Postsynaptic Receptor Sensitivity Research Articles

Modeling the drug withdrawal syndrome in zebrafish (<i>Danio rerio</i>)

The central pathological link in addictive states is the drug withdrawal syndrome. Usually, severe manifestations of the withdrawal syndrome are associated with reduced sensitivity of postsynaptic receptors (desensitization), lower density of receptors and impaired transport of neurotransmitters, and the rebound effect. Zebrafish is an effective tool in the study of classic withdrawal symptoms and special cases of withdrawal of other selected psychoactive drugs.

Serotonin 5-HT1A and 5-HT1B receptor-mediated inhibition of glutamatergic transmission onto rat basal forebrain cholinergic neurones.

Cholinergic neurones in the basal forebrain (BF) project into various brain regions and receive excitatory inputs from the cortex and brain stem. These cholinergic neurones receive serotonergic fibres from the dorsal raphe nuclei. This study was aimed to elucidate serotonin (5-HT)-induced modulation of glutamatergic transmission onto rat BF cholinergic neurones identified with Cy3-192IgG. Excitatory postsynaptic currents (EPSCs) were evoked by focal stimulation. Bath application of either 5-HT, the 5-HT1A receptor agonist 8-OH-DPAT (DPAT), or the 5-HT1B receptor agonist CP93129 (CP), inhibited the amplitude of EPSCs. In the presence of both 5-HT1A and 5-HT1B receptor antagonists, the 5-HT-induced effect disappeared. The paired-pulse ratio (PPR) and coefficient of variation (CV) of the EPSCs were increased by CP, whereas DPAT had no effect on PPR or CV. DPAT inhibited the inward currents induced by puff application of l-glutamate, which were unaffected by CP. DPAT suppressed the amplitude of miniature EPSCs (mEPSCs) without affecting their frequency. CP decreased the frequency of mEPSCs in more than half of the neurones examined, whereas the amplitude was unaffected. DPAT or CP alone inhibited the NMDA receptor-mediated currents. 5-HT-induced inhibition of EPSCs was reduced in the presence of ω-agatoxin TK (Aga). Furthermore, CP-induced inhibition of EPSCs was eliminated in the presence of Aga. DPAT-induced inhibition of EPSCs was unchanged in the presence of Aga. These results suggest that activation of 5-HT1A receptors reduces the sensitivity of postsynaptic glutamate receptors to glutamate, whereas presynaptic activation of 5-HT1B receptors inhibits glutamate release by blocking P/Q-type calcium channels. KEY POINTS: We performed a patch-clamp study to investigate serotonin (5-HT)-induced modulation of glutamatergic transmission onto cholinergic neurones in the rat basal forebrain slices. Excitatory postsynaptic currents (EPSCs) were inhibited by 5-HT as well as agonists of 5-HT1A or 5-HT1B receptors. 5-HT-induced inhibition was antagonized by co-application of 5-HT1A and 5-HT1B receptor antagonists. The effects of 5-HT receptor agonists on the paired-pulse ratio, coefficient of variation of EPSCs, inward currents induced by puff application of l-glutamate as well as miniature EPSCs suggest that activation of 5-HT1A receptors decreases the sensitivity of postsynaptic glutamate receptors to glutamate, whereas 5-HT1B receptors presynaptically inhibit glutamate release. The 5-HT1B agonist-induced inhibition was eliminated in the presence of a P/Q-type calcium channel blocker, whereas the 5-HT1A agonist still inhibited the EPSCs even in the presence of the blocker. The present study reveals different pre- and postsynaptic mechanisms underlying 5-HT1A and 5-HT1B receptor-mediated modulation of excitatory transmission.

Molecular encoding and synaptic decoding of context during salt chemotaxis in C. elegans

Animals navigate toward favorable locations using various environmental cues. However, the mechanism of how the goal information is encoded and decoded to generate migration toward the appropriate direction has not been clarified. Here, we describe the mechanism of migration towards a learned concentration of NaCl in Caenorhabditis elegans. In the salt-sensing neuron ASER, the difference between the experienced and currently perceived NaCl concentration is encoded as phosphorylation at Ser65 of UNC-64/Syntaxin 1 A through the protein kinase C(PKC-1) signaling pathway. The phosphorylation affects basal glutamate transmission from ASER, inducing the reversal of the postsynaptic response of reorientation-initiating neurons (i.e., from inhibitory to excitatory), guiding the animals toward the experienced concentration. This process, the decoding of the context, is achieved through the differential sensitivity of postsynaptic excitatory and inhibitory receptors. Our results reveal the mechanism of migration based on the synaptic plasticity that conceptually differs from the classical ones.

Tapentadol Suppresses Glutamatergic Transmission and Neuronal Firing in Rat Hippocampal CA3 Pyramidal Neurons

Background: Tapentadol, a centrally acting oral analgesic, activates µ-opioid receptor and inhibits norepinephrine reuptake. Given that glutamate plays a crucial role in mediating pain, this study investigated the influence of tapentadol on spontaneous glutamatergic synaptic transmission and evoked neuronal excitability in rat hippocampal CA3 pyramidal neurons, which has been suggested to be involved in nociceptive perception. Methods: We used electrophysiological technique to determine the effect of tapentadol on spontaneous excitatory postsynaptic currents (sEPSC), glutamate-activated currents, and neuronal excitability in CA3 pyramidal neurons in rat hippocampal slices. We also used isolated nerve terminals (synaptosomes) prepared from the rat hippocampus to examine the effect of tapentadol on glutamate release. Results: Whole-cell patch clamp recordings revealed that tapentadol effectively decreased the frequencies of sEPSCs and miniature EPSCs (mEPSCs) without changing their amplitudes in hippocampal CA3 pyramidal neurons. However, glutamate-evoked inward currents were not affected by tapentadol. Further, tapentadol decreased 4-aminopyridine-induced glutamate release from hippocampal synaptosomes, and this effect was prevented by chelating the extracellular Ca²⁺ ions and blocking the N- and P/Q-type Ca²⁺ channels. In addition, burst firing induced by 4-aminopyridine and tonic repetitive firing induced by depolarizing pulses were attenuated by tapentadol. Conclusions: We conclude that tapentadol inhibits glutamatergic synaptic transmission, without modifying postsynaptic receptor sensitivity, and that this decline of excitation consequently suppresses neuronal hyperexcitability in the hippocampal CA3 area.

Brimonidine enhances inhibitory postsynaptic activity of OFF- and ON-type retinal ganglion cells in a Wistar rat chronic glaucoma model

Glaucoma is a multifactorial disease in which retinal ganglion cells (RGCs) undergo excitotoxic damage, leading to their degeneration. The α2-adrenoceptor (α2-AR) agonist brimonidine exerts a neuroprotective effect by regulating postsynaptic excitatory N-methyl-D-aspartate (NMDA) receptor activity in RGCs. However, researchers have not clearly determined whether or how brimonidine regulates inhibitory synaptic transmission in rat models of chronic glaucoma. Whole-cell voltage-clamp and current-clamp recordings were performed in ON- and OFF-type RGCs in retinal slices. Brimonidine directly and acutely enhanced γ-aminobutyric acidergic (GABAergic) transmission mediated by ionotropic GABAA receptors in ON- and OFF-type RGCs in rat retinal slices; this effect occurred at the synaptic terminals and was independent of action potentials and multi-synaptic connections. The highly selective α2-AR antagonist yohimbine blocked the effects of brimonidine. Regarding the postsynaptic GABA receptor sensitivity, brimonidine also increased the amplitude of the GABA-induced current. Additionally, compared to RGCs from the control group, the frequencies and amplitudes of spontaneous excitatory postsynaptic currents (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) did not change after brimonidine gravity perfusion. Brimonidine significantly decreased the spontaneous firing frequency of rat RGCs with intact synaptic inputs and decreased the resting membrane potential of RGCs, changes that were blocked by the highly selective GABAA receptor antagonist SR95531. SR95531 alone increased spontaneous action potentials and the resting membrane potential. Based on these findings, an α2-AR agonist facilitated the frequency of the GABAergic inhibitory postsynaptic currents (IPSCs), directly increased the amplitude of the postsynaptic GABA-induced current (GABA receptor reactivity/sensitivity), suppressed the firing frequency of spontaneous action in RGCs with intact synaptic inputs and decreased the resting membrane potential of RGCs, thus deactivating RGCs from the neural network level and reducing the excitotoxic damage occurring during the pathological process of chronic glaucoma.

