Four-day intragastric treatment with the positive allosteric modulator of the GABAB receptor, ASP8062 (1, 3, and 10 mg/kg), suppressed operant oral alcohol self-administration in male and female Sprague Dawley (SD) rats (Haile et al., Psychopharmacology 238:2587–2600, 2021). Conversely, in a double-blind placebo-controlled trial, 6-week treatment with ASP8062 (25 mg/day, corresponding to the 3-mg/kg rat dose) failed to attenuate alcohol craving and consumption in individuals with moderate or severe alcohol use disorder (AUD) (Schacht et al., Alcohol Clin Exp Res 48:2352–2363, 2024). Reverse-translational dose-ranging studies in animal models of AUD were suggested. In keeping with this purpose, the present study tested ASP8062 on operant oral alcohol self-administration in selectively bred Sardinian alcohol-preferring (sP) rats, a validated animal model of AUD. Female sP rats were trained to lever-respond for alcohol under the fixed ratio 5 schedule of reinforcement. Once lever-responding for alcohol was high and steady, rats underwent a 4-day intragastric treatment with ASP8062 (3, 10, and 17 mg/kg). Only the 17-mg/kg dose reduced, by approximately 40
Dopamine release in the nucleus accumbens (NAc) core is shaped by local inhibitory microcircuits, yet whether this regulation differs between sexes remains unknown. Here, we investigated sex differences in GABA-A and GABA-B receptor regulation of dopamine release in the NAc core and determined whether these mechanisms are altered by repeated cocaine exposure. Using ex vivo fast-scan cyclic voltammetry, we measured dopamine release in the NAc core of male and female mice following pharmacological manipulation of GABA-A and GABA-B receptors. Single-nucleus RNA sequencing data were analyzed to assess sex differences in GABA receptor subunit expression. Finally, mice received repeated cocaine injections (10 mg/kg, i.p., five consecutive days), and dopamine release regulation by GABA receptors was assessed 24 hours after the final injection. GABA-A and GABA-B receptors exerted distinct, sexually dimorphic control over dopamine release. GABA-B receptor antagonism increased dopamine release in males but not females; GABA-A receptor antagonism produced stronger enhancement of dopamine release in females. These differences were not explained by broad differences in receptor expression or responsiveness to receptor activation, suggesting sex differences in the engagement of local GABAergic circuits. Interestingly, GABA-B regulation occurs indirectly through cholinergic interneurons, whereas GABA-A regulation was independent of cholinergic input, potentially suggesting a more direct mechanism at dopamine axon terminals. Repeated cocaine exposure selectively attenuated GABA-A–dependent modulation in females. Together, these findings identify divergent GABAergic pathways that tune dopamine output across sexes and reveal how cocaine reshapes these microcircuits, offering a mechanistic basis for sex differences in addiction vulnerability.
Freezing has historically been the primary measure of conditioned fear, despite evidence that defensive behaviors are diverse and sexually dimorphic. Although mu-opioid receptor (MOR) signaling regulates fear learning and conditioned analgesia, its influence on diverse defensive behaviors remains unclear. This study investigated the effects of systemic MOR antagonism on freezing, darting, shock responsivity, and ultrasonic vocalizations (USVs) during fear conditioning and recall in male and female rats. Adult male and female Sprague Dawley rats received naloxone (5 mg/kg, i.p.) or saline before auditory fear conditioning consisting of seven tone-shock pairings. Fear recall was assessed 24 hours later through three tone presentations in a novel context. Naloxone produced sex- and behavior-specific effects. During conditioning, naloxone increased baseline and early-tone freezing in males, whereas females exhibited reduced shock-response velocity and increased post-shock freezing. Darting and USV production were not significantly affected. During recall, freezing did not differ between treatment groups. However, naloxone-treated females exhibited fewer alarm callers overall, but increased vocalization among animals that called. Systemic naloxone differentially modulates defensive behaviors in male and female rats, highlighting sex-dependent effects of opioid receptor antagonism on conditioned fear expression. The dissociation between freezing and alarm calling during recall further suggests that these behaviors may reflect distinct components of fear processing.
One of parkinsonian signs is tremor; the mechanism of this dysfunction is unclear. There are indications that IL-1β, IL-6, and noradrenaline (NA) located in the locus coeruleus (LC) and thalamus participate in regulation of parkinsonian tremor (PT). We sought i) to determine the ability of IL-1β and IL-6 to induce tremulous jaw movements (TJMs), a rat model of PT; and ii) to characterize a link between TJMs development and NA metabolism in the LC and some thalamic nuclei. Experiments were conducted in male Wistar rats of 530–570 days of age. IL-1β and IL-6 were injected intracerebroventricularly for 10 day at 1.0–25.0 pg and 10.0–250.0 pg, respectively; concentrations of NA and its metabolite 3,4-dihydroxyphenylglycol (DHPG) were determined by HPLC. TJMs were counted by standard method. Interleukins administered separately were ineffective; in contrast, IL-1β at 25.0 pg combined with IL-6 at 250.0 pg significantly stimulated TJM response and increased NA, DHPG, and DHPG/NA ratios in the LC and ventral anterior thalamic nucleus (VATN); NA metabolism in the paraventricular and posterior intralaminar thalamic nuclei did not change. The number of TJMs positively correlated with levels of NA in the LC and VATN. The effect of IL-1β–IL-6 combination was reversed by β-antagonist propranolol but not α1- and α2- antagonists terazosin and yohimbine. The results advance our understanding of the mechanism underlying parkinsonian-like tremor in rats. The presented data suggests that IL-1β, IL-6, and β-receptors are a potential triple-target in therapy of PT.
Nicotine pharmacokinetics (PK) and subjective effects influence the abuse liability of electronic nicotine delivery systems (ENDS). This two-arm randomized crossover pharmacokinetic study assessed nicotine delivery from and subjective responses to four JUUL2 ENDS products (Virginia Tobacco and Fresh Menthol flavors [5
