Nonspecific Behavioral Effects Research Articles

Negative modulation of AMPA receptors bound to transmembrane AMPA receptor regulatory protein γ-8 blunts the positive reinforcing properties of alcohol and sucrose in a brain region-dependent manner in male mice.

The development and progression of alcohol use disorder (AUD) are widely viewed as maladaptive neuroplasticity. The transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) regulatory protein γ8 (TARP γ-8) is a molecular mechanism of neuroplasticity that has not been evaluated in AUD or other addictions. To address this gap in knowledge, we evaluated the mechanistic role of TARP γ-8 bound AMPAR activity in the basolateral amygdala (BLA) and ventral hippocampus (vHPC) in the positive reinforcing effects of alcohol, which drive repetitive alcohol use throughout the course of AUD, in male C57BL/6J mice. These brain regions were selected because they exhibit high levels of TARP γ-8 expression and send glutamate projections to the nucleus accumbens (NAc), which is a key nucleus in the brain reward pathway. Site-specific pharmacological inhibition of AMPARs bound to TARP γ-8 in the BLA via bilateral infusion of the selective negative modulator JNJ-55511118 (0-2µg/µl/side) significantly decreased operant alcohol self-administration with no effect on sucrose self-administration in behavior-matched controls. Temporal analysis showed that reductions in alcohol-reinforced response rate occurred > 25min after the onset of responding, consistent with a blunting of the positive reinforcing effects of alcohol in the absence of nonspecific behavioral effects. In contrast, inhibition of TARP γ-8 bound AMPARs in the vHPC selectively decreased sucrose self-administration with no effect on alcohol. This study reveals a novel brain region-specific role of TARP γ-8 bound AMPARs as a molecular mechanism of the positive reinforcing effects of alcohol and non-drug rewards.

Pimavanserin reverses multiple measures of anxiety in a rodent model of post-traumatic stress disorder

Pimavanserin is a highly selective 5-HT2A inverse agonist in current medical use. Prior studies suggest that 5-HT2A serotonin receptors may play a role in anxiety and emotional memory. Therefore, pimavanserin was tested in a rat model of PTSD to determine whether it might ameliorate PTSD-like symptoms. The lifetime prevalence of PTSD is estimated to be 125% higher in women than men. Consequently, in an effort to create a robust model of PTSD that was more representative of human PTSD prevalence, 20-week old female rats of the emotionally hyperreactive Lewis strain were used for these studies. The rats were single-housed and exposed twice to restraint stress coupled with predator odor or to a sham-stressed condition. Twenty days after the second stress or sham-stress exposure, rats were injected with saline alone or with 0.3 or 1.0 mg/kg pimavanserin, doses that were confirmed to substantially block 5-HT2A receptor activity in this study without causing any non-specific behavioral or adverse effects. One hour later, rats were tested for anxiety through acoustic startle response, the elevated plus-maze and three parameters of open field behavior. Five days later, blood was sampled for plasma corticosterone. The stressed/saline-injected rats had higher anxiety scores and corticosterone levels than sham-stressed/saline-injected rats. Pimavanserin significantly and generally dose-dependently reversed these persistent stress effects, but had no significant effect on the behavioral measures in normal, non-stressed rats. These results, consistent with a role for the 5-HT2A receptor, suggest that pimavanserin might have potential to reduce some consequences of traumatic stress.

Dorsomedial prefrontal cortex activation disrupts Pavlovian incentive motivation.

The dorsomedial prefrontal cortex (dmPFC) is known to make important contributions to flexible, reward-motivated behavior. However, it remains unclear if the dmPFC is involved in regulating the expression of Pavlovian incentive motivation, the process through which reward-paired cues promote instrumental reward-seeking behavior, which is modeled in rats using the Pavlovian-instrumental transfer (PIT) task. The current study examined this question using a bidirectional chemogenetic strategy in which inhibitory (hM4Di) or excitatory (hM3Dq) designer G-protein coupled receptors were virally expressed in dmPFC neurons, allowing us to later stimulate or inhibit this region by administering CNO prior to PIT testing. We found that dmPFC inhibition did not alter the tendency for a reward-paired cue to instigate instrumental reward-seeking behavior, whereas dmPFC stimulation disrupted the expression of this motivational influence. Neither treatment altered cue-elicited anticipatory activity at the reward-delivery port, indicating that dmPFC stimulation did not lead to more widespread motor suppression. A reporter-only control experiment indicated that our CNO treatment did not have non-specific behavioral effects. Thus, the dmPFC does not mediate the expression of Pavlovian incentive motivation but instead has the capacity to exert pronounced inhibitory control over this process, suggesting that it is involved in adaptively regulating cue-motivated behavior.