Differences in multihormonal responses to the dopamine agonist apomorphine between unipolar and bipolar depressed patients

BackgroundA large number of studies suggest that dopaminergic function may be impaired in depressed patients, particularly in bipolar patients. The dopamine D2/D1 agonist apomorphine (APO) can be useful in the evaluation of dopaminergic function. However, most studies show conflicting results in APO test responses when evaluating unipolar and bipolar depressed patients. Thus, the objective of this study was to apply the APO test to assess whether hypothalamic-pituitary dopaminergic function is altered in unipolar and bipolar depression. MethodsWe evaluated multihormonal responses to APO test (0.75 mg subcutaneous) in 134 drug-free DSM-IV major depressed inpatients (54 with bipolar depression [BD] and 80 with unipolar depression [UD]), compared with 36 healthy controls (HCs). We also examined the cortisol response to the dexamethasone suppression test (DST, 1 mg orally) in all subjects. ResultsNo significant differences in prolactin (PRL), cortisol, adrenocorticotropin (ACTH) or growth hormone (GH) baseline values were found across the three groups. ACTH/cortisol and GH responses to APO were also comparable. BD patients showed lower PRL suppression to APO than did UD patients and HCs (both p < 0.00001). Although responses to DST were comparable between UD and BD patients, the former exhibited higher post-DST cortisol levels than did HCs (p < 0.05). ConclusionsOur results suggest that BD patients, unlike UD patients, have altered post-synaptic D2 receptor sensitivity at the pituitary level. This alteration does not seem secondary to hypercortisolemia. These findings, if confirmed by other studies with larger samples, may support the use of dopamine agents in BD patients treatment.

Chronic morphine selectively sensitizes the effect of D1 receptor agonist on presynaptic glutamate release in basolateral amygdala neurons that project to prelimbic cortex

Drug addiction is a brain disorder characterized by chronic, compulsive use of drugs. Previous studies have found a number of chronic morphine-induced changes in the brain at molecular levels. A study from our lab showed that chronic morphine-induced increase in the expression of presynaptic D1 receptors in basolateral amygdala (BLA) neurons played an important role in environmental cue-induced retrieval of morphine withdrawal memory. However, the downstream neurocircuitry of chronic morphine-induced increase presynaptic D1 receptors in the BLA remains to be elucidated. Using retrogradely labelling technique combined with whole-cell patch-clamp methods, our results showed that (1) chronic morphine sensitized the effect of D1 receptor agonist on presynaptic glutamate release in BLA neurons that projected to the prelimbic cortex (PrL), but had no influence on that in BLA neurons that projected to the nucleus accumbens (NAc) or the CA1 of the hippocampus; (2) chronic morphine sensitized the effect of D1 receptor agonist on action potential firing in BLA neurons that projected to the PrL, but without affecting the intrinsic excitability and the sensitivity of postsynaptic glutamate receptors to glutamate in BLA neurons that projected to the PrL. These results suggest that chronic morphine selectively sensitizes the effect of D1 receptor agonist on presynaptic glutamate release in BLA neurons that project to PrL and induces a sensitization of the effect of D1 receptor agonist on action potential firing in BLA neurons that project to the PrL.

