Central Behavioral Effects Research Articles

Chronic Behavioral and Neurochemical Effects of Four Novel N-Benzyl-2-phenylethylamine Derivatives Recently Identified as "Psychoactive" in Adult Zebrafish Screens.

Potently affecting human and animal brain and behavior, hallucinogenic drugs have recently emerged as potentially promising agents in psychopharmacotherapy. Complementing laboratory rodents, the zebrafish (Danio rerio) is a powerful model organism for screening neuroactive drugs, including hallucinogens. Here, we tested four novel N-benzyl-2-phenylethylamine (NBPEA) derivatives with 2,4- and 3,4-dimethoxy substitutions in the phenethylamine moiety and the -F, -Cl, and -OCF3 substitutions in the ortho position of the phenyl ring of the N-benzyl moiety (34H-NBF, 34H-NBCl, 24H-NBOMe(F), and 34H-NBOMe(F)), assessing their behavioral and neurochemical effects following chronic 14 day treatment in adult zebrafish. While the novel tank test behavioral data indicate anxiolytic-like effects of 24H-NBOMe(F) and 34H-NBOMe(F), neurochemical analyses reveal reduced brain norepinephrine by all four drugs, and (except 34H-NBCl) - reduced dopamine and serotonin levels. We also found reduced turnover rates for all three brain monoamines but unaltered levels of their respective metabolites. Collectively, these findings further our understanding of complex central behavioral and neurochemical effects of chronically administered novel NBPEAs and highlight the potential of zebrafish as a model for preclinical screening of small psychoactive molecules.

Study of Central Nervous System Depressant and Behavioral Activity of Ethanolic Extract of Clitoria Annuain Albino Rats

Objective: The objective was to evaluate depressant effects on central nervous system (CNS) and behavioral effects of ethanol extract of clitoria annua and to find the phytochemical responsible for these activities with possible mode of action. Materials & Method: The central nervous system (CNS) depressant activity of C. annua was evaluated by the classical models of depression as Rota rod method, Actophotometer test, tail suspension, and thiopental sodium induced sleeping time tests in Rat. The Rats were divided into Normal, Standard, and two test groups containing five rats each. The test groups received extract at the doses of 200, and 400 mg/kg body weight orally where as the Normal group received distilled water (0.1 ml/mice, p.o.). Diazepam (2 mg/kg, i.p.) was used as standard drug. Results: It is clear that the plant extract significantly decreased the locomotor activity of rats in Rota rod method and Actophotometer test when compared to the normal (p < 0.05). It is observed that the extract showed significantly (p < 0.05) increased in immobility time in tail suspension test in mice. In addition, the extract produced prolongs the sleeping time with onset of action in contrast to the normal group. Conclusions: The present work depicts the evaluation of possible CNS depressant activity of C. annua in mice models. EECA can be a safe and effective approach/alternative for the treatment of number of CNS depressant disorders. More extensive study is required to fractionate, purify, and identify the exact mechanism of action CNS Depressant activity present in ethanolic extract of Clitoria annua with its active ingredients.

Tracking oxytocin functions in the rodent brain during the last 30 years: From push‐pull perfusion to chemogenetic silencing

A short overview is provided of the last 30 years of oxytocin (and vasopressin) research performed in our laboratories, starting with attempts to monitor the release of this nonapeptide in the rodent brain during physiological conditions such as suckling in the lactating animal. Using push-pull perfusion and microdialysis approaches, release patterns in hypothalamic and limbic brain regions could be characterised to occur from intact neuronal structures, to be independent of peripheral secretion into blood, and to respond differentially to various stimuli, particularly those related to reproduction and stress. Parallel efforts focused on the functional impact of central oxytocin release, including neuroendocrine and behavioural effects mediated by nonapeptide receptor interactions and subsequent intraneuronal signalling cascades. The use of a variety of sophisticated behavioural paradigms to manipulate central oxytocin release, along with pharmacological, genetic and pharmacogenetic approaches, revealed multiple consequences on social behaviours, particularly social fear.