Phencyclidine-induced cognitive impairments in repeated touchscreen visual reversal learning tests in rats

Reversal learning, a component of executive functioning, is commonly impaired among schizophrenia patients and is lacking effective treatment. N-methyl-ᴅ-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP), impair reversal learning of rodents. Touchscreen-based pairwise visual discrimination and reversal test is a translational tool to assess reversal learning in rodents. However, to fully exploit this task in testing of novel compounds, it is necessary to perform several reversal learning experiments with trained animals. Firstly, we assessed whether PCP-induced deficits in visual reversal learning in rats would be detectable with a short (5 sessions) reversal learning phase, and whether the short reversal phases could be repeated with novel stimulus pairs. Secondly, we assessed whether the PCP-induced deficits in reversal learning could be seen upon repeated PCP challenges with the same animals. Finally, we tested the effect of a novel compound, a selective α2C adrenoceptor antagonist, ORM-13070, to reverse PCP-induced cognitive deficits in this model. A 4-day PCP treatment at a dose of 1.5 mg/kg/day impaired early reversal learning in male Lister Hooded rats without inducing non-specific behavioral effects. We repeated the reversal learning experiment four times using different stimulus pairs with the same animals, and the PCP-induced impairment was evident in every single experiment. The α2C adrenoceptor antagonist ameliorated the PCP-induced cognitive deficits. Our results suggest that repeated PCP challenges in the touchscreen set-up induce schizophrenia-like cognitive deficits in visual reversal learning, improve throughput of the test and provide a protocol for testing novel drugs.

Effects of sucrose and high fructose corn syrup consumption on spatial memory function and hippocampal neuroinflammation in adolescent rats.

Excessive consumption of added sugars negatively impacts metabolic systems; however, effects on cognitive function are poorly understood. Also unknown is whether negative outcomes associated with consumption of different sugars are exacerbated during critical periods of development (e.g., adolescence). Here we examined the effects of sucrose and high fructose corn syrup-55 (HFCS-55) intake during adolescence or adulthood on cognitive and metabolic outcomes. Adolescent or adult male rats were given 30-day access to chow, water, and either (1) 11% sucrose solution, (2) 11% HFCS-55 solution, or (3) an extra bottle of water (control). In adolescent rats, HFCS-55 intake impaired hippocampal-dependent spatial learning and memory in a Barne's maze, with moderate learning impairment also observed for the sucrose group. The learning and memory impairment is unlikely based on nonspecific behavioral effects as adolescent HFCS-55 consumption did not impact anxiety in the zero maze or performance in a non-spatial response learning task using the same mildly aversive stimuli as the Barne's maze. Protein expression of pro-inflammatory cytokines (interleukin 6, interleukin 1β) was increased in the dorsal hippocampus for the adolescent HFCS-55 group relative to controls with no significant effect in the sucrose group, whereas liver interleukin 1β and plasma insulin levels were elevated for both adolescent-exposed sugar groups. In contrast, intake of HFCS-55 or sucrose in adults did not impact spatial learning, glucose tolerance, anxiety, or neuroinflammatory markers. These data show that consumption of added sugars, particularly HFCS-55, negatively impacts hippocampal function, metabolic outcomes, and neuroinflammation when consumed in excess during the adolescent period of development.

Activation of peroxisome proliferator-activated receptor γ in brain inhibits inflammatory pain, dorsal horn expression of Fos, and local edema

Systemic administration of thiazolidinediones reduces peripheral inflammation in vivo, presumably by acting at peroxisome proliferator-activated receptor gamma (PPARgamma) in peripheral tissues. Based on a rapidly growing body of literature indicating the CNS as a functional target of PPARgamma actions, we postulated that brain PPARgamma modulates peripheral edema and the processing of inflammatory pain signals in the dorsal horn of the spinal cord. To test this in the plantar carrageenan model of inflammatory pain, we measured paw edema, heat hyperalgesia, and dorsal horn expression of the immediate-early gene c-fos after intracerebroventricular (ICV) administration of PPARgamma ligands or vehicle. We found that ICV rosiglitazone (0.5-50 microg) or 15d-PGJ(2) (50-200 microg), but not vehicle, dose-dependently reduced paw thickness, paw volume and behavioral withdrawal responses to noxious heat. These anti-inflammatory and anti-hyperalgesia effects result from direct actions in the brain and not diffusion to other sites, because intraperitoneal and intrathecal administration of rosiglitazone (50 microg) and 15d-PGJ(2) (200 microg) had no effect. PPARgamma agonists changed neither overt behavior nor motor coordination, indicating that non-specific behavioral effects do not contribute to PPAR ligand-induced anti-hyperalgesia. ICV administration of structurally dissimilar PPARgamma antagonists (either GW9662 or BADGE) reversed the anti-inflammatory and anti-hyperalgesic actions of both rosiglitazone and 15d-PGJ(2). To evaluate the effects of PPARgamma agonists on a classic marker of noxious stimulus-evoked gene expression, we quantified Fos protein expression in the dorsal horn. The number of carrageenan-induced Fos-like immunoreactive profiles was less in rosiglitazone-treated rats as compared to vehicle controls. We conclude that pharmacological activation of PPARgamma in the brain rapidly inhibits local edema and the spinal transmission of noxious inflammatory signals.