Involvement of Ventral Periaqueductal Gray Dopaminergic Neurons in Propofol Anesthesia.

Propofol can promote presynaptic GABA release, inhibit presynaptic glutamate release and increase postsynaptic GABAA receptor sensitivity, which eventually inhibits the activity of vPAG DA neurons and thereby influences the state of consciousness.

Differential sensitivity of presynaptic and postsynaptic GABAB receptors in rat ventrolateral periaqueductal gray.

The ventrolateral periaqueductal gray (PAG) in the midbrain plays a key role in the descending pain modulatory system. γ-Aminobutyric acid type B (GABAB) receptors belong to a metabotropic receptor subfamily and mediate both presynaptic and postsynaptic effects in PAG. It has been well documented that activation of GABAB receptors yields analgesia in some PAG subdivisions. In the present study, employing whole-cell patch-clamp recordings on acute rat PAG slices, we simultaneously monitored the responses of presynaptic and postsynaptic GABAB receptors. We found that the GABAB agonist, baclofen, exhibits less efficacy and potency at GABAB postsynaptic versus presynaptic receptors. This sensitivity bias may contribute to synapse homeostasis and implicate a novel pharmacotherapy treatment.

A modulatory role of ASICs on GABAergic synapses in rat hippocampal cell cultures.

Rapid acidification occurring during synaptic vesicle release can activate acid-sensing ion channels (ASICs) both on pre- and postsynaptic neurons. In the latter case, a fraction of postsynaptic current would be mediated by cation-selective acid-sensing ion channels. Additionally, in both cases, activation of acid-sensing ion channels could modulate synaptic strength by affecting transmitter release and/or sensitivity of postsynaptic receptors. To address potential involvement of acid-sensing ion channels in mediation/modulation of synaptic transmission at hippocampal GABAergic synapses, we studied effects of three structurally different blockers of acid-sensing ion channels on evoked postsynaptic currents using the patch-clamp technique. We found that GABAergic postsynaptic currents, recorded below their reversal potential as inward currents, are suppressed by all the employed blockers of acid-sensing ion channels. These currents were suppressed by ~ 20 % in the presence of a novel blocker 5b (1 μM) and by ~30 % in the presence of either amiloride (25 μM) or diminazene (20 μM). In the same cells the suppression of postsynaptic currents, recorded above their reversal potential as outward currents was statistically insignificant. These results imply that the effects of blockers in our experiments are at least partially postsynaptic. On the other hand, in the case of mediation of a fraction of postsynaptic current by acid-sensing ion channels, an increase of outward currents would be expected under our experimental conditions. Our analysis of a bicuculline-resistant fraction of postsynaptic currents also suggests that effects of the blockers are predominantly modulatory. In this work we present evidence for the first time that acid-sensing ion channels play a functional role at hippocampal GABAergic synapses. The suppressing effect of the blockers of acid-sensing ion channels on GABAergic transmission is due, at least partially, to a postsynaptic but (predominantly) modulatory mechanism. We hypothesize that the modulatory effect is due to functional crosstalk between ASICs and GABAA-receptors recently reported in isolated neurons, however, verification of this hypothesis is necessary.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0269-4) contains supplementary material, which is available to authorized users.

Effects of cocaine history on postsynaptic GABA receptors on dorsal raphe serotonin neurons in a stress-induced relapse model in rats

