Kegg Pathway: Anxiolytics

Prostaglandins Leukot Essent Fatty Acids. 2009 Nov 9;
Ross BM

Anxiety disorders are a common group of psychiatric illnesses which have significant personal, family and societal costs. Current treatments have limited efficacy in many patients highlighting a need for new therapeutic approaches to be explored. Anxiety disorders exhibit marked comorbity with mood disorders suggesting the existence of mechanistic similarities. Such a notion is supported by observations that some conventional pharmacotherapies are both effective antidepressants and Anxiolytics. As such, given that omega-3 PUFA supplementation may be effective in the treatment of major depressive disorder it is reasonable to propose that they may also possess anxiolytic properties. Experimental data in support of such a hypothesis is currently lacking although reduced abundance of omega-3 PUFA have been reported in patients with anxiety, while supplementation with omega-3 PUFA appears to inhibit activation of the HPA axis and can ameliorate some of the symptoms of anxiety. Clinical investigations carried out to date have, however, involved small numbers of participants. Larger trials using a variety of omega-3 PUFA species in clinically well-defined patients with anxiety will be required to demonstrate a therapeutic role for omega-3 PUFA in these disorders. Given the excellent side effect profile of omega-3 PUFA as well as their strong theoretical rationale, such future trials appear justified.

Proc Natl Acad Sci U S A. 2009 Nov 17; 106(46): 19575-19580
Jones KA, Srivastava DP, Allen JA, Strachan RT, Roth BL, Penzes P

The 5-HT(2A) serotonin receptor is the most abundant serotonin receptor subtype in the cortex and is predominantly expressed in pyramidal neurons. The 5-HT(2A) receptor is a target of several hallucinogens, antipsychotics, Anxiolytics, and antidepressants, and it has been associated with several psychiatric disorders, conditions that are also associated with aberrations in dendritic spine morphogenesis. However, the role of 5-HT(2A) receptors in regulating dendritic spine morphogenesis in cortical neurons is unknown. Here we show that the 5-HT(2A) receptor is present in a subset of spines, in addition to dendritic shafts. It colocalizes with PSD-95 and with multiple PDZ protein-1 (MUPP1) in a subset of dendritic spines of rat cortical pyramidal neurons. MUPP1 is enriched in postsynaptic density (PSD) fractions, is targeted to spines in pyramidal neurons, and enhances the localization of 5-HT(2A) receptors to the cell periphery. 5-HT(2A) receptor activation by the 5-HT(2) receptor agonist DOI induced a transient increase in dendritic spine size, as well as phosphorylation of p21-activated kinase (PAK) in cultured cortical neurons. PAK is a downstream target of the neuronal Rac guanine nucleotide exchange factor (RacGEF) kalirin-7 that is important for spine remodeling. Kalirin-7 regulates dendritic spine morphogenesis in neurons but its role in neuromodulator signaling has not been investigated. We show that peptide interference that prevents the localization of kalirin-7 to the postsynaptic density disrupts DOI-induced PAK phosphorylation and spine morphogenesis. These results suggest a potential role for serotonin signaling in modulating spine morphology and kalirin-7's function at cortical synapses.

J Biomed Biotechnol. 2009; 2009: 749575
Mandas A, Iorio EL, Congiu MG, Balestrieri C, Mereu A, Cau D, Dessì S, Curreli N

It is generally accepted that oxidative stress is involved in HIV infection. However, the role in oxidative balance of Highly Active Antiretroviral Therapy (HAART) is still debated. In our study we assessed serum oxidant and antioxidant levels in an HIV-1-infected population treated with HAART, and compared them with those of untreated HIV-1 patients and HIV-1-negative subjects. The study included 116 HIV-1-infected patients (86 HAART-treated and 30 untreated), and 46 HIV-negative controls. Serum oxidant levels were significantly higher in the HIV-1 treated group as compared to untreated and control groups. In addition, a decrease of serum total antioxidant status was observed in the HIV-1 treated group. To be noted is that patients who rigorously follow antiretroviral therapy (optimal HAART adherence) have significantly higher oxidative status than those who do not closely follow the therapy (poor HAART adherence). Analysis of variance revealed no significant further increase in oxidative status in HIV-1-infected patients taking antiretroviral and other drugs with the exception of psychiatric drugs (e.g. Anxiolytics or antidepressants). Taken together, our results indicate that HAART may affect oxidative stress in HIV-1-infected patients and suggest that antiretroviral therapy plays an important role in the synergy of HIV infection and oxidative stress.

BMC Womens Health. 2009; 9: 30
Nkwo PO

BACKGROUND: Effective management of menopause is an important way to improve the quality of life of the increasing number of older women. The study sought to find out if Nigerian Gynaecologists offer effective treatment for severe menopausal symptoms. METHODS: 126 Nigerian Gynaecologists representing the six health zones of Nigeria were interviewed to determine the menopausal symptoms they had ever encountered in their practices, frequency of the symptoms, treatments ever offered for severe symptoms including their attitude to, and practice of hormone replacement therapy. RESULTS: A Nigerian Gynaecologist encountered an average of one patient with menopausal symptoms every three months (range: 0-3 patients per month). The commoner symptoms they encountered were hot flushes (88%), insomnia (75.4%), depression (58.0%), irritability (56.3%), night sweats (55.6%) and muscle pains (54.8%) while urinary symptoms (16.7%) and fracture (1.6%) were less common. Treatments ever offered for severe symptoms were reassurance (90.5%), Anxiolytics (68.3%), analgesics (14.3), HRT (7.9%), Vitamins (4%), Beta-blockers (3.2%) and Danazol (2.4%). These treatments were offered as a matter of institutional traditions rather than being based on any evidence of their efficacy. CONCLUSION: The result revealed that most Nigerian Gynaecologists prefer reassurance and Anxiolytics for managing severe menopausal symptoms instead of evidence-based effective therapies. A policy of mandatory continuing medical education for Nigerian physicians is recommended to ensure evidence-based management of gynaecological problems, including menopause.

J Neurosci. 2009 Oct 21; 29(42): 13401-9
Yasaka T, Hughes DI, Polgár E, Nagy GG, Watanabe M, Riddell JS, Todd AJ

Pure NMDA receptor (NMDAr)-mediated EPSCs, thought to correspond to "silent" glutamatergic synapses that lack AMPA receptors (AMPArs), have been observed in superficial spinal dorsal horn of neonatal but not adult rats. Recent anatomical studies suggest that AMPArs are present at virtually all glutamatergic synapses in this region in adults. We used antigen retrieval to examine colocalization of AMPArs and PSD-95 (a marker for glutamatergic synapses) in laminae I-II of neonatal and adult rats. We found a high degree of colocalization in all cases, which suggests that AMPArs are present in the great majority of glutamatergic synapses even in neonatal animals. We therefore reexamined evidence for silent synapses by performing blind whole-cell recordings from superficial dorsal horn neurons in slices from neonatal or adult rats, with focal stimulation to activate glutamatergic synapses. On some occasions in both neonatal (10 of 109, 9%) and adult (9 of 77, 12%) slices, NMDAr-mediated EPSCs were observed when the holding potential was raised to +50 mV at a stimulus strength that had failed to evoke AMPAr-mediated EPSCs. However, in all cases tested, AMPAr-mediated EPSCs were then observed when the cell was returned to -70 mV; this and other properties of the EPSCs suggest that they do not represent genuine silent synapses. When compared with previous findings, our results indicate that the appearance of silent synapses depends on experimental protocol. This suggests that pure NMDAr-mediated EPSCs seen in previous studies do not correspond to AMPAr-lacking synapses but result from another mechanism, for example, loss of labile AMPArs from recently formed synapses.

J Neurosci. 2009 Oct 21; 29(42): 13222-31
Zhang SY, Xu M, Miao QL, Poo MM, Zhang XH

Homeostatic regulation of synaptic strength in response to persistent changes of neuronal activity plays an important role in maintaining the overall level of circuit activity within a normal range. Absence of miniature EPSCs (mEPSCs) for a few hours is known to cause upregulation of excitatory synaptic strength, suggesting that mEPSCs contribute to the maintenance of excitatory synaptic functions. In the present study, we found that the absence of mEPSCs for 1-3 h also resulted in homeostatic suppression of presynaptic functions of inhibitory synapses in acute cortical slices from juvenile rats, as suggested by the reduced frequency (but not amplitude) of miniature IPSCs (mIPSCs) as well as the reduced amplitude of IPSCs. This homeostatic regulation depended on endocannabinoid (eCB) signaling, because blockade of either the activation of cannabinoid type-1 receptors (CB1Rs) or the synthesis of its endogenous ligand 2-arachidonoylglycerol (2-AG) abolished the suppression of inhibitory synapses caused by the absence of mEPSCs. Blockade of group I metabotropic glutamate receptors (mGluR-I) also abolished the suppression of inhibitory synapses, consistent with the mGluR-I requirement for eCB synthesis and release in cortical synapses. Furthermore, this homeostatic regulation also required eukaryotic elongation factor-2 (eEF2)-dependent protein synthesis, but not gene transcription. Activation of eEF2 alone was sufficient to suppress the mIPSC frequency, an effect abolished by inhibiting CB1Rs. Thus, mEPSCs contribute to the maintenance of inhibitory synaptic function and the absence of mEPSCs results in presynaptic suppression of inhibitory synapses via protein synthesis-dependent elevation of eCB signaling.

