ABSTRACT
Background: Drug seeking behavior occurs in response to environmental contexts and drug-associated cues. The presence of these pervasive stimuli impedes abstinence success. ß-adrenergic receptors (ß-ARs) have a long-standing historical implication in driving processes associated with contextual memories, including drug-associated memories in substance use disorders. However, sex differences in the role of ß-adrenergic receptors in drug memories remain unknown. Hypothesis: Prior reports indicate a selective role for ß2-ARs in retrieval and retention of contextual drug memories in males, and substantial sex differences exist in the expression of ß-ARs of male and female rats. Therefore, we hypothesized that there are sex differences in selective recruitment of ß-ARs during different stages of memory encoding and retrieval. Methods: The role of ß-ARs in driving retrieval and learning of contextual cocaine memories was investigated using cocaine conditioned place preference (CPP) in adult male and female Sprague-Dawley rats. Rats were infused directly to the dorsal hippocampus with Propranolol (ß1 and ß2) or ICI-118,551 (ß1) and/or Betaxolol (ß2), immediately prior to testing (retrieval), or paired to each cocaine (10 mg/kp, IP) conditioning session (learning). Results: In males, administration of either ß1, ß2, or combined ß1 and ß2-ARs before the initial CPP testing reduced the expression of a CPP compared to vehicle administration. In females, ß2-ARs transiently decreased CPP memories, whereas ß1 had long lasting but not immediate effects to decrease CPP memories. Additionally, ß1 and combined ß1 and ß2-ARs had immediate and persistent effects to decrease CPP memory expression. DG Fos + neurons predicted cocaine CPP expression in males, whereas CA1 and CA3 Fos + neurons predicted cocaine CPP expression in females. Conclusion: There are significant sex differences in the role of dorsal hippocampus ß-ARs in the encoding and expression of cocaine conditioned place preference. Furthermore, sub regions of the dorsal hippocampus appear to activate differently between male and female rats during CPP. Therefore DG, CA3, and CA1 may have separate region- and sex-specific impacts on driving drug- associated, or context-associated cues.
ABSTRACT
Engagement in sexual behavior can impact neurosteroidogenesis, in particular production of the prohormone testosterone (T) and likely its subsequent metabolism to 5α-androstane-3α-17ß-Diol (3α-Diol) or aromatization to estradiol (E2). Androgens and their metabolites vary across the lifespan and impact many behaviors, including cognition, anxiety, and sexual behavior. Thus, we hypothesized that mating may alter cognitive performance via androstane neurosteroids in an age- and experience-dependent manner. We first investigated if exposure to mating during memory consolidation could enhance performance in the novel object recognition task (NOR). Male rats were trained in NOR and then immediately exposed to mating-relevant or control stimuli. Following a 4 h inter-trial interval (ITI), male rats were tested for object memory. Male rats that were exposed to a receptive female during the ITI had better performance in NOR. We then investigated if these effects were due to novelty associated with mating. Male rats were exposed to mating-relevant stimuli and identified as sexually responsive (SR) or sexually non-responsive (SNR) based on a median split of engagement in mating with the stimulus female. We found that a brief history (10 min session daily for five consecutive days) of sexual history substantially influenced performance in the NOR task, such that SR males had better performance in the NOR task, but only when presented with the opportunity to mate during the ITI. As T levels substantially decrease with age in male rodents, we investigated whether the effects of long-term sexual experience (10 months) influenced neurosteroids and NOR performance in mid-aged (12 months old) males. Mid-aged SR males maintain neural T; however, they have decreased neural E2 and decreased cognitive performance at 12 months compared to mid-aged SNR rats. In sexually experienced rats, those with better cognitive performance had greater levels of T metabolites (e.g., 3α-Diol in mated SR males, E2 in mid-aged SNR rats). While naïve males that were mated during the ITI had better cognitive performance, T metabolites were decreased compared to controls. These findings suggest that T metabolites, but not the prohormone, may influence learning dependent on sexual proclivity, experience, and proximate opportunity to mate.