Rostral–caudal differences in the effects of intra-VTA muscimol on cocaine self-administration

We have found that dopamine (DA) in the ventral tegmental area (VTA) plays an important role in cocaine self-administration. DA in the VTA acts at D1-type receptors on the terminals of GABA afferents causing release of this neurotransmitter. Thus, the neurochemical pathways whereby VTA DA might be involved in cocaine self-administration may include GABA neurotransmission. In the present study, we investigated this possibility. Rats were prepared with intravenous catheters and bilateral guide cannulae positioned to allow microinjections directly into the VTA or a site 1 mm dorsal to it. The rats were then trained to self-administer cocaine (1.0 mg/kg/injection) under a fixed-ratio 1 schedule of reinforcement and tested with microinjections of muscimol (0, 0.05 and 0.1 μg/0.25 μl) or picrotoxin (0, 0.025 and 0.05 μg/0.25 μl) or trained under a progressive ratio (PR) schedule and tested with vehicle and 0.05 μg/0.25 μl muscimol. Muscimol in the VTA, but not immediately dorsal to it, significantly reduced cocaine intake under the FR1 schedule. Furthermore, when analyzed by rostral/caudal site of injection, it was found that rostral injections of muscimol significantly reduced cocaine self-administration whereas caudal injections produced non-significant decreases in self-administration. Inspection of individual records revealed no signs of non-specific behavioral effects of the muscimol treatments. Muscimol in the rostral VTA also significantly increased break points in responding under the PR schedule. Intra-VTA picrotoxin did not significantly affect cocaine self-administration. These data suggest that stimulation of GABA-A receptors in the VTA is involved in cocaine self-administration and reward and that this involvement is more pronounced in the rostral than in the caudal VTA.

Behavioral effects of short-term administration of lithium and valproic acid in rats

Lithium and valproic acid are mood-stabilizing agents that are often used to manage the episodes of mania and depression that characterize bipolar disorder. These agents develop clinical efficacy with chronic treatment, but the neurobiological actions that contribute to their therapeutic effects remain unclear. The present work was designed to study and compare various behavioral effects of short-term administration of lithium chloride (LiCl) and valproic acid (VPA) in rats. Specifically, we examined the effects of acute and sub-acute injections of these agents on locomotor activity, behavior in the forced swim test (FST), and intracranial self-stimulation (ICSS) thresholds. Locomotor activity studies were used to identify the range of doses with gross behavioral effects in rats. At doses below those that suppressed activity (total distance traveled, in cm) in 1-h test sessions, LiCl had prodepressant-like effects: it increased immobility in the FST, an effect opposite to that typically seen with standard antidepressants, and it increased ICSS thresholds, an effect similar to that typically seen during withdrawal from drugs of abuse. In contrast, VPA had no effects in the FST or on ICSS thresholds. This work identifies potentially important characteristics that distinguish the drugs at doses below those that produce non-specific behavioral effects, and thus serves as a basis for designing and interpreting studies of long-term treatment.

Highlights from the Literature

Highlights from the Literature

Mechanisms of oleoylethanolamide-induced changes in feeding behavior and motor activity

Oleoylethanolamide (OEA), a lipid synthesized in the intestine, reduces food intake and stimulates lipolysis through peroxisome proliferator-activated receptor-alpha. OEA also activates transient receptor potential vanilloid type 1 (TRPV1) in vitro. Because the anorexigenic effect of OEA is associated with delayed feeding onset and reduced locomotion, we examined whether intraperitoneal administration of OEA results in nonspecific behavioral effects that contribute to the anorexia in rats. Moreover, we determined whether circulating levels of other gut hormones are modulated by OEA and whether CCK is involved in OEA-induced anorexia. Our results indicate that OEA reduces food intake without causing a conditioned taste aversion or reducing sodium appetite. It also failed to induce a conditioned place aversion. However, OEA induced changes in posture and reduced spontaneous activity in the open field. This likely underlies the reduced heat expenditure and sodium consumption observed after OEA injection, which disappeared within 1 h. The effects of OEA on motor activity were similar to those of the TRPV1 agonist capsaicin and were also observed with the peroxisome proliferator-activated receptor-alpha agonist Wy-14643. Plasma levels of ghrelin, peptide YY, glucagon-like peptide 1, and apolipoprotein A-IV were not changed by OEA. Finally, antagonism of CCK-1 receptors did not affect OEA-induced anorexia. These results suggest that OEA suppresses feeding without causing visceral illness and that neither ghrelin, peptide YY, glucagon-like peptide 1, apolipoprotein A-IV, nor CCK plays a critical role in this effect. Despite that OEA-induced anorexia is unlikely to be due to impaired motor activity, our data raise a cautionary note in how specific behavioral and metabolic effects of OEA should be interpreted.

Evidence for Onset of Antipsychotic Effects Within the First 24 Hours of Treatment

It is widely held that there is a delayed onset of antipsychotic action and that any early effects represent nonspecific behavioral effects. Recent research has shown that antipsychotic action begins within the first week. The authors tested the hypothesis that psychosis improves within the first 24 hours of antipsychotic treatment. In this multicenter, double-blind, placebo-controlled study, 311 patients with a diagnosis of schizophrenia spectrum disorder and an acute exacerbation were randomly assigned to receive 10 mg i.m. of olanzapine, 7.5 mg i.m. of haloperidol, or intramuscular placebo. Subjects were rated with structured rating scales (Positive and Negative Syndrome Scale and Clinical Global Impression) at baseline, 2 hours, and 24 hours. The olanzapine and haloperidol groups showed greater resolution of overall symptoms than the placebo group; for the olanzapine group, this effect was evident at 2 hours. A factor analysis showed that an independent change in psychosis (which included conceptual disorganization, hallucinatory behavior, unusual thought content) was evident within the first 24 hours for both drugs. This improvement in core psychosis was not mediated unidirectionally by changes in nonspecific behavioral effects or other psychopathology. These data suggest that the onset of antipsychotic action is early and that the magnitude of this action grows with time. This clinical reality calls into question some prevailing hypotheses regarding the mechanism of action of antipsychotics and suggests that antipsychotic action may be more proximally related to the blockade of dopamine transmission than was originally thought.

Microinfusion of antineuronal antibodies into rodent striatum: Failure to differentiate between elevated and low titers

An autoimmune-mediated mechanism has been proposed for several pediatric movement disorders. In a three-center (Brown, Yale, and Johns Hopkins) collaborative effort, serum antineuronal antibodies (ANAb) were measured by use of ELISA or immunohistochemical techniques on 35 children (mean age 11.4 years) with Tourette syndrome, attention deficit hyperactivity disorder, and/or obsessive compulsive disorder. Eight sera, 4 containing the highest and 4 the lowest levels of ANAb, were identified at each institution. Selected sera (total of 9 with elevated and 7 with low ANAb) were re-encoded and sent to each center for infusion into the ventrolateral striatum of 16 male Sprague–Dawley rats. Animals were observed for behavioral abnormalities for 3 days before the start of infusion, during infusion on days 2–4, and for 2 days after infusion. Combined stereotypy scores increased after antibody infusion, but there was no significant effect based on serum titer ( p = 0.85). Scores differed among centers, but analyses based on individual institutional data again failed to show an effect based on elevated or low ANAb values (Brown, p = 0.95; Yale and Johns Hopkins, p = 0.81). Post hoc studies with sham surgery and infusion of phosphate-buffered saline support suggestions of nonspecific behavioral effects unrelated to antibody titer. This report emphasizes that any conclusions about antibody-mediated movement disorders that are based upon results from the rodent infusion model must be considered with caution.

Memory facilitation by methylene blue: Dose-dependent effect on behavior and brain oxygen consumption

Methylene blue administered post-training improves memory retention in avoidance and appetitive tasks, and restores spatial memory impaired by an inhibitor of cytochrome oxidase. Methylene blue may improve memory retention by increasing brain oxygen utilization. We investigated which doses improve memory without nonspecific behavioral effects, and whether methylene blue enhances brain oxygen consumption. Different doses were evaluated 24 h after administration in wheel running, feeding, open field habituation and object recognition tests. The 1–10 mg/kg methylene blue-treated rats were not different from saline-treated rats in locomotion or feeding behavior. The 50–100 mg/kg doses decreased running wheel behavior. The 4 mg/kg dose improved behavioral habituation and object memory recognition. Dose-dependent effects of methylene blue on brain oxygen consumption revealed that low concentrations increased brain oxygen consumption in vitro and 24 h after in vivo administration. Therefore, methylene blue doses that increase brain oxygen consumption also facilitate memory retention.

Are NMDA receptors involved in opiate-induced neural and behavioral plasticity? A review of preclinical studies.

Research over the past decade demonstrating that NMDA receptor antagonists have the ability to inhibit opiate tolerance, sensitization and physical dependence has led to the suggestion that NMDA receptors may have a critical role in opiate-induced neural and behavioral plasticity. However, there have been suggestions that the effects of NMDA receptor antagonists on these phenomