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Central sensitization is one form of long-term plasticity in the central nervous system. Sustained activation of primary sensory fibers supplying dorsal horn can induce long-lasting increases in the discharge amplitude of primary afferent synapses. This is similar to the long-term potentiation that occurs in many other CNS regions. Drugs that limit the short-duration wind-up component of central sensitization include sodium channel blockers, NMDA antagonists, fast-acting opioids and the calcium-channel ligands gabapentin and pregabalin (S-3-(aminomethyl)-5-methylhexanoic acid). Pregabalin, like gabapentin, binds selectively to the Ca V α 2 δ auxiliary subunit of presynaptic voltage-gated calcium channels. The conformational changes induced by this binding inhibit abnormally intense neuronal activity by reducing the synaptic release of glutamate and other neurotransmitters. Recent identification in animal models of increased Ca V α 2 δ protein expression in chronic pain, allodynia, and hyperalgesia have drawn additional interest to drugs that bind the Ca V α 2 δ site. Experimental studies with animal models and healthy human volunteers have shown that pregabalin reduces nociceptive responses, particularly in conditions involving central sensitization. Since these actions occur with relatively modest effects on physiological and cognitive functions, pregabalin may be an important consideration in the pharmacotherapy of otherwise difficult-to-treat pain syndromes. Perspective This focus article discusses how the central nervous system plasticity phenomenon, central sensitization, is established in the induction and maintenance of chronic pain, allodynia, and hyperalgesia. In addition, it explores the neurophysiologic actions of the calcium-channel ligands gabapentin and pregabalin in limiting pathological manifestations of central sensitization.

Background Fibromyalgia, as defined by the American College of Rheumatology, is characterized by widespread pain lasting for at least 3 months, with pain in at least 11 out of 18 tender points when palpated with digital pressure. Objective The authors investigated the relationship between changes in pain and symptoms of anxiety and depression, using data from pregabalin clinical trials. Method Results from three double-blind, placebo-controlled trials of pregabalin monotherapy in fibromyalgia (8–14 weeks) were pooled, and baseline to end-point changes in pain and Hospital Anxiety and Depression Scale (HADS) scores were analyzed. Path-analysis evaluated the association between improvements in anxiety and depression and pain relief. Results Baseline HADS scores indicated moderate-to-severe anxiety in 38% of patients and moderate-to-severe depressive symptoms in 27%. The improvement in pain was not related to baseline levels of anxiety or depression. The correlation between changes in pain and depressive or anxiety symptoms was low-to-moderate. Pathanalysis showed that most of the pain relief observed with pregabalin treatment was a direct analgesic effect and was not explained by improvement in mood. Conclusion Response to treatment of pain in the pregabalin trials did not depend on baseline levels of anxiety or depressive symptoms, and pregabalin improved pain in fibromyalgia patients with or without depressive or anxiety symptoms. Changes in the level of anxiety or depression had a low-tomoderate impact on pain reduction. Pain reduction with pregabalin treatment appeared to result mostly from a direct treatment effect, rather than an indirect effect mediated through improvement in anxiety or depressive symptoms.

Time to onset of pain relief and improvement in allodynia in 269 patients with postherpetic neuralgia was examined in a 4-week randomized trial comparing flexibly dosed pregabalin (150–600 mg/d), fixed-dose pregabalin (300 mg/d), and placebo. For each patient with clinically meaningful pain reduction (≥30%) at end point, onset of pain relief was defined as the first study day on which a patient reported ≥1-point reduction in pain relative to baseline. Average dose achieved was 396 mg/d in the flexible-dose group compared with 295 mg/d in the fixed-dose group. Median pain relief onset times were 3.5 days (flexible-dose), 1.5 days (fixed-dose), and >4 weeks (placebo). Compared with placebo, significantly more patients in both pregabalin treatment groups achieved ≥30% and ≥50% pain reduction at end point. Almost 95% of patients had brush-evoked allodynia, with 68% having moderate to severe allodynia (≥40/100 mm). At baseline, pain and allodynia were highly correlated. Independent of treatment assignment, improvement in pain and improvement in allodynia were significantly correlated. Allodynia could serve as a useful surrogate outcome measure in future studies. Pregabalin was significantly better than placebo in alleviating allodynia (flexible-dose reduction, 26 mm; fixed-dose, 21 mm; placebo, 12 mm). Discontinuation rates due to adverse events were more frequent in the fixed-dose group. Perspective A flexible-dose regimen reduces discontinuations, facilitates higher final doses, and results in a slightly greater pain relief. Allodynia (touch-evoked pain) can be of disabling severity and is present in nearly all patients with postherpetic neuralgia. Allodynia severity is correlated with pain severity and improvement in allodynia is correlated with clinical response.