The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Stressors and stress hormones can inhibit the dorsal raphe nucleus (DRN)-5-HT system, which composes the majority of forebrain-projecting 5-HT. This inhibition is mediated via stimulation of GABA synaptic activity at DRN-5-HT neurons. Using swim stress-induced reinstatement of morphine conditioned place-preference, recent data from our laboratory indicate that morphine history sensitizes DRN-5-HT neurons to GABAergic inhibitory effects of stress. Moreover, GABAA receptor-mediated inhibition of the serotonergic DRN is required for this reinstatement. In our current experiment, we tested the hypothesis that GABAergic sensitization of DRN-5-HT neurons is a neuroadaptation elicited by multiple classes of abused drugs across multiple models of stress-induced relapse by applying a chemical stressor (yohimbine) to induce reinstatement of previously extinguished cocaine self-administration in Sprague-Dawley rats. Whole-cell patch-clamp recordings of GABA synaptic activity in DRN-5-HT neurons were conducted after the reinstatement. Behavioral data indicate that yohimbine triggered reinstatement of cocaine self-administration. Electrophysiology data indicate that 5-HT neurons in the cocaine group exposed to yohimbine had increased amplitude of inhibitory postsynaptic currents compared to yoked-saline controls exposed to yohimbine or unstressed animals in both drug groups. These data, together with previous findings, indicate that interaction between psychostimulant or opioid history and chemical or physical stressors may increase postsynaptic GABA receptor density and/or sensitivity in DRN-5-HT neurons. Such mechanisms may result in serotonergic hypofunction and consequent dysphoric mood states which confer vulnerability to stress-induced drug reinstatement.

Implementation of Linear Sensory Signaling via Multiple Coordinated Mechanisms at Central Vestibular Nerve Synapses

Signal transfer in neural circuits is dynamically modified by the recent history of neuronal activity. Short-term plasticity endows synapses with nonlinear transmission properties, yet synapses in sensory and motor circuits are capable of signaling linearly over a wide range of presynaptic firing rates. How do such synapses achieve rate-invariant transmission despite history-dependent nonlinearities? Here, ultrastructural, biophysical, and computational analyses demonstrate that concerted molecular, anatomical, and physiological refinements are required for central vestibular nerve synapses to linearly transmit rate-coded sensory signals. Vestibular synapses operate in a physiological regime of steady-state depression imposed by tonic firing. Rate-invariant transmission relies on brief presynaptic action potentials that delimit calcium influx, large pools of rapidly mobilized vesicles, multiple low-probability release sites, robust postsynaptic receptor sensitivity, and efficient transmitter clearance. Broadband linear synaptic filtering of head motion signals is thus achieved by coordinately tuned synaptic machinery that maintains physiological operation within inherent cell biological limitations.

Effects of acute and sustained administration of vortioxetine on the serotonin system in the hippocampus: electrophysiological studies in the rat brain.

RationaleVortioxetine is a novel multimodal antidepressant that is a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, an inhibitor of the serotonin (5-HT) transporter, and a 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist in vitro. In vivo studies have shown that vortioxetine enhances levels of 5-HT and desensitizes 5-HT1A autoreceptors.ObjectivesThe aim of the present study was to investigate the effects of acute and long-term administration of vortioxetine on the terminal 5-HT1B receptor and the tonic activation of 5-HT1A receptor in the rat hippocampus.MethodsThese receptors were assessed following vortioxetine administration acutely or subcutaneously using minipumps for 14 days. These studies were carried out using in vivo electrophysiological recording, microiontophoresis, and stimulation of the ascending 5-HT fibers.ResultsVortioxetine enhanced the inhibitory effect of the stimulation of the 5-HT bundle at a high, but not low frequency and reversed the inhibitory effect of the 5-HT1B receptor agonist CP 94253. These results indicate that this compound acted as a 5-HT1B receptor partial agonist. Vortioxetine inhibited 5-HT reuptake but did not dampen the sensitivity of postsynaptic 5-HT1A receptors on pyramidal neurons. Long-term administration of vortioxetine and escitalopram (both at 5 mg/kg/day) induced an increase of tonic activation of the 5-HT1A receptors in CA3 pyramidal neurons, resulting in an increase in 5-HT transmission. In addition, vortioxetine decreased the function of terminal 5-HT1B autoreceptor following its sustained administration.ConclusionsDesensitization of 5-HT1B autoreceptor and an increase of tonic activation of 5-HT1A receptors in the hippocampus may contribute to the antidepressant effect of vortioxetine.

SLO-2 potassium channel is an important regulator of neurotransmitter release in Caenorhabditis elegans.

Slo2 channels are prominent K+ channels in mammalian neurons but their physiological functions are not well understood. Here we investigate physiological functions and regulation of the C. elegans homologue SLO-2 in motor neurons through electrophysiological analyses of wild-type and mutant worms. We find that SLO-2 is the primary K+ channel conducting delayed outward current in cholinergic motor neurons, and one of two K+ channels with this function in GABAergic motor neurons. Loss-of-function mutation of slo-2 increases the duration and charge transfer rate of spontaneous postsynaptic current bursts at the neuromuscular junction, which are physiological signals used by motor neurons to control muscle cells, without altering postsynaptic receptor sensitivity. SLO-2 activity in motor neurons depends on Ca2+ entry through EGL-19, an L-type voltage-gated Ca2+ channel (CaV1), but not on other proteins implicated in either Ca2+ entry or intracellular Ca2+ release. Thus, SLO-2 is functionally coupled with CaV1 and regulates neurotransmitter release.

Pre- and postsynaptic mechanisms underlying inhibition of hypoglossal motor neuron excitability by riluzole

Riluzole is the sole treatment for amyotrophic lateral sclerosis (ALS), but its therapeutically relevant actions on motor neurons are not well defined. Whole cell patch-clamp recordings were made from hypoglossal motor neurons (HMs, n = 25) in brain stem slices from 10- to 23-day-old rats anesthetized with pentobarbital sodium to investigate the hypothesis that riluzole inhibits HMs by multiple mechanisms. Riluzole (20 μM) hyperpolarized HMs by decreasing an inward current, inhibited voltage-gated persistent Na(+) and Ca(2+) currents activated by slow voltage ramps, and negatively shifted activation of the hyperpolarization-activated cationic current (IH). Repetitive firing of HMs was strongly inhibited by riluzole, which also increased action potential threshold voltage and rheobase and decreased amplitude and maximum rise slope but did not alter the maximal afterhyperpolarization amplitude or decay time constant. HM rheobase was inversely correlated with persistent Na(+) current density. Glutamatergic synaptic transmission was inhibited by riluzole by both pre- and postsynaptic effects. Riluzole decreased activity-dependent glutamate release, as shown by decreased amplitude of evoked and spontaneous excitatory postsynaptic currents (EPSCs), decreased paired-pulse ratio, and decreased spontaneous, but not miniature, EPSC frequency. However, riluzole also decreased miniature EPSC amplitude and the inward current evoked by local application of glutamate onto HMs, suggesting a reduction of postsynaptic glutamate receptor sensitivity. Riluzole thus has a marked inhibitory effect on HM activity by membrane hyperpolarization, decreasing firing and inhibiting glutamatergic excitation by both pre- and postsynaptic mechanisms. These results broaden the range of mechanisms controlling motor neuron inhibition by riluzole and are relevant to researchers and clinicians interested in understanding ALS pathogenesis and treatment.

Use of Electroconvulsive Therapy in Parkinson Disease With Residual Axial Symptoms Partially Unresponsive to L-Dopa

Mental dysfunction and especially gait disorders, such as freezing and postural instability in "on phase," are partially unresponsive to dopaminergic therapy late in the course of Parkinson disease (PD). Some of them have been related to decreased sensitivity of postsynaptic dopaminergic receptors, and it is known that electroconvulsive therapy (ECT) enhances the sensitivity of these receptors. The aim of this study was to determine the efficacy and safety of ECT in patients with advanced Parkinson disease with symptoms partially unresponsive to L-dopa. Neurologic (Parkinson's Disease Questionnaire, Unified Parkinson's Disease Rating Scale, Tinetti Scale, and the Sit-to-Stand test), psychiatric (structured interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Hamilton Depression Rating Scale) and neuropsychological (Mini Mental State Examination, executive functions, declarative and procedural memory, visual processing, and reaction time) evaluation was performed on 9 patients with a diagnosis of L-dopa-resistant PD by the Movement Disorders Working Group. This evaluation was done before and after 8 sessions of bitemporal ECT. Six patients completed the study. Statistically significant differences were found in the number of steps and freezing episodes in the on phase when they were compared before and after the ECT administration. However, no statistically significant differences were found in the "off" phenomena, motor fluctuations, or dyskinesias before and after ECT administration. No patient showed psychiatric symptoms before, during, or after the ECT. No statistically significant differences were observed in the neuropsychological results between the pretreatment and posttreatment evaluations. All patients showed transient amnesia after the ECT administration, which lasted for 48 hours. Electroconvulsive therapy could be a safe and effective therapeutic option in L-dopa-resistant patients with PD with predominantly axial "on" phenomena; nevertheless, it needs to be confirmed in later studies.