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4'-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects.

para-Methyl-4-methylaminorex (4,4'-DMAR) is a phenethylamine derivative with psychostimulant activity whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated a high-performance liquid chromatography-tandem mass spectrometry method to measure the compound's concentrations in plasma, and we applied it to describe the pharmacokinetic properties of 4,4'-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,4'-DMAR after intraperitoneal injection as well as its central behavioral effects. Locomotor activity increased after a single injection of 10 mg/kg, peaking at 2 hours and disappearing at 5 hours; in these conditions, brain absorption was very rapid, (tmax = 30-60 minutes) and large (brain-to-plasma ratio = 24); the half-life was approximately 50 minutes. After 14 daily doses, the compound's effect on locomotor activity was greater (approximately 20% compared with the effect after the first dose), but not for pharmacokinetic reasons. Using high-resolution mass spectrometry, we also identified four metabolites of cis-4,4'-DMAR in the plasma and brain of treated rats. Semiquantitative analysis indicated low brain permeability and very low brain concentrations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the para-methyl group (M2) persisted in the plasma longer and at higher concentrations than the parent molecule and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,4'-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.

Relationship between central behavioral effects and peripheral sympathetic neurotransmission functionality during acute cocaine withdrawal syndrome in adult rats

ABSTRACTBackground: Acute cocaine withdrawal syndrome (ACWS) is characterized as a set of organic alterations triggered by abrupt discontinuation of chronic cocaine consumption, usually occurring at 24–40 hours after withdrawal. However, little is known about the relationship between central and peripheral sympathetic neurotransmission during ACWS. Objective and Methods: We investigated the mechanisms involved in central and peripheral sympathetic neurotransmission and how ACWS affects the sympathetic functionality. Cocaine was administered twice daily for 5 days in Wistar rats (at least 5 in each group): on the first and second day, 15 mg/kg/i.p.; third day, 20 mg/kg/i.p.; and finally in the last two days, 30 mg/kg/i.p. Subsequently, at 1, 24, 48 and 120 h after cocaine administration the following experiments were done: (i) at the central level, behavioral tests of open-field and elevated plus maze; and (ii) at the peripheral level, tests of catecholamine release, function of α2-adrenergic receptors (α2-ARs), imidazoline receptors (I1,2-Rs), L-type voltage-gated (Cav1.2) Ca2+ channels and α1-ARs. Results: During ACWS, rats showed hypolocomotion and exacerbation of anxiogenic-effects 24 h after cocaine withdrawal. Likewise, a decrease in the catecholamine release and activity of α2-ARs/I1,2-Rs at 24–48 h after cocaine withdrawal was observed. A decrease in Cav1.2 channels and α1-ARs function at 48 h after cocaine withdrawal was observed. Conclusions: The relationship of central and peripheral sympathetic neurotransmission during ACWS possibly due to a failure in activation and/or inactivation of presynaptic α2-ARs/I1,2-Rs, may offer a potential target for attenuating ACWS.

Quantitative Magnetization Transfer Imaging as a Biomarker for Effects of Systemic Inflammation on the Brain

BackgroundSystemic inflammation impairs brain function and is increasingly implicated in the etiology of common mental illnesses, particularly depression and Alzheimer’s disease. Immunotherapies selectively targeting proinflammatory cytokines demonstrate efficacy in a subset of patients with depression. However, efforts to identify patients most vulnerable to the central effects of inflammation are hindered by insensitivity of conventional structural magnetic resonance imaging. MethodsWe used quantitative magnetization transfer (qMT) imaging, a magnetic resonance imaging technique that enables quantification of changes in brain macromolecular density, together with experimentally induced inflammation to investigate effects of systemic inflammatory challenge on human brain microstructure. Imaging with qMT was performed in 20 healthy participants after typhoid vaccination and saline control injection. An additional 20 participants underwent fluorodeoxyglucose positron emission tomography following the same inflammatory challenge. ResultsThe qMT data demonstrated that inflammation induced a rapid change in brain microstructure, reflected in increased magnetization exchange from free (water) to macromolecular-bound protons, within a discrete region of insular cortex implicated in representing internal physiologic states including inflammation. The functional significance of this change in insular microstructure was demonstrated by correlation with inflammation-induced fatigue and fluorodeoxyglucose positron emission tomography imaging, which revealed increased resting glucose metabolism within this region following the same inflammatory challenge. ConclusionsTogether these observations highlight a novel structural biomarker of the central physiologic and behavioral effects of mild systemic inflammation. The widespread clinical availability of magnetic resonance imaging supports the viability of qMT imaging as a clinical biomarker in trials of immunotherapeutics, both to identify patients vulnerable to the effects of systemic inflammation and to monitor neurobiological responses.

The hypothalamic–neurohypophysial system: genomes, genes and genetics

The hypothalamic–neurohypophysial system: genomes, genes and genetics

Study of central nervous system depressant and behavioral activity of an ethanol extract of Achyranthes aspera (Agadha) in different animal models.

Background:Achyranthes aspera Linn., an indigenous herb, has been reported to have antifertility, antihyperlipidemic, antidiabetic, immunomodulatory, anticarcinogenic, diuretic, cardiotonic, analgesic anti-inflammatory, hypnotic, antifungal, antibacterial, and central antinociceptive activities.Aims:This study was designed to evaluate depressant effects on central nervous system (CNS) and behavioral effects of ethanol extract of A. aspera (EEAA) and to find the phytochemical responsible for these activities.Materials and Methods:The pharmacological assays used to study CNS depressant effect in albino mice were rota rod and actophotometer performance test. Effects on behavioral activity were studied using open field test. The extract was given intraperitoneally (i.p.) at a dose of 400 mg/kg. Diazepam (2 mg/kg body weight i.p.) was used as standard.Statistical Analysis Used:Data were analyzed by using analysis of variance followed by Dunnett's test. P < 0.05 was considered significant.Results:Phytochemical screening revealed presence of triterpenoids, saponins, alkaloids (betaine, achyranthine), and steroids as major constituents. The result of this study reflected that EEAA (400 mg/kg i.p.) decreased locomotor activity, produced muscle relaxation, and showed anxiolytic activity.Conclusions:EEAA exhibit CNS depressant and significant anxiolytic activity comparable to diazepam.

Gastric Electrical Stimulation for Obesity: The Need for a New Device Using Wider Pulses

Gastric electrical stimulation (GES) has been proposed as a therapeutic option for obesity. However, its clinical efficacy is not proven, and its mechanisms remain largely unknown. To compare the peripheral and central neural and behavioral effects in rats of GES with a pulse width currently used in clinical trials (GES-A: 6 mA, 0.3 ms, 40 Hz, 2 s on, 3 s off) and GES with a wider pulse (GES-B: same as GES-A, except that the pulse width is 3 ms). Experiment 1: assessing gastric volume changes as a result of GES. Experiment 2: recording the extracellular potentials of a single neuron in the paraventricular nucleus (PVN) with GES. Experiment 3: determining the effects of GES on oxytocin-immunoreactive (OT-IR) neuron expression in the hypothalamus. Experiment 4: determining the effects of GES on food intake and body weight. GES-B, but not GES-A, significantly increased gastric volume. GES-B activated a higher percentage of gastric distention-responsive neurons in the PVN (93% vs. 81%, P = 0.021) and elicited more intensive neuronal responses than GES-A. The number of OT-IR neurons was significantly increased in the PVN and supraoptic nucleus with both methods of GES compared with control groups. The increase in OT-IR neurons in the PVN was higher with GES-B than with GES-A. A 1-week GES treatment significantly reduced daily food intake and body weight. GES-B was more potent than GES-A in producing weight loss (P < 0.001). The effects of GES depend on the stimulation pulse width. GES with a wider pulse is more effective both peripherally and centrally and more potent in reducing body weight in rats.

Central ghrelin increases anxiety in the Open Field test and impairs retention memory in a passive avoidance task in neonatal chicks

Ghrelin (Grh) is an endogenous ligand for the growth hormone secretagogue receptor. Although Ghr stimulates feeding in rats, it inhibits feeding in neonatal chicks. However, little is known about other central behavioral effects of Ghr. Therefore, we investigated the Ghr effects, injected intracerebroventricularly, on anxiety and memory retention of neonatal chicks in an Open Field test and in a one-trial passive avoidance task, respectively. In the Open Field test, the administration of Ghr in a dose-dependent manner increased the latency to ambulate but decreased ambulation activity, indicating an anxiogenic effect. Furthermore, chicks trained on a passive avoidance task and injected with a dose of 30 pmol of Ghr immediately after training showed an impairment of memory retention. However, there were no significant effects on the number of pecks during the pretraining, training, retention and discrimination. In addition, different doses of Ghr produced an inhibition in food intake at different times after injection. Our results indicate that Ghr induces anxiogenesis in chicks. Moreover, we have shown for the first time that Ghr can decrease memory retention in a non-mammalian species, suggesting that Ghr may play an important role in the processes of memory retention in birds.