Sexual dysfunction has been reported in both men and women with epilepsy. Associated factors are diverse but include, among others, antiepileptic drugs. We present the cases of 5 men who reported mild to moderate erectile dysfunction or impotence for the first time when treated with the new antiepileptic drug pregabalin as add-on therapy.

SUMMARYBackgroundAlthough guidelines recommend use of oral 5-aminosalicylates (5-ASAs) asfirst-line therapy in patients with mild to moderate ulcerative colitis (UC)and ulcerative proctitis (UP) and steroids with or without 5-ASAs in thosemore severely ill, little is known about how UC and UP are actually treated.AimTo document treatment of new-onset UC and UP in routine clinical practice.MethodsUsing a large US health insurance database, we identified all persons withnew-onset UC or UP between 1 January 2005 and 31 December 2007,based on: (i) initial receipt of an oral 5–ASA, mesalazine (mesalamine) sup-pository, 5-ASA enema, steroid, antimetabolite, budesonide or TNF inhibi-tor; (ii) sigmoidoscopy/colonoscopy in prior 30 days resulting in a newdiagnosis of UC or UP and (iii) no prior encounters for Crohn’s disease.We examined patterns of pharmacotherapy over 1 year.ResultsWe identified 1516 UC patients and 636 UP patients who met study entrycriteria. In UC, initial therapies most frequently used were oral 5-ASAs(53% of patients), oral 5-ASAs and systemic steroids (12%), systemic ste-roids (8%) and mesalazine suppositories (6%); in UP, mesalazine supposito-ries (42%) and oral 5-ASAs (19%) were most often used, followed bycombination therapy (14%), mesalazine enema (11%) and rectal steroids(10%). Few patients received maintenance therapy, and there was limiteduse of antimetabolites and biological agents.ConclusionsOral 5-ASAs and systemic steroids are the mainstay of treatment inpatients with new-onset ulcerative colitis; in those with new-onset ulcerativeproctitis, it is mesalazine suppositories. Care of these patients appears con-sistent with treatment guidelines.Aliment Pharmacol Ther

Summary Purpose This study assessed the comparative efficacy of pregabalin for refractory partial seizures. Methods Four-hundred and thirty-four patients with partial seizures were randomized to pregabalin, lamotrigine, or placebo as adjunctive therapy for 17 weeks of double-blind treatment. In phase I (11 weeks), pregabalin was titrated over 1 week and lamotrigine over 5 weeks to fixed dosages of 300 mg/day for both. In phase II (6 weeks), patients not yet seizure-free were increased to pregabalin 600 mg/day or lamotrigine 400 mg/day. Results During phase I, there was a nonsignificant trend toward a greater reduction in seizures with pregabalin versus placebo and lamotrigine. Across the 17 weeks of treatment, pregabalin showed a median percentage reduction from baseline in seizure frequency of −20.0% ( p = .001) versus placebo, and −9.7% ( p = .080) versus lamotrigine. The responder rate (≥50% reduction in seizure frequency) for pregabalin exceeded that of placebo (36% vs 21%; p = .007) and lamotrigine (36% vs 24%; p = .04). Adverse events were consistent with the known safety profiles of pregabalin and lamotrigine. Discussion Pregabalin was demonstrated to be noninferior to lamotrigine in the treatment of refractory partial seizures. Overall conclusions were complicated by an unusually large and heterogeneous placebo response.

Central sensitization is one form of long-term plasticity in the central nervous system. Sustained activation of primary sensory fibers supplying dorsal horn can induce long-lasting increases in the discharge amplitude of primary afferent synapses. This is similar to the long-term potentiation that occurs in many other CNS regions. Drugs that limit the short-duration wind-up component of central sensitization include sodium channel blockers, NMDA antagonists, fast-acting opioids and the calcium-channel ligands gabapentin and pregabalin (S-3-(aminomethyl)-5-methylhexanoic acid). Pregabalin, like gabapentin, binds selectively to the Ca(V)α₂δ auxiliary subunit of presynaptic voltage-gated calcium channels. The conformational changes induced by this binding inhibit abnormally intense neuronal activity by reducing the synaptic release of glutamate and other neurotransmitters. Recent identification in animal models of increased Ca(V)α₂δ protein expression in chronic pain, allodynia, and hyperalgesia have drawn additional interest to drugs that bind the Ca(V)α₂δ site. Experimental studies with animal models and healthy human volunteers have shown that pregabalin reduces nociceptive responses, particularly in conditions involving central sensitization. Since these actions occur with relatively modest effects on physiological and cognitive functions, pregabalin may be an important consideration in the pharmacotherapy of otherwise difficult-to-treat pain syndromes.This focus article discusses how the central nervous system plasticity phenomenon, central sensitization, is established in the induction and maintenance of chronic pain, allodynia, and hyperalgesia. In addition, it explores the neurophysiologic actions of the calcium-channel ligands gabapentin and pregabalin in limiting pathological manifestations of central sensitization.