Long-term administration of the dopamine D3/2 receptor agonist pramipexole increases dopamine and serotonin neurotransmission in the male rat forebrain

Long-term administration of the dopamine (DA) D2-like (D3/2) receptor agonist pramipexole (PPX) has been previously found to desensitize D2 autoreceptors, thereby allowing a normalization of the firing of DA neurons and serotonin (5-HT)1A autoreceptors, permitting an enhancement of the spontaneous firing of 5-HT neurons. We hypothesized that PPX would increase overall DA and 5-HT neurotransmission in the forebrain as a result of these changes at the presynaptic level. Osmotic minipumps were implanted subcutaneously in male Sprague-Dawley rats, delivering PPX at a dose of 1 mg/kg/d for 14 days. The in vivo electrophysiologic microiontophoretic experiments were carried out in anesthetized rats. The sensitivity of postsynaptic D2 receptors in the prefrontal cortex (PFC) remained unaltered following PPX administration, as indicated by the unchanged responsiveness to the microiontophoretic application of DA. Their tonic activation was, however, significantly increased by 104% compared with the control level. The sensitivity of postsynaptic 5-HT1A receptors was not altered, as indicated by the unchanged responsiveness to the microiontophoretic application of 5-HT. Similar to other antidepressant treatments, long-term PPX administration enhanced the tonic activation of 5-HT1A receptors on CA3 pyramidal neurons by 142% compared with the control level. The assessment of DA and 5-HT neuronal tone was restricted to the PFC and the hippocampus, respectively. Chronic PPX administration led to a net enhancement in DA and 5-HT neurotransmission, as indicated by the increased tonic activation of postsynaptic D2 and 5-HT1A receptors in forebrain structures.

Morphine history sensitizes postsynaptic GABA receptors on dorsal raphe serotonin neurons in a stress-induced relapse model in rats

The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Previous work has shown that the dorsal raphe nucleus (DR)-5-HT system is inhibited by swim stress via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor (CRF). Additionally, the DR 5-HT system is regulated by opioids. The present study tests the hypothesis that the DR 5-HT system regulates stress-induced opioid relapse. In the first experiment, electrophysiological recordings of GABA synaptic activity in 5-HT DR neurons were conducted in brain slices from Sprague-Dawley rats that were exposed to swim stress-induced reinstatement of previously extinguished morphine conditioned place preference (CPP). Behavioral data indicate that swim stress triggers reinstatement of morphine CPP. Electrophysiology data indicate that 5-HT neurons in the morphine-conditioned group exposed to stress had increased amplitude of inhibitory postsynaptic currents (IPSCs), which would indicate greater postsynaptic GABA receptor density and/or sensitivity, compared to saline controls exposed to stress. In the second experiment, rats were exposed to either morphine or saline CPP and extinction, and then 5-HT DR neurons from both groups were examined for sensitivity to CRF in vitro. CRF induced a greater inward current in 5-HT neurons from morphine-conditioned subjects compared to saline-conditioned subjects. These data indicate that morphine history sensitizes 5-HT DR neurons to the GABAergic inhibitory effects of stress as well as to some of the effects of CRF. These mechanisms may sensitize subjects with a morphine history to the dysphoric effects of stressors and ultimately confer an enhanced vulnerability to stress-induced opioid relapse.