Anesth Analg. 2009 Nov; 109(5): 1684-7
Paraskeva A, Chatziara V, Siafaka I, Zotou M, Fassoulaki A

BACKGROUND: We investigated a possible effect of ondansetron on the duration of sensory and motor block produced by ropivacaine. METHODS: Fifty male patients undergoing transurethral surgery received either 8 mg oral ondansetron the evening before surgery plus IV 8 mg ondansetron 15 min before subarachnoid anesthesia or placebo. All patients received 2.2 mL of 0.75% plain ropivacaine intrathecally. Sensory and motor block were assessed 30 min after the intrathecal injection and every 30 min thereafter until recovery from the motor block. RESULTS: Thirty minutes after spinal injection of ropivacaine, we first measured, in both groups, the time to maximum block for both sensory and motor modalities. The maximum level of the sensory block, defined as decreased sensation, was T8 in the control and T6 in the ondansetron group, and absence of sensation was defined as T11 and T9 for the control and the ondansetron groups, respectively. Regarding block duration, 180 min after spinal injection, sensory block was detected in 11 of 22 and 16 of 24 patients and motor block in 1 of 22 and 0 of 24 in the control and ondansetron groups, respectively. Sensory and motor block did not differ between groups at any measured time point. CONCLUSIONS: Ondansetron had no effect on the subarachnoid sensory or motor block produced by ropivacaine.

Anesth Analg. 2009 Nov; 109(5): 1645-50
Sen H, Sizlan A, Yanarates O, Emirkadi H, Ozkan S, Dagli G, Turan A

BACKGROUND: Gabapentin and ketamine are popular analgesic adjuvants for improving perioperative pain management. We designed this double-blind, placebo-controlled study to test and compare the preventive effects of perioperative ketamine and gabapentin on early and chronic pain after elective hysterectomy. METHODS: Sixty patients undergoing abdominal hysterectomy were randomly assigned to 1 of the following 3 groups: control group received oral placebo capsules and bolus plus infusion of saline; ketamine group received oral placebo capsules and, before incision, 0.3 mg/kg IV bolus and 0.05 mgxkg(-1)xh(-1) infusion of ketamine until the end of surgery; and gabapentin group received oral gabapentin 1.2 g and bolus plus infusion of saline. The anesthetic technique was standardized, and the postoperative assessments included verbal rating scales for pain and sedation, IV morphine usage, quality of recovery assessment, recovery of bowel function, resumption of normal activities, and patient satisfaction with their pain management. Patients were questioned at 1, 3, and 6 mo after surgery for chronic postoperative pain. RESULTS: Postoperative pain scores were significantly lower in the gabapentin group compared with the ketamine and control groups, and patient-controlled analgesia morphine use was significantly reduced in both treatment groups (versus control group) (P < 0.001). Total patient-controlled analgesia morphine use was decreased by 35% and 42% in the ketamine and gabapentin groups, respectively, compared with the control group (P < 0.001). Patient satisfaction with pain treatment was significantly improved in the ketamine and gabapentin groups compared with the control group (P < 0.001). The incidence of incisional pain and related pain scores at the 1-, 3-, and 6-mo follow-up were significantly lower in the gabapentin group compared with the ketamine and control groups (P < 0.001). CONCLUSION: Gabapentin and ketamine are similar in improving early pain control and in decreasing opioid consumption; however, gabapentin also prevented chronic pain in the first 6 postoperative months.

