Enhancement of neuronal excitability in the medial prefrontal cortex following prenatal morphine exposure.

The clinical use and abuse of opioids during human pregnancy have been widely reported. Several studies have demonstrated that opioids cross the placenta in rats during late gestation, and prenatal morphine exposure has been shown to have negative outcomes in cognitive function. The medial prefrontal cortex (mPFC) is believed to play a crucial role in cognitive processes, motivation, and emotion, integrating neural information from several brain areas and sending converted information to other structures. Dysfunctions in this area have been observed in numerous psychiatric and neurological disorders, including addiction. This current study aimed to compare the electrophysiological properties of mPFC neurons in rat offspring prenatally exposed to morphine. Pregnant rats were injected with morphine or saline twice a day from gestational days 11-18. Whole-cell patch-clamp recordings were performed in male offspring on postnatal days 14-18. All recordings were obtained in current-clamp configuration from mPFC pyramidal neurons to assess their electrophysiological properties. The results revealed that prenatal exposure to morphine shifted the resting membrane potential (RMP) to less negative voltages and increased input resistance and duration of action potentials. However, the amplitude, rise slope, and afterhyperpolarization (AHP) amplitude of the first elicited action potentials were significantly decreased in rats prenatally exposed to morphine. Moreover, the sag voltage ratio was significantly decreased in the prenatal morphine group. Our results suggest that the changes observed in the electrophysiological properties of mPFC neurons indicate an elevation in neuronal excitability following prenatal exposure to morphine.

Acute adolescent morphine exposure improves dark avoidance memory and enhances long-term potentiation of ventral hippocampal CA1 during adulthood in rats.

Adolescence represents a distinctive vulnerable period when exposure to stressful situations including opioid exposure can entail lasting effects on brain and can change neural mechanisms involved in memory formation for drug-associated cues, possibly increasing vulnerability of adolescents to addiction. Herein, the effects of acute adolescent morphine exposure (AAME, two injections of 2.5 mg/kg SC morphine on PND 31) were therefore investigated 6 weeks later (adulthood) on avoidance memory and hippocampal long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in transvers slices from the ventral hippocampus in adult male rats using field recordings technique. Animal body weight was measured from PND 31 throughout PND 40 and also in four time points with 1 week intervals from adolescence to adulthood (PNDs 48, 55, 62 and 69) to evaluate the effect of AAME on the weight gain. We showed that there were no effects on body weight, anxiety-like behaviour and locomotor activity, even until adulthood. There was an improved dark avoidance memory during adulthood. Finally, AAME had no effects on baseline synaptic responses and resulted in a decrease in the mean values of the field excitatory postsynaptic potential slopes required to evoke the half-maximal population spike amplitude and an enhancement of LTP magnitude (%) in the ventral CA1 during adulthood. Briefly, our results suggest long-lasting effects of acute adolescent morphine exposure on the ventral hippocampus, which begin the enhancing of synaptic plasticity and the improving of emotional memory in adulthood.

Prenatal exposure to morphine enhances excitability in locus coeruleus neurons.

Opioid abuse during pregnancy may have noteworthy effects on the child's behavioral, emotional and cognitive progression. In this study, we assessed the effect of prenatal exposure to morphine on electrophysiological features of locus coeruleus (LC) noradrenergic neurons which is involved in modulating cognitive performance. Pregnant dams were randomly divided into two groups, that is a prenatal saline treated and prenatal morphine-treated group. To this end, on gestational days 11-18, either morphine or saline (twice daily, s.c.) was administered to pregnant dams. Whole-cell patch-clamp recordings were conducted on LC neurons of male offspring. The evoked firing rate, instantaneous frequency and action potentials half-width, and also input resistance of LC neurons significantly increased in the prenatal morphine group compared to the saline group. Moreover, action potentials decay slope, after hyperpolarization amplitude, rheobase current, and first spike latency were diminished in LC neurons following prenatal exposure to morphine. In addition, resting membrane potential, rise slope, and amplitude of action potentials were not changed by prenatal morphine exposure. Together, the current findings show a significant enhancement in excitability of the LC neurons following prenatal morphine exposure, which may affect the release of norepinephrine to other brain regions and/or cognitive performances of the offspring.

The efficacy of transdiagnostic cognitive behavioural therapy on reducing negative affect, anxiety sensitivity and improving perceived control in children with emotional disorders - a randomized controlled trial.

In response to the high rate of comorbidity among different types of emotional disorders in children, Transdiagnostic Unified Protocol of Emotional disorder in children (UP-C) was developed to address common underlying mechanisms in the development and maintenance of emotional disorders using empirically supported cognitive and behavioural strategies. Although, studies supported the effectiveness of this protocol in the treatment of wide range of emotional disorders, further studies are needed to examine its effect on transdiagnostic factors. The present study aimed to investigate the efficacy of the UP-C on negative affect, anxiety sensitivity and perceived control in children with emotional disorders. During this randomized controlled trial, 34 children aged 7 to 13 with emotional disorders were randomly assigned to treatment (n=18) and control (n=16) groups. The treatment group and their parents received 15 sessions of UP-C. Negative Affect Schedule for Children (PANASNA- C), Children's Anxiety Sensitivity Index (CASI), Anxiety Control Questionnaire-Children (ACQ-C) were carried out in all phases (pre-treatment, post-treatment, 3 and 8 months follow- up). The results showed that following UP-C, negative affect (hedges'g=2.01) and anxiety sensitivity (hedges'g=1.05) were significantly reduced, and perceived control (hedges'g= -2.36) was significantly improved. The results remained relatively constant during the follow-ups. Findings provide evidence that the UP-C has significant effect on negative affect, anxiety sensitivity and perceived control as roots of emotional disorders.

Prenatal exposure to morphine impairs attention and impulsivity in adult rats.

RATIONALE: An alarming number of neonates born with prenatal exposure to morphine has resulted from the opioid epidemic; however, the long-term effects of prenatal opioid exposure on offspring behavior remain relatively unknown. In this study, we evaluated whether prenatal exposure to the mu opioid receptor agonist, morphine, has enduring effects on cognitive functions in adult life. METHODS: On embryonic days 11-18 (E11-E18), female pregnant rats were injected subcutaneously with either morphine or saline twice daily. Adult male offspring that was prenatally exposed to saline or morphine was trained in the 5-choice serial reaction time test (5-CSRTT) to test their cognitive abilities under baseline conditions. Next, these rats were treated with saline (1 ml/kg), naloxone (1 mg/kg), and acute morphine (1, 3, 5 mg/kg), subcutaneously, once daily and following drug challenges rats were tested in the 5-CSRTT. Meanwhile, behavioral performance on training days between opioid drug challenges were analyzed to monitor possible drug-induced shifts in baseline performance. As a final experiment in order to investigate subchronic exposure to morphine, rats were injected with 5 mg/kg morphine for 5 days and then naloxone in the last day of the experiment (day 6). RESULTS: Firstly, during acquisition of a stable baseline in the training phase, rats prenatally exposed to morphine showed delayed learning of the task demands. Furthermore, under baseline responding the rats prenatally exposed to morphine showed declined inhibitory control demonstrated by increased impulsive and compulsive-like responding compared to rats prenatally exposed to saline. Moreover, acute and subchronic morphine challenges in the rats prenatally exposed to morphine caused a deficit in visuospatial attention in comparison with saline treatment as well as the rats prenatally exposed to saline. These effects were abolished by naloxone. CONCLUSION: The current findings indicate a direct causal effect of prenatal morphine exposure on inhibitory control and task learning later in life, as well as deficits in attention following morphine exposure in adulthood.