Serotonin syndrome following introduction of venlafaxine following withdrawal of phenelzine: implications for drug washout periods

We report here a case of serotonin syndrome (SS) following initiation of venlafaxine 2 weeks after withdrawal of a monoamine oxidase inhibitor (MAOI), phenelzine, and also following repeated retrials of venlafaxine initiation. The case has clinically important implications regarding the period of time necessary for monoamine oxidase biosynthesis following use of an irreversible MAOI. SS is characterized by the presence of autonomic nervous system symptoms (such as hyperthermia, diaphoresis, mydriasis, nausea, shivering, hypertension, tachycardia, and diarrhoea), mental status changes (such as agitation, hypomania, and confusion), and neuromuscular abnormalities (such as myoclonus, incoordination, hyperreflexia, tremors, clonus, and muscle rigidity [Sternbach, 2003]). SS can be a life-threatening condition and occurs acutely due to markedly increased serotonin levels in brain, often following a coprescription or overdose of serotonergic drugs. These drugs can increase serotonin levels by inhibiting metabolism (such as MAOI), increasing formation (such as l-tryptophan), inhibiting reuptake (such as selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs)), increase release (such as amphetamines) or increasing postsynaptic receptor sensitivity (such as lithium). Overdose with a SSRI alone results in mild SS in about 15% of people but does not usually lead to severe toxicity [Isbister et al. 2007]. The occurrence of the syndrome is highest with a combination of SSRIs and MAOIs, though it is also reported with other serotonergic drug combinations. Sternbach described criteria to diagnose SS (Table 1) and highlighted the importance of identifying it since it is usually reversible following discontinuation of the offending drug(s), supportive treatment and addition of a serotonin antagonist (such as cyproheptadine or chlorpromazine) in more severe cases [Sternbach, 1991]. Table 1. Sternbach’s criteria [Modified after Sternbach 1991]. There have been previous case reports of patients who experienced an SS when a serotonin reuptake inhibitor (SRI) has been introduced after the traditionally recommended 2-week washout from an irreversible MAOI [Sternbach, 2003]. However, we have been unable to identify any instance in the literature where a patient has been rechallenged with a SRI (such as an SSRI, SNRI or a TCA) after a further period of washout following the occurrence of SS.

Dopamine receptor changes after long-term haloperidol treatment in rats.

Abstract Tardive dyskinesia is a neurological syndrome associated with prolonged neuroleptic treatment of schizophrenic patients (Crane 1968; Faurbye 1970; Faurbye et al 1964). It has been suggested that tardive dyskinesia results from chemical denervation of central dopamine neurons and subsequent development of supersensitivity of the postsynaptic receptor (Rubovits &amp; Klawans 1972). Experiments based on animal models of tardive dyskinesia support this hypothesis. Chronic neuroleptic treatment increases postsynaptic dopamine receptor sensitivity when measured either behaviourally or biochemically (Christensen et al 1976; Klawans &amp; Rubovits 1972; Moore &amp; Thornburg 1975; Sayers et al 1975; Tarsy &amp; Baldessarini 1974; Von Voigtlander et al 1975). The molecular basis for this behavioural change has been reported to be an increase in the number of receptor sites with no change in their affinity as measured by 3H-neuroleptic binding to striatal membrane homogenates (Burt et al 1977; Klawans et al 1977; Muller &amp; Seeman 1977). Previous biochemical reports of the development of model tardive dyskinesia after neuroleptic treatment of animals have generally used treatment periods of 3 weeks or less (Burt et al 1977; Klawans et al 1977; Muller &amp; Seeman 1977). Only one report treated animals for longer periods (Clow et al 1978). In the present experiments we studied the kinetics of [3H]spiroperidol binding to rat caudate nucleus homogenates after 3 and 10 weeks of haloperidol treatment.