Anesth Analg. 2009 Nov; 109(5): 1606-11
Tamdee D, Charuluxananan S, Punjasawadwong Y, Tawichasri C, Patumanond J, Sriprajittichai P

BACKGROUND: Ondansetron is effective for the treatment of intrathecal morphine-induced pruritus. There is evidence that kappa-opioid receptor agonists have antipruritic activity. Pentazocine is an agonist of kappa-opioid receptors and partial agonist at mu-opioid receptors. We therefore performed a randomized, double-blind trial to compare the efficacy of pentazocine and ondansetron for the treatment of pruritus associated with intrathecal injection of morphine in patients undergoing cesarean delivery. METHODS: Two hundred eight parturients who developed moderate to severe pruritus after the administration of intrathecal morphine were randomly allocated to 2 groups: IV pentazocine 15 mg (n = 104) and IV ondansetron 4 mg (n = 104). The successful treatment of pruritus (no or mild pruritus) and other adverse effects were determined 15 min after study drug administration, and patients were observed for recurrence of pruritus for 4 h. RESULTS: The treatment success rate at 15 min was higher in the pentazocine group (96.1%) than in the ondansetron group (80.8%) (95% confidence interval of difference: 7.0%, 23.8%; P = 0.001). The recurrence rate of moderate to severe pruritus within 4 h after treatment in the pentazocine group (12.0%) was lower than in the ondansetron group (32.1%) (P = 0.001). There were no significant differences between groups in nausea/vomiting, sedation, shivering, pain scores, and pain at injection site. No respiratory depression was observed. CONCLUSIONS: Pentazocine 15 mg is superior to ondansetron 4 mg for the treatment of intrathecal morphine-induced pruritus and has a lower recurrence rate. The side effects after treatment are mild.

Anesth Analg. 2009 Nov; 109(5): 1379-81
Gottschalk A

Ideggyogy Sz. 2009 Sep 30; 62(9-10): 355-8
Zsombók T

Expert Rev Neurother. 2009 Oct; 9(10): 1463-74
De la Gándara J, San Molina L, Rubio G, Rodriguez-Morales A, Hidalgo Borrajo R, Burón JA

BACKGROUND: Risperidone long-acting injectable (RLAI) is the first long-acting formulation of an atypical antipsychotic introduced into clinical practice. RLAI combines the benefits of atypical antipsychotic agents with an extended duration of activity and is intended for long-term management of schizophrenia. This study evaluated the use of RLAI as part of a long-term management strategy in patients with an acute episode of schizophrenia. OBJECTIVES: The primary objective was to determine clinicians' approaches to the use of RLAI in patients with an acute exacerbation of schizophrenia by examining the prescribing patterns of antipsychotic and other psychotropic medications. Other objectives were to evaluate the overall safety of switching patients to RLAI from previous antipsychotic therapy and to determine patients', caregivers' and relatives' attitudes towards RLAI treatment. Methods: The Safety and Profile of Handling and Employing of Risperdal Consta in Emergency/Acute Care Settings (SPHERE) study was an observational, non-interventional, multicenter, retrospective study involving a large cohort of patients with acute psychotic exacerbation who attended Spanish emergency/acute care facilities (between August and December 2003) and were treated with RLAI during hospitalization. RESULTS: A total of 1232 patients (70% men; mean age 37 years; median of 8 months since most recent admission) were included in the analyses; 79% had been receiving antipsychotic therapy prior to admission. All patients received RLAI post-stabilization. The main reasons for initiating RLAI were the need for long-term treatment (76%) and a low adherence to previous treatment (71%). RLAI doses administered during hospitalization were: 25 (26%), 37.5 (29%), 50 (42%) and 75-100 mg (3%). The mean number of injections per patient (2 +/- 1) and mean hospitalization time (25 +/- 16 days) indicated that RLAI was administered every 2 weeks as per the manufacturer's recommendations. All patients were discharged on RLAI treatment; 62% were prescribed concomitant therapy, mainly oral risperidone (39%), Anxiolytics (25%), antiparkinsonians (15%), hypnotics (11%) and anticonvulsants (11%). Only 5.7% of patients reported adverse events, most commonly extrapyramidal symptoms (1.1%) and somnolence (0.9%). CONCLUSIONS: As part of a long-term management strategy aimed at improving treatment adherence in schizophrenic patients, RLAI was prescribed to a wide spectrum of patients with an acute episode of schizophrenia during hospitalization and at the time of discharge from emergency/acute care facilities. RLAI was well tolerated in the study population and the overall impression of patients, primary caregivers and relatives to RLAI therapy was positive.

