oxepins and Substance-Withdrawal-Syndrome

To determine whether intrinsic mechanisms drive supraoptic nucleus oxytocin neuron excitation during morphine withdrawal, we calculated the probability of action potential (spike) firing with time after each spike for oxytocin neurons in morphine-naive and morphine-dependent rats in vivo and measured changes in intrinsic membrane properties in vitro. The opioid receptor antagonist, naloxone, increased oxytocin neuron post-spike excitability in morphine-dependent rats; this increase was greater for short interspike intervals (<0.1 s). Naloxone had similar, but smaller (P=0.04), effects in oxytocin neurons in morphine-naive rats. The increased post-spike excitability for short interspike intervals was specific to naloxone, because osmotic stimulation increased excitability without potentiating excitability at short interspike intervals. By contrast to oxytocin neurons, neither morphine dependence nor morphine withdrawal increased post-spike excitability in neighbouring vasopressin neurons. To determine whether increased post-spike excitability in oxytocin neurons during morphine withdrawal reflected altered intrinsic membrane properties, we measured the in vitro effects of naloxone on transient outward rectification (TOR) and after-hyperpolarization (AHP), properties mediated by K+ channels and that affect supraoptic nucleus neuron post-spike excitability. Naloxone reduced the TOR and AHP (by 20% and 60%, respectively) in supraoptic nucleus neurons from morphine-dependent, but not morphine-naive, rats. In vivo, spike frequency adaptation (caused by activity-dependent AHP activation) was reduced by naloxone (from 27% to 3%) in vasopressin neurons in morphine-dependent, but not morphine-naive, rats. Thus, multiple K+ channel inhibition increases post-spike excitability for short interspike intervals, contributing to the increased firing of oxytocin neurons during morphine withdrawal.

Topics: Action Potentials; Animals; Drug Interactions; Female; Hypothalamus; In Vitro Techniques; Morphine; Morphine Dependence; Naloxone; Naphthalenes; Narcotic Antagonists; Narcotics; Neurons; Oxepins; Oxytocin; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Saline Solution, Hypertonic; Substance Withdrawal Syndrome; Time Factors

Approximately 15% of child-bearing women develop postpartum depression (PPD), and many women with PPD experience anxious symptoms. It has been proposed that PPD is precipitated by the dramatic decline in reproductive hormones that occurs just after childbirth. To examine this hypothesis, ovariectomized female Sprague-Dawley rats underwent a hormone-simulated pregnancy (HSP) regimen; during the subsequent hormone withdrawal period, rats were tested in the forced swim test or elevated plus-maze, animal models of depression and anxiety, respectively. The HSP regimen consisted of injections with progesterone and escalating doses of estradiol benzoate for 22 days; control rats received daily vehicle injections. One, two, four or seven days after the last hormone injection, separate groups of rats were tested once on either the forced swim test or the elevated plus-maze. To examine any hormone withdrawal-induced changes in activity levels, spontaneous locomotor activity was measured at the same time points. At 2 and 4 days after the last hormone injection, HSP-treated females displayed significant increases in immobility relative to vehicle-treated females in the forced swim test. Behavior on the elevated plus-maze did not differ between the HSP and control groups at any of the withdrawal time points. There were also no differences in spontaneous locomotor activity between the HSP and control females at any of the withdrawal time points. The results of this study suggest that postpartum hormone withdrawal may contribute to depressive symptoms experienced after giving birth, and that the HSP-hormone withdrawal protocol may provide a useful animal model of PPD.

Topics: Animals; Behavior, Animal; Depression, Postpartum; Disease Models, Animal; Estradiol; Female; Maternal Behavior; Maze Learning; Motor Activity; Naphthalenes; Ovariectomy; Oxepins; Progesterone; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Swimming; Time Factors