Low doses of cocaine decrease, and high doses increase, anxiety-like behavior and brain progestogen levels among intact rats

Abstract

There are sex and hormonal differences in response to cocaine that have been demonstrated in people and animal models. Cocaine can alter secretion of progestogens, such as progesterone (P), and its neuroactive metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP). However, little research has been done on the neuroendocrine effects in the initiation phase of cocaine use. We hypothesize that some sex/hormonal differences in initiation phase responses to cocaine may be related to formation of progestogens. To investigate the role of progestogens in sex differences in response to acute cocaine, male and female rats in the high (proestrous) or low (diestrous) progestogen phase of the estrous cycle were administered cocaine (0, 5, 10, or 20 mg/kg, IP). We examined cocaine's acute neuroendocrine effects on P and 3α,5α-THP levels, as well as its effects on acute psychomotor stimulation, anxiety, and sexual behaviors. Among rats that had P and/or 3α,5α-THP levels increased in response to cocaine, enhanced acute psychomotor stimulation was observed. Results suggest that cocaine produces U-shaped curves for progestogens, and anxiety-like behaviors. Male rats were less susceptible to these effects of cocaine than were proestrous or diestrous female rats. However, cocaine's disruption of sexual behaviors was similar among males and proestrous females. These data suggest a complex interaction between hormonal milieu and the neuroendocrine and behavioral effects of cocaine.

Cocaine-, caffeine-, and stress-evoked cocaine reinstatement in high vs. low impulsive rats: Treatment with allopregnanolone

“…Cocaine has been shown to induce stress hormones, which is attenuated by ALLO (Frye, 2007), and it is possible that COC and a high dose of CAFF differentially affect stress pathways in LoI and HiI rats. Previous work has shown an induction of ALLO by COC (Kohtz et al, 2010). Therefore, another explanation is that HiI and LoI rats could produce different levels of ALLO in response to COC and CAFF, so that treatment with ALLO might affect HiI and LoI differently.…”

A single exposure to cocaine during development elicits regionally-selective changes in basal basic Fibroblast Growth Factor (FGF-2) gene expression and alters the trophic response to a second injection

“…Further, the reduction observed 7 days after the first exposure to cocaine might impair working memory, as shown by Sudai and colleagues following a similarly high dosage of cocaine (Sudai et al 2011). Notably, since a single injection of cocaine is sufficient to induce anxiety in rats (Kohtz et al 2010), an effect that has been linked to lower levels of hippocampal FGF-2 (Eren- Kocak et al 2011;Turner et al 2011), our data suggest that reduced FGF-2 levels in the hippocampus may represent a sign of vulnerability for cocaine-induced anxiety: This observation is intriguing since it appears that, during adolescence, acute psychostimulant exposure recapitulates anxiety-like behaviors that are usually only seen following chronic mild stress (Kompagne et al 2008). Further experiments will explore the potential relevance of such reduction to psychiatric-like disorders.…”

Estrous Cycle and HIV-1 Tat Protein Influence Cocaine-Conditioned Place Preference and Induced Locomotion of Female Mice

“…Manipulating estradiol and progesterone concentrations demonstrates psychomotor activity of acutely administered cocaine to be attenuated when progesterone largely opposes estradiol, but this effect is reversed as estradiol is increased to ~5-fold physiological concentrations [70]. These effects of progesterone may further be influenced by actions of downstream progestogen metabolites, such as allopregnanolone, the biosynthesis of which is altered by cocaine in a dose-dependent manner [71], and which may be required for progesterone's effects to attenuate cocaine-seeking in female rats [72, 73]. Thus, identifying the effects and mechanisms of estradiol/progestogen therapies is warranted for future research into the modulation of drug reward and abuse by HIV.…”