J Nerv Ment Dis. 2009 Oct; 197(10): 715-21
Chavira DA, Stein MB, Golinelli D, Sherbourne CD, Craske MG, Sullivan G, Bystritsky A, Roy-Byrne PP

This study's aim was to prospectively examine and identify a model of demographic, clinical, and attitudinal variables that impact improvement among patients with panic disorder. Subjects were 232 primary care patients meeting criteria for DSM-IV panic disorder. Eligible patients were randomly assigned to a collaborative care intervention or to treatment as usual. Assessments occurred at 3-month intervals during the course of 1 year. In final multivariate logistic regression models, patients with higher anxiety sensitivity and higher neuroticism scores at baseline were less likely to show clinical improvement (using a criterion of 20 or less on the Anxiety Sensitivity Index) at 3 months. Those who were non-white, had higher anxiety sensitivity, and higher overall phobic avoidance at baseline were less likely to show clinical improvement at 12 months. A greater understanding of these predictors may help clinicians identify who is at greatest risk for persistent panic-related symptoms and to plan the intensity of interventions accordingly.

Neuropsychopharmacol Hung. 2009 Jun; 11(2): 55-6
Túry F, Németh A

Clin Toxicol (Phila). 2009 Nov; 47(9): 889-93
Vallersnes OM, Lund C, Duns AK, Netland H, Rasmussen IA

OBJECTIVE: An epidemic of scopolamine poisonings occurred in Oslo in 2008 among users of illicit drugs, caused by fake Rohypnol pills. The clinical features, diagnostic process, and handling of the epidemic are presented. METHODS: Suspected cases of scopolamine poisoning were extracted by reviewing registration forms from an ongoing prospective clinical study of acute poisonings in Oslo. Medical records of extracted contacts were examined and cases included according to specified clinical criteria. RESULTS: Forty-four cases of probable scopolamine poisoning were registered. Main clinical features were mydriasis, visual hallucinations, plucking behavior, agitation, and coma. No clinical diagnosis of anticholinergic syndrome was made prior to forensic analysis of the tablets, the most frequent diagnosis up to this point being unspecified drug-induced psychosis. Later in the epidemic, scopolamine poisoning became the dominating diagnosis. Ten patients were admitted to psychiatric hospitals, the rest recovered in medical units, or left health care against medical advice. DISCUSSION: Scopolamine poisonings are rare, but the resulting anticholinergic syndrome is well described. The syndrome was not recognized until the forensic analysis result strikingly changed how the patients were diagnosed and handled. A unique aspect of this epidemic was the intoxicating agent being scopolamine-containing tablets looking like Rohypnol, sold and used under the impression of being the latter. CONCLUSION: Recognizing the anticholinergic syndrome is important to provide proper treatment. Forensic analysis was the key to correct diagnosis in this outbreak, demonstrating its importance in verifying an epidemic of poisoning by fake drugs.

Cell. 2009 Oct 16; 139(2): 380-92
Eroglu C, Allen NJ, Susman MW, O'Rourke NA, Park CY, Ozkan E, Chakraborty C, Mulinyawe SB, Annis DS, Huberman AD, Green EM, Lawler J, Dolmetsch R, Garcia KC, Smith SJ, Luo ZD, Rosenthal A, Mosher DF, Barres BA

Synapses are asymmetric cellular adhesions that are critical for nervous system development and function, but the mechanisms that induce their formation are not well understood. We have previously identified thrombospondin as an astrocyte-secreted protein that promotes central nervous system (CNS) synaptogenesis. Here, we identify the neuronal thrombospondin receptor involved in CNS synapse formation as alpha2delta-1, the receptor for the anti-epileptic and analgesic drug gabapentin. We show that the VWF-A domain of alpha2delta-1 interacts with the epidermal growth factor-like repeats common to all thrombospondins. alpha2delta-1 overexpression increases synaptogenesis in vitro and in vivo and is required postsynaptically for thrombospondin- and astrocyte-induced synapse formation in vitro. Gabapentin antagonizes thrombospondin binding to alpha2delta-1 and powerfully inhibits excitatory synapse formation in vitro and in vivo. These findings identify alpha2delta-1 as a receptor involved in excitatory synapse formation and suggest that gabapentin may function therapeutically by blocking new synapse formation.