Administration of vasopressin V2 receptor agonist compensated the peripheral but not the central behavioral effects of the vasopressin deficiency in Brattleboro rats

Administration of vasopressin V2 receptor agonist compensated the peripheral but not the central behavioral effects of the vasopressin deficiency in Brattleboro rats

Analgesic, learning and memory and anxiolytic effects of insulin in mice

Insulin is a polypeptide hormone that is present in mammals and its main function is the maintenance of adequate blood sugar level. Insulin receptors are widely but unevenly distributed in the brain. Insulin has been reported to be involved in the regulation of neurotransmitters release. It has also been linked to the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Although there is abundant literature on the study of biochemical and molecular properties of insulin, there has been no literature on its central behavioural effects on anxiety and pain relief among other behavioural effects. This study therefore investigates whether insulin has any anxiolytic and other CNS effects. This experiment was carried out in mice using animal behavioural models including a hot plate analgesic test, holeboard and elevated plus maze for anxiolytic test. A Y-maze was used for the locomotor activity and spontaneous alternation investigations. Mice were administered intraperitoneally with insulin at different doses of 0.5, 1.0 and 2.0 IU/kg. The results obtained showed that insulin has no analgesic activity, however, it caused significant central inhibitory effects by decreasing both locomotor activity in both holeboard and Y-maze models and also decreased the exploratory behaviour in holeboard at doses administered dose-dependently indicating its sedative effects. In elevated plus maze, insulin had no effects on percentage of open arm entries at all doses but had a significant effect on percentage of open arm duration at the dose of 1.0 IU/kg only. Insulin administration at lower doses (0.5 and 1.0 IU/kg, i.p.) had no effect on spatial working memory, however, it had significant spatial working memory impairment at the dose of 2.0 IU/kg, i.p. in mice. The study showed that insulin has several neuropharmacological effects at doses used.

Neuropsychotoxicity of Abused Drugs: Potential of Dextromethorphan and Novel Neuroprotective Analogs of Dextromethorphan With Improved Safety Profiles in Terms of Abuse and Neuroprotective Effects

Drug abuse involving dextromethorphan, an antitussive, has been a social problem in various geographic locations since the 1960s. Ironically, high doses of the drug confer neuroprotective activity with central nervous system and behavioral effects. Accumulating evidence suggests that metabolism to phencyclidine-like dextrorphan is not essential for the neuroprotective activity of dextromethorphan. Here, we review the neuroprotective properties of dextromethorphan and its potential for abuse and the potential neuroprotective effects of the drug’s analogs and 3-hydroxymorphinan, a metabolite of dextromethorphan. These compounds may provide a novel therapeutic direction for the treatment of neurodegenerative diseases such as convulsive or parkinsonian-like disorders.

Design and Synthesis of the First Selective Agonists for the Rat Vasopressin V1bReceptor: Based on Modifications of Deamino-[Cys]arginine Vasopressin at Positions 4 and 8

The neurohypophyseal peptides arginine vasopressin (AVP) and oxytocin (OT) mediate a wide variety of peripheral and central physiological and behavioral effects by acting on four different G-protein coupled receptors, termed V1a (vascular), V1b (pituitary), V2 (renal), and OT (uterine). We recently reported that d[Cha4]AVP (A), d[Leu4]AVP (B), d[Orn4]AVP (C), and d[Arg4]AVP (D) have high affinity and are selective agonists for the human V1b receptor. However, peptides A-D were subsequently shown to be potent antidiuretic agonists in the rat and are, thus, not selective V1b agonists in the rat. Peptides A-D served as leads for the studies reported here. They were modified at position 8 by Lys, ornithine (Orn), diaminobutyric acid (Dab), and diaminopropionic acid (Dap) to give d[Cha4,Lys8]VP (1), d[Cha4,Orn8]VP (2), d[Cha4,Dab8]VP (3), d[Cha4,Dap8]VP (4), d[Leu4,Lys8]VP (5), d[Leu4,Orn8]VP (6), d[Leu4,Dab8]VP (7), d[Leu4,Dap8]VP (8), d[Orn4,Lys8]VP (9), d[Orn4,Orn8]VP (10), d[Arg4,Lys8]VP (11), d[Arg4,Orn8]VP (12), and d[Arg4,Dab8]VP (13). All peptides were synthesized by the Merrifield solid-phase method. Their binding and functional properties were evaluated in rat AVP V1a, V1b, and V2 receptors and on the rat OT receptor expressed either in native tissues or in stably transfected cells. They were also examined in rat vasopressor, antidiuretic, and in in vitro (no Mg++) oxytocic assays. Functional studies performed on chinese hamster ovary cells expressing the different AVP/OT receptors confirm that d[Cha4,Lys8]VP (1), d[Cha4,Dab8]VP (3), d[Leu4,Lys8]VP (5), and d[Leu4,Dap8]VP (8) are the first selective agonists for the rat V1b receptor. These selective V1b agonists are promising new tools for studies of the role of the V1b receptor in the rat.

Anxiolytic Effect of Hepatocyte Growth Factor Infused into Rat Brain

Background: Hepatocyte growth factor (HGF) has the capacity to selectively direct thalamocortical projections into an intermediate target, the pallidum, and eventually to their final cortical destination. HGF may have a role in the mediation of anxiety. Very little is known about other central behavioral effects of HGF. Objective: Our aim was to determine what effect HGF has on anxiety in rats. Methods: HGF was infused at a constant rate into cerebral lateral ventricles and its effect on anxiety in rats was monitored. Results: In the elevated plus maze test and the black and white box test, HGF administration caused all indicators of anxiety to increase. No significant effect on general locomotor activity was seen. Conclusion: HGF infusion into the brain produces an anxiolytic effect.

Central activity of hydroalcoholic extracts from Erythrina velutina and Erythrina mulungu in mice

This work studied the central behavioural effects of hydroalcoholic extracts from the stem bark of Erythrina velutina and Erythrina mulungu on the elevated plus maze, open field, and rota rod tests in mice. These medicinal plants belong to the Fabaceae family and are popularly used in Brazil for their effects on the central nervous system. Single doses of the extracts were administered orally (200, 400 or 800 mg kg(-1)) or intraperitoneally (200 or 400 mg kg(-1)) to female mice. A reduction of the locomotor activity was observed in the open field test with both hydroalcoholic extracts after intraperitoneal treatment with all doses, but only with the highest dose after oral administration. In addition, oral and intraperitoneal administration of the extracts decreased the incidence of rearing and grooming. Decreases in the number of entries in the open (NEOA) and closed (NECA) arms of the elevated plus maze were observed after the administration of the highest dose (800 mg kg(-1), p.o.) of both hydroalcoholic extracts, and this effect may be due to the decrease in locomotor activity. These hydroalcoholic extracts failed to affect the motor coordination in the rota rod test. In conclusion, we showed that the hydroalcoholic extracts of E. velutina and E. mulungu have depressant effects on the central nervous system, which, at least partially, corroborates the popular use of these species as tranquilizers in Brazilian popular medicine.

Ghrelin increases anxiety-like behavior and memory retention in rats

Ghrelin is a peptide found in the hypothalamus and stomach that stimulates food intake and whose circulating concentrations are affected by nutritional state. Very little is known about other central behavioral effects of ghrelin, and thus, we investigated the effects of ghrelin on anxiety and memory retention. The peptide was injected intracerebroventricularly in rats and we performed open-field, plus-maze, and step-down tests (inhibitory avoidance). The administration of ghrelin increased freezing in the open field and decreased the number of entries into the open spaces and the time spent on the open arms in the plus-maze, indicating an anxiogenic effect. Moreover, the peptide increased in a dose-dependent manner the latency time in the step-down test. A rapid and prolonged increase in food intake was also observed. Our results indicate that ghrelin induces anxiogenesis in rats. Moreover, we show for the first time that ghrelin increases memory retention, suggesting that the peptide may influence processes in the hippocampus.

Chapter 17 Neuroendocrine and emotional changes in the post-partum period

As well as having widespread effects on many aspects of mammalian physiology, the hormones of both the reproductive and stress axes can directly and indirectly influence behavior. Here we review possible mechanisms through which centrally active hormones of the female reproductive system and the hypothalamo-pituitary-adrenal stress axis may interact to influence behavior and mood states during the post-partum period. We will focus primarily on the behavioral effects of selected neuropeptide hormones, in particular oxytocin, vasopressin and corticotrophin-releasing hormone. The literature documenting central behavioral effects of these neuropeptides arises almost exclusively from research in experimental animals. In particular, it has been reported that during lactation in rats there are high blood and brain levels of oxytocin. At the same time there is a reduction in corticotrophin-releasing hormone in the brain and in its secretion in response to stress. These changes may contribute to optimal maternal care of the offspring. Correlational studies of peptides and behavior in the post-partum period also support the hypothesis that neuropeptides may influence human physiology and behavior. Studies of post-partum women reveal powerful regulatory effects of lactation on the reactivity of the hypothalamo-pituitary-adrenal axis and of autonomic and immune systems, especially in the face of challenge. The integrative function of neural systems that influence both reproduction and the hypothalamo-pituitary-adrenal axis suggests one central mechanism for mediating the effects of environmental challenges.

