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Rationale Once dependent on alcohol or opioids, negative affect may accompany withdrawal. Dependent individuals are hypothesized to “self-medicate” in order to cope with withdrawal, which promotes escalated drug or alcohol use. Objectives The current study aimed to develop a reliable animal model to assess symptoms that occur during spontaneous alcohol and opioid withdrawal. Methods Dependence was induced using intermittent alcohol exposure or pulsatile heroin delivery and assessed for the presence of withdrawal symptoms during acute withdrawal by measuring somatic signs, behavior in the forced swim test (FST) and air-puff induced 22-kHz ultrasonic vocalizations (USVs). Additional animals subjected to eight weeks of alcohol vapor exposure were evaluated for altered somatic signs, operant alcohol self-administration and 22-kHz USV production, as well as performance in the elevated plus-maze (EPM). Results During spontaneous withdrawal from pulsatile heroin or intermittent alcohol vapor, animals displayed increased somatic withdrawal signs, FST immobility and 22-kHz USV production, but did not show any behavioral change in the EPM unless the duration of exposure was extended to four weeks. Following eight weeks of alcohol vapor exposure, animals displayed somatic withdrawal signs, escalated alcohol self-administration and increased 22-kHz USVs. Conclusions These paradigms provide consistent methods to evaluate the behavioral ramifications, and neurobiological substrates, of alcohol and opioid dependence during spontaneous withdrawal. As immobility in the FST and percent open-arm time in the EPM were dissociable, with 22-kHz USVs paralleling immobility in the FST, assessment of air-puff induced 22-kHz USVs could provide an ethologically-valid alternative to the FST.

Negative affect promotes dysregulated alcohol consumption in non-dependent and alcohol-dependent animals, and cues associated with negative affective states induce withdrawal-like symptoms in rats. This study was designed to test the hypotheses that: (1) the kappaopioid receptor (KOR) system mediates phenotypes related to alcohol withdrawal and withdrawal-like negative affective states and (2) cues associated with negative affective states would result in dysregulated alcohol consumption when subsequently presented alone. To accomplish these goals, intracerebroventricular infusion of the KOR antagonist nor-binaltorphimine (nor-BNI) was assessed for the ability to attenuate the increase in 22-kHz ultrasonic vocalizations (USVs) associated with alcohol withdrawal and KOR activation in adult male wistar rats. Furthermore, cues associated with a KOR agonist-induced negative affective state were assessed for the ability to dysregulate alcohol consumption and the efficacy of intracerebroventricular KOR antagonism to reduce such dysregulation was evaluated. KOR antagonism blocked the increased number of 22-kHz USVs observed during acute alcohol withdrawal and a KOR agonist (U50,488) resulted in a nor-BNI reversible increase in 22-kHz USVs (mimicking an alcohol-dependent state). Additionally, cues associated with negative affective states resulted in escalated alcohol self-administration, an effect that was nor-BNI sensitive. Taken together, this study implicates negative affective states induced by both alcohol withdrawal and conditioned stimuli as being produced, in part, by activity of the DYN/KOR system.

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SUMMARY In a patient with myasthenic syndrome neuro-muscular transmission was characterised by depression and facilitation. The relative extent of these two processes varied between muscles, and in the one muscle with time. Guanidine HCI treatment corrected the electrophysiological defect. Oral choline increased muscle action potential amplitude in response to single shocks. Intravenous choline produced features indicating cholinergic autonomic stimulation. Pimozide and plasmapheresis had no effect. Animal in-vivo and in-vitro studies performed to detect a circulating factor which interferes with neuro-muscular transmission were negative.The myasthenic syndrome (MYS) is a well defined clinical entity.' There remain a number of unresolved aspeo**, including a lack of knowledge of the cause and mechanism of the disorder. We have quantified certain parameters of neuromuscular transmission in one patient with MYS in order to further define the pathophysiology of this condition. The transmission defect in MYS has two components, characterised by depression and facilitation. A variation in magnitude of these components with time, and at different neuro-muscular junctions, is demonstrated. This could explain the apparent concurrent presence of transmission features of myasthenia gravis (MG) and MYS which have been reported in scme patients.2-4The effect of certain pharmacological agents, in particular choline, was assessed, and the influence of plasmapheresis noted. The patient's serum was tested for its effect on n-euro-muscular transmission in animal in-vivo and in-vitro preparations. Patients and methodsA 56 year old woman presented with several months history of proximal weakness. Thyroid function tests were in the toxic range: T3 7-5