Chemosphere. 2009 Nov; 77(10): 1257-74
Calisto V, Esteves VI

Psychiatric pharmaceuticals, such as Anxiolytics, sedatives, hypnotics, and antidepressants, are among the most prescribed active substances throughout the world. The occurrence of these widely used compounds in environmental matrices (wastewaters, surface, ground and drinking waters, soils, sediments, bio-solids and tissue), as well as the first studies indicating their high persistence and toxicity to non-target organisms, justify the growing concern about these emerging environmental pollutants. Despite this increasing interest, there is a considerable lack of knowledge about the environmental fate of a large number of psychiatric pharmaceuticals and further research about this topic is needed. This paper aims to review the literature data related to the occurrence, persistence, environmental fate and toxicity for non-target organisms of this group of pharmaceuticals. The analytical methods developed for the determination of psychiatric medicines in environmental matrices are also highlighted.

Ugeskr Laeger. 2009 Oct 5; 171(41): 2999-3003
Jørgensen VR

INTRODUCTION: The consumption of benzodiazepines (BZ) and cyclopyrrolones (CP) has attracted great interest in recent years due to the serious side-effects associated with these drugs. Two medical practices introduced a more restrictive approach to the prescription of BZ and CP. The intervention reduced the total consumption of anxiolytica by 75% and hypnotica by 90% during the two and a half year period. There is a general lack of knowledge about whether an intervention of this nature reduces drug consumption in general, or merely substitutes the consumption of drugs. Here, antidepressants (AD) are especially relevant substitutes. MATERIAL AND METHODS: In two medical practices, the consumption of AD was followed before, during and after the intervention. Consumption was followed via the Danish Medicines Agency's website Ordiprax, which listed the amount of prescription medicines sold from pharmacies. RESULTS: The total quantity of prescribed AD remained unchanged in the two practices (p = 0.05). There were minor shifts in prescription classes. This result should be seen in the context of the consumption of AD in the county as a whole, which rose by 8.6% per annum during the intervention period. CONCLUSION: In the primary sector, it is possible to reduce the amount of BZ and CP without causing a concomitant increase in the prescription of AD. The two medical practices of the present survey did not introduce a deliberately restrictive approach, but simply an increasing awareness when prescribing to patients, especially regarding the duration of prescriptions.

J Neurosci. 2009 Oct 7; 29(40): 12617-24
Perkins AM, Ettinger U, Davis R, Foster R, Williams SC, Corr PJ

Drugs that are clinically effective against generalized anxiety disorder preferentially alter rodent risk assessment behavior, whereas drugs that are clinically effective against panic disorder preferentially alter rodent flight behavior. The theoretical principle of "defensive direction" explains the pattern of associations between emotion and defensive behavior in terms of the differing functional demands arising from cautious approach to threat (anxiety) versus departure from threat (fear), offering the prospect that clinically important emotions may be explained using a single rubric of defense. We used a within-subjects, placebo-controlled, design to test this theory, measuring the effects of citalopram and lorazepam on the defensive behavior of 30 healthy adult male humans. We indexed human defensive behavior with a translation of an active avoidance task used to measure rodent defense and found that lorazepam significantly reduced the intensity of defensive behavior during approach to threat (hypothetically anxiety-related) but not departure from threat (hypothetically fear-related). Contrary to prediction, citalopram did not affect either form of defensive reaction. Since lorazepam is a drug with well established anxiety reducing properties, these data support the hypothesis that anxiety is an emotion elicited by threat stimuli that require approach. These data also contribute to the validation of a novel human analog of an established experimental model of rodent fear and anxiety.

Ross Fiziol Zh Im I M Sechenova. 2009 Aug; 95(8): 793-801
Saul'skaia NB, Fofonova NV, Sudorgina PV

In Spregue-Dawley rats by means of in vivo microdialysis combined with HPLC analysis, presentation of a chamber in which a conditioned fear response was previously acquired (tone(+) +footshock), resulted in an increase in extracellular level of citrulline (an NO co-product) in the medial nucleus accumbens. This increase was prevented by intraaccumbal infusion of 7-nitraindazole (0.5 mM), an NO synthase inhibitor. It was less than a rise in citrulline extracellular level induced by a combined presentation the chamber and the tone, but did not differ from citrulline changes occurring during the chamber presentation in the lateral nucleus accumbens. The data obtained indicate that conditioned signals of danger cause neuronal NO synthase activation in the medial and, probably, in the lateral nucleus accumbens which produces the rise in extracellular citrulline level and, likely, in NO formation in this brain area.