The behavioural effects of pramipexole, a novel dopamine receptor agonist

Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydrochloride) is a novel dopamine D 2 family receptor agonist with a predominant action on D 2 autoreceptors and with some D 3 vs. D 2 receptor preference. The central behavioural effects of pramipexole given subcutaneously to rats (male Wistar) and mice (Albino Swiss) are presented in this paper. Used in low doses (0.001–0.1 mg/kg), pramipexole induced locomotor hypoactivity which was antagonized by a low dose of spiperone; at higher doses (0.3, 1 mg/kg) it evoked hyperactivity which was inhibited by haloperidol, sulpiride and clozapine, but not by SCH 23390 ( R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrochloride). Pramipexole (0.1–1.0 mg/kg) antagonized the akinesia induced by combined pretreatment with reserpine (5 mg/kg) and α-methyl- p-tyrosine (250 mg/kg). Pramipexole (0.1–1 mg/kg) potentiated the hyperkinetic effect of l-DOPA ( l-3,4-dihydroxyphenylalanine) (50 and 200 mg/kg, together with benserazide, 50 mg/kg) in naive and monoamine-depleted (reserpine+α-methyl- p-tyrosine) rats. The higher doses of pramipexole (1 and 3 mg/kg) evoked stereotypy which was antagonized by pretreatment with sulpiride or clozapine. The catalepsy induced by haloperidol, spiperone or fluphenazine was antagonized by pramipexole (1–3 mg/kg). Pramipexole (1 mg/kg) induced hypothermia in mice, which was antagonized by sulpiride. The obtained results indicate that pramipexole: (i) at low doses stimulates the dopamine D 2 presynaptic autoreceptors; (ii) at higher doses stimulates dopamine D 2 postsynaptic receptors. An effect on the dopamine D 3 receptor cannot be excluded. At low doses pramipexole may have antipsychotic activity, and at higher ones antiparkinsonian activity. © 1997 Elsevier Science B.V. All rights reserved.

Central cardiovascular and behavioral effects of carboxy- and amino-terminal fragments of substance P in conscious rats

The central cardiovascular and behavioral effects of carboxy- (SP 5–11, SP 6–11, SP 7–11, SP 8–11) and amino- (SP 1–7, SP 1–9) terminal substance P (SP) fragments were compared with those of SP 1–11 in conscious rats. In addition, the ability of these SP-fragments to induce desensitization of the central NK 1 receptor was investigated. SP 1–11 (50 pmol) injected i.c.v. induced an increase in mean arterial blood pressure (MAP), heart rate (HR) and a typical behavioral response consisting of face washing (FW), hindquarter grooming (HQG) and wet-dog shakes (WDS). The cardiovascular and behavioral responses to equimolar doses of SP 5–11 and SP 6–11 were similar to those of SP 1–11, however, only SP 5–11 induced exactly the same behavioral pattern as SP 1–11. SP 6–11 was more potent in inducing FW and WDS than SP 1–11 or SP 5–11. The carboxy-terminal SP-fragments, SP 7–11 and SP 8–11, and the amino-terminal SP-fragments, SP 1–7, SP 1–9, did not elicit any significant cardiovascular or behavioral responses. Pretreatment with SP 1–11 reduced the cardiovascular and behavioral responses to subsequent injections of SP 1–11. Of all SP-fragments tested, only SP 5–11 was able to attenuate the cardiovascular and behavioral responses to SP 1–11. Our results demonstrate that SP 6–11 represents the shortest carboxy-terminal amino acid sequence, that after i.c.v. injection, elicits the same cardiovascular response as SP 1–11, but fails to desensitize the NK 1 receptor. The carboxy-terminal fragment, SP 5–11, is the shortest amino acid sequence which produces the same pattern of central cardiovascular and behavioral responses as SP 1–11 and also retains the ability to desensitize the NK 1 receptor like SP 1–11.