Enhancing Effects of Nicotine on Ethanol Reinforcement: A Reinforcer Demand Analysis

Abstract Background Alcohol is often consumed with tobacco, and dependence to alcohol and tobacco are highly comorbid. In addition, there are differences in the prevalence of nicotine- and alcohol-abuse between the sexes. Nicotine produces enhancing effects on the value of other reinforcers, which may extend to alcohol. Methods Male and female Wistar rats were trained to self-administer 15% ethanol solution in 30-minute sessions. Once ethanol self-administration was established, demand for ethanol was evaluated using an exponential reinforcer demand method, in which the response cost per reinforcer delivery was systematically increased over blocks of several sessions. Within each cost condition, rats were preinjected with nicotine (0.05, 0.1, 0.2, or 0.4 mg/kg base, SC) or saline 5 minutes before self-administration sessions. The effects of nicotine dose and biological sex were evaluated using the estimates generated by the reinforcer demand model. Results Under saline conditions, males showed greater sensitivity to ethanol reinforcement than females. Nicotine enhanced the reinforcement value of alcohol and this varied with sex. In both sexes, 0.4 mg/kg nicotine decreased intensity of ethanol demand. However, 0.05, 0.1, and 0.2 mg/kg nicotine decreased elasticity of ethanol demand in females, but not in males. Conclusions Nicotine enhances ethanol reinforcement, which may partially drive comorbidity between nicotine-abuse and alcohol-abuse. Males showed signs of greater ethanol reinforcement value than females under saline conditions, and nicotine attenuated this effect by increasing ethanol reinforcement value in the females. These findings highlight that a complete understanding of alcohol-abuse must include a thorough study of alcohol use in the context of other drug use, including nicotine. Implications Nicotine dose dependently enhances the alcohol reinforcement value in a manner that is clearly influenced by biological sex. Under saline baseline conditions, males show lower elasticity of demand for alcohol reinforcement than females, indicative of greater reinforcement value. However, nicotine attenuated this difference by enhancing alcohol reward in the females. Specifically, low-to-moderate doses (0.05–0.2 mg/kg) of nicotine decreased elasticity of alcohol demand in female rats, increasing the perseverance of their alcohol taking behavior. These data indicate that the well-documented reward-enhancing effects of nicotine on sensory reinforcement extend to alcohol reinforcement and that these vary with biological sex.

Download Full-text

7,8-Dihydroxyflavone Enhances Cue-Conditioned Alcohol Reinstatement in Rats

Brain Sciences ◽

10.3390/brainsci10050270 ◽

2020 ◽

Vol 10 (5) ◽

pp. 270 ◽

Cited By ~ 1

Author(s):

Samuel J. Hogarth ◽

Elvan Djouma ◽

Maarten van den Buuse

Keyword(s):

Body Weight ◽

Progressive Ratio ◽

Ethanol Exposure ◽

Ethanol Solution ◽

Female Rats ◽

Male Rats ◽

Sprague Dawley ◽

Self Administration ◽

Bdnf Expression ◽

Sprague Dawley Rats

Alcohol use disorder (AUD) is a detrimental disease that develops through chronic ethanol exposure. Reduced brain-derived neurotrophic factor (BDNF) expression has been associated with AUD and alcohol addiction, however the effects of activation of BDNF signalling in the brain on voluntary alcohol intake reinstatement and relapse are unknown. We therefore trained male and female Sprague Dawley rats in operant chambers to self-administer a 10% ethanol solution. Following baseline acquisition and progressive ratio (PR) analysis, rats were split into drug and vehicle groups during alcohol lever extinction. The animals received two weeks of daily IP injection of either the BDNF receptor, TrkB, agonist, 7,8-dihydroxyflavone (7,8-DHF), or vehicle. During acquisition of alcohol self-administration, males had significantly higher absolute numbers of alcohol-paired lever presses and a higher PR breakpoint. However, after adjusting for body weight, the amount of ethanol was not different between the sexes and the PR breakpoint was higher in females than males. Following extinction, alcohol-primed reinstatement in male rats was not altered by pretreatment with 7,8-DHF when adjusted for body weight. In contrast, in female rats, the weight-adjusted potential amount of ethanol, but not absolute numbers of active lever presses, was significantly enhanced by 7,8-DHF treatment during reinstatement. Analysis of spontaneous locomotor activity in automated photocell cages suggested that the effect of 7,8-DHF was not associated with hyperactivity. These results suggest that stimulation of the TrkB receptor may contribute to reward craving and relapse in AUD, particularly in females.

Download Full-text

Enhanced heroin self-administration and distinct dopamine adaptations in female rats

Neuropsychopharmacology ◽

10.1038/s41386-021-01035-0 ◽

2021 ◽

Author(s):

Brianna E. George ◽

Samuel H. Barth ◽

Lindsey B. Kuiper ◽

Katherine M. Holleran ◽

Ryan T. Lacy ◽

...

Keyword(s):

Female Rats ◽

Self Administration

Download Full-text

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

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyz050 ◽

2019 ◽

Vol 22 (11) ◽

pp. 710-723 ◽

Cited By ~ 8

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.

Download Full-text