Summary Purpose: To determine the time at which pregabalin demonstrates seizure-suppressing activity when given as adjunctive treatment to patients with refractory partial seizures. Methods: Data from four similar 12-week, randomized, double-blind, placebo-controlled, parallel-group trials in patients with refractory partial seizures were pooled to provide an adequate sample to compare the proportion of patients free of seizures on each study day between pregabalin (combined 150–600 mg/day groups) and placebo (combined groups). A generalized estimating equation (GEE) statistical model was used to perform pairwise comparisons on each study day. In several pregabalin dosage groups the dosage was escalated during days 1–7, whereas in others pregabalin was initiated at a fixed dosage without escalation. Results: The proportion of patients free of seizures on any treatment day was greater in the combined pregabalin groups compared with baseline. Differences were not observed between the placebo group and baseline. A significantly greater proportion of patients were free of seizures in the combined pregabalin 150–600 mg/day and the pregabalin 600 mg/day fixed-dosage groups compared with the placebo groups from treatment day 2 onward (p

Sleep disturbances are common in patients with fibromyalgia (FM). The objective of this analysis was to evaluate the effects of pregabalin on sleep in patients with FM.Analyses were based on two randomized, double-blind, placebo-controlled trials of pregabalin (300mg, 450mg, and 600mg daily) in adult FM patients. Sleep outcomes included the Medical Outcomes Study (MOS) Sleep Scale and a daily diary assessment of sleep quality. Treatment effects were evaluated using analysis of covariance. Clinically important differences (CID) in the Sleep Quality Diary and MOS Sleep Disturbance scores were estimated using mixed-effects models of changes in scores as a function of patients' global impressions of change. Mediation modeling was used to quantify the direct treatment effects on sleep in contrast to indirect influence of the treatment on sleep via pain.A total of 748 and 745 patients were randomized in the respective studies. Patients were predominantly Caucasian females, average age 48-50 years, on average had FM for 9-10 years, and experienced moderate to severe baseline pain. Pregabalin significantly improved the Sleep Quality Diary (P0.001), MOS Sleep Disturbance (P0.01), MOS Quantity of Sleep (P0.003), and MOS Sleep Problems Index scores (P0.02) relative to placebo. Treatment effects for the 450mg and 600mg groups exceeded the estimated CID thresholds of 0.83 and 7.9 for the Sleep Quality Diary and MOS Sleep Disturbance scores, respectively. Mediation models indicated that 43-80% of the benefits on sleep (versus placebo) were direct effects of pregabalin, with the remainder resulting from an indirect effect of treatment via pain relief.These data demonstrate improvement in FM-related sleep dysfunction with pregabalin therapy. The majority of this benefit was a direct effect of pregabalin on the patients' insomnia, while the remainder occurred through the drug's analgesic activity.

The purpose of this study was to investigate the effects of noradrenergic agents infused into the anterior hypothalamus on feline affective defense responses elicited by electrical stimulation of the ventromedial hypothalamus. Anterior hypothalamic sites which are known to receive inputs from both the ventromedial hypothalamus and ascending noradrenergic pathways were selected for pharmacological analysis. Intracerebral infusions of NE (1.2-2.4 nmol) into the anterior hypothalamus significantly reduced the threshold current required to elicit the hissing component of affective defense via electrical stimulation of the ventromedial hypothalamus. Maximal threshold reductions (17 +/- 3% to 20 +/- 3%) were observed 30 min following infusion. Anterior hypothalamic infusions of clonidine facilitated feline affective defense by reducing hissing current thresholds by 18 +/- 4%. Clonidine-induced changes in response thresholds parallel those obtained with NE. Both NE-induced and clonidine-induced reductions in current thresholds were reversible by pre- and post-treatment of the anterior hypothalamic sites with yohimbine. These results demonstrate that the reductions in response thresholds are mediated by post-synaptic alpha 2-adrenoceptors located within the anterior hypothalamus. Thus the noradrenergic system may play an important role in the regulation of affective aggressive behavior.

The purpose of the study was to assess the efficacy and safety of pregabalin monotherapy in patients with fibromyalgia in a randomized, double-blinded, placebo-controlled trial. After 1 week of single-blinded administration of placebo, 750 patients meeting American College of Rheumatology criteria for fibromyalgia were randomly assigned to pregabalin (300 mg/d, 450 mg/d, 600 mg/d) or placebo, administered twice daily for 14 weeks. The primary outcome variable was comparison of end point mean pain scores, derived from daily diary ratings of pain intensity (0 to 10 scale), between each of the pregabalin groups and the placebo group. If positive, additional primary efficacy parameters included the Patient Global Impression of Change (PGIC) and the Fibromyalgia Impact Questionnaire (FIQ) total score. Compared with placebo-treated patients, mean changes in pain scores at the end point in pregabalin-treated patients were significantly greater (P.001: 300 mg/d, -0.71; 450 mg/d, -0.98; 600 mg/d, -1.00). Compared with placebo, significantly more pregabalin-treated patients reported improvement on PGIC (P.01 for all 3 pregabalin doses) and significant improvements in total FIQ score for the 450 mg/d (P = .004) and the 600 mg/d (P = .003) doses. Compared with placebo, all 3 doses of pregabalin were associated with significant improvement in sleep. The most commonly reported pregabalin-related adverse events were dizziness and somnolence, which tended to be dose-related.This randomized, placebo-controlled trial of 300, 450, and 600 mg/d of pregabalin monotherapy demonstrated that all 3 doses were efficacious for up to 14 weeks for the treatment of fibromyalgia and were well tolerated by most patients. These results provide evidence that pregabalin is an important treatment option for patients with fibromyalgia.

Objective: To characterize change from baseline weight over time for pregabalin and placebo administration. Methods: Asymptotic fraction of baseline weight was modeled with a nonmixture model and a mixture model as a function of baseline weight, exposure, time, covariate effects, and subject-specific random effects. Model fit was assessed using standard diagnostic plots. Predictive performance was assessed using both data similar to the original data, and open-label data. Results: The nonmixture model indicated that a typical patient (baseline weight 82 kg) receiving placebo or 300 mg/day pregabalin approached an asymptotic fractional change from baseline weight of [mean (95% prediction interval for typical individual)] 0.7% (−5.5% to 7.4%) or 2.5% (−3.8% to 9.1%), respectively, with a half-life of 17 days. Substantial between-subject variability is observed, with some drug-treated subjects remaining weight neutral or losing weight, at all levels of exposure. Structural fixed effects parameters for the two submodels (mixture model) were in close agreement with each other and with those for the nonmixture model. The mixture model described two subpopulations differing in interindividual variability. No significant interindividual-varying covariates influencing the mixture probabilities were identified other than exposure. Both models had adequate fit; both models performed well during external validation. Predictive performance (nonmixture model) was adequate to ~900 days. Conclusions: The weight of a typical 82-kg patient receiving placebo or pregabalin (300 mg/day) approaches an asymptotic fractional change from baseline weight of 0.7%, or 2.5%, respectively, with a half-life of 17 days. Substantial between-subject variability remains unexplained.

Summary: Purpose: To evaluate pregabalin as add-on therapy for patients with partial seizures administered as fixed dose or as flexible dose adjusted to optimal seizure reduction and tolerability. Methods: Patients receiving antiepileptic drugs (98.8% between 1 and 3 AEDs; 1.2% on more than 3 AEDs) and experiencing ≥4 partial seizures during the 6-week baseline period and no 4-week seizure-free interval were randomized (1:2:2) to placebo (n = 73), pregabalin fixed dose (600 mg/day BID; n = 137), or pregabalin flexible dose (n = 131; 150 and 300 mg/day for 2 weeks each; 450 and 600 mg/day for 4 weeks each, BID) for 12 weeks. Dosage could be adjusted based on tolerability and maintained when a 4-week seizure-free period was achieved. Primary efficacy parameter was reduction in seizure frequency from baseline. Results: Both pregabalin regimens significantly reduced seizure frequency compared with placebo, by 35.4%, for flexible dose (p = 0.0091) and 49.3% for fixed dose (p = 0.0001) versus 10.6% for placebo, and the fixed-dose group was superior to the flexible-dose group (p = 0.0337). Most adverse events were mild or moderate. Discontinuation rates due to adverse events were 6.8% (placebo), 12.2% (pregabalin flexible dose), and 32.8% (pregabalin fixed dose). Patients receiving pregabalin fixed dose discontinued due to adverse event earlier than other groups. Conclusions: Pregabalin administered twice daily, either as fixed (600 mg/day), or as flexible (150–600 mg/day) dose, was highly effective and generally well-tolerated as add-on therapy for partial seizures with or without secondary generalization. Lower incidence of adverse events and discontinuations were achieved in patients receiving pregabalin when dosing was individualized to optimize efficacy and tolerability.

Background and Aims:Sleep disturbance is prominent in fibromyalgia (FM). This 14-week, randomized, double-blind, placebo-controlled study, evaluated the effect of pregabalin on pain and sleep-related outcomes in FM.Methods:Patients meeting ACR (FM) diagnostic criteria were randomized to pregabalin 300, 450, or 600mg/d (BID) or placebo for 14 weeks (A0081077). Primary efficacy parameter: LOCF endpoint mean pain score (MPS). At baseline and endpoint, patients completed the Medical Outcomes Sleep (MOS) Sleep Scale. Mean Sleep Quality scores (11-point numeric ratings) were derived from patient daily diaries.Results:745 randomized patients: 95% female, mean age=50 years, baseline MPS: 6.7. Placebo-corrected differences from baseline to endpoint in MPS were: 300mg/d, -0.71 (p=.0009); 450mg/d, -0.98 (p

Although common in patients with PHN ( 50%), dynamic allodynia has not been routinely evaluated in large RCTs. We evaluated the effect of pregabalin, an alpha-2-delta ligand, on Visual Analog Scale (VAS) ratings of dynamic (brush-evoked) allodynia in PHN in this placebo-controlled RCT. The study consisted of a 7-day screening period, 28-day treatment phase, and 1-week taper. Patients ( 18y) with PHN for 3 months, pain VAS score of 40mm (100-mm scale), who completed the daily pain NRS 4 times (average daily score 4; 0-10 scale) during 7-day screening. Time-to-onset of clinically meaningful pain relief (1-point improvement in daily pain score in patients achieving 30% decrease in weekly pain score at endpoint) was the primary efficacy measure, with VAS allodynia being a secondary measure and the focus of this analysis. A total of 91 patients were randomized to flexible-dosage pregabalin (optimized dose 150-600mg/d BID); 88 to fixed-dosage 300mg/d; and 90 to placebo for 4 weeks. Median time-to-onset of pain relief was 3.5d, 1.5d, and 4wks for flexible, fixed, and placebo, respectively and corresponded to meaningful pain relief achieved in 69.2%, 58.0%, and 30% of treatment groups, respectively. Fixedand flexible-dosage pregabalin appeared superior to placebo as early as Days 1 and 2, respectively. Most patients (approx. 66%) had moderate-to-severe allodynia at baseline. Baseline-to-endpoint LS-mean changes in brush-evoked allodynia in PHN-affected areas for flexible-, fixed-dosage, and placebo groups were: 26.23 (P 0.0001) 20.81 (P 0.0075), and 11.83. Significant improvement of pregabalin over placebo was seen at Week 1. Endpoint improvement in allodynia correlated with improvement in pain for all groups. Improvements in mean weekly pain score and brush-evoked allodynia rating significantly correlated with improvement on PGIC. Both pregabalin regimens were well-tolerated. Both pregabalin regimens were associated with early-onset clinically meaningful, sustained pain relief and corresponding improvements in dynamic allodynia and PGIC scores in PHN patients.

Introduction:This study (A0081057) was designed to evaluate the long-term safety and efficacy of pregabalin treatment of fibromyalgia (FM).Methods:In this 1-year, open-label (OL) extension of a 13-week randomized, placebo-controlled trial of pregabalin FM patients had the option of continuing pregabalin at doses of 150 to 600 mg/d. Efficacy was measured by the Short-Form McGill Pain Questionnaire (SF-MPQ), which included sensory and affective pain descriptors, Present Pain Intensity (PPI) index, and a Visual Analog Scale (VAS).Results:429 of 431 screened patients entered OL treatment, 249 (58%) completed, 70 (16.3%) discontinued due to an adverse event (AE), and 110 (25.7%) discontinued for other reasons. Median duration of treatment with pregabalin was 357 days (range, 1-402 days); 114 received pregabalin for ≥1 year. No clinically meaningful increases in dose were noted over the OL treatment period. Weighted mean dose was 414 mg/d in the first 3 months of treatment and 444 mg/d after 9 months of treatment. SF-MPQ sensory, affective, and total scores were improved relative to baseline, VAS pain score decreased 21 points (0-100 scale), and PPI decreased 0.9 point (0-5 scale). The most frequently reported all-causality AEs were dizziness, somnolence, peripheral edema, and increased weight, most of which were mild to moderate in intensity and of limited duration.Conclusions:Pregabalin administered for up to 1 year was generally well tolerated by FM patients without evidence of dose increase over time. The sustained improvement in pain measures during OL treatment was consistent with that in shorter term double-blind trials.

Aims:Examine the evidence for a relationship between pregabalin effect on pain and baseline anxiety and depressive symptoms in patients with fibromyalgia (FM).Background:Chronic pain and concomitant anxiety and depressive symptoms are common in patients with FM, as well as in other chronic pain disorders. Pregabalin was effective for treating pain in FM patients in three parallel group RCTs (105, 1056, 1077) where data for anxiety and depressive symptom levels were collected.Design/Methods:Patients meeting ACR criteria for FM with a pain VAS score ≥40 mm were followed for 8-14 weeks in 3 randomized, double-blind, placebo-controlled trials. Patients (N=2022) received 150, 300, 450 or 600mg/d pregabalin or placebo. The primary efficacy parameter was change in endpoint Mean Pain Score (MPS) (range 0 [no pain]-10[worst possible pain]). Regression analyses evaluated whether changes in pain bore any relation to the baseline Hospital Anxiety and Depression Scales (HADS-A) and (HADS-D) levels.Results:Pregabalin 300, 450, and 600 mg/d, but not 150 mg/d, showed statistically significant improvements in pain compared with placebo (p

The purpose of this study was to describe the pathways which mediate feline affective defense and quiet biting attack behavior elicited from the midbrain central gray. In these experiments, methods of [3H]leucine and 2-deoxy-[14C]glucose (2-DG) radioautography were utilized in concert with the technique of electrical and chemical brain stimulation. Affective defense behavior elicited from the midbrain central gray is characterized by marked vocalization such as hissing and growling, pupillary dilatation, urination and piloerection. In contrast, quiet biting attack elicited from the midbrain central gray lacks overt autonomic signs observed with affective defense response as well as the stalking component which is typically associated with stimulation of the lateral hypothalamus. Nevertheless, central gray-elicited attack resulted in a directed bite of the neck of an anesthetized rat in a manner similar to that observed from the hypothalamus. Affective defense was elicited from the dorsal half of the midbrain central gray, while quiet biting attack was obtained following stimulation of the ventral half of the midbrain central gray, thus indicating a functional differentiation of the central gray with respect to these two forms of aggression. In a separate series of experiments, affective defense or quiet biting attack response was identified by electrical stimulation through a cannula electrode situated in the midbrain central gray. The affective defense responses were subsequently elicited following microinjections of D,L-homocysteic acid through the same cannula electrode in order to demonstrate that these responses were the result of direct stimulation of cell bodies within the central gray. Then, one of the following autoradiographic tracing procedures was utilized: (1) [3H]leucine was injected through a cannula electrode and the animal was sacrificed after a 4- to 14-day survival period; or (2) a 2-DG solution was systemically injected and electrical stimulation was applied through the cannula electrode in order to metabolically activate the pathways associated with each of these responses. In general, the pattern of labelled target regions as indicated by 3H-amino acid radioautography was similar to that obtained from the 2-DG autoradiographic analysis. The principal ascending pathway associated with affective defense was traced to the anteromedial hypothalamus and medial thalamus. Concerning descending projections, label was traced into the central tegmental fields of the midbrain and pons, locus coeruleus and motor and main sensory nuclei of the trigeminal complex.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of norepinephrine microinjected into the anterior hypothalamus were examined in feline affective defense behavior elicited by electrical stimulation of the region of the ventromedial nucleus. Anterior hypothalamic sites from which affective defense behavior could also be elicited by electrical stimulation and which are known to receive inputs from both the ventromedial nucleus and brainstem noradrenergic neurons were selected for pharmacological analysis. Intracerebral injections of 250 ng (1 nM) and 500 ng (2 nM) quantities of norepinephrine placed into the anterior hypothalamus resulted in a significant lowering of the attack thresholds. These reductions in response thresholds which were reversed by either pre- or post-treatment with yohimbine, indicate that the noradrenergic system may play an important role in the regulation of affective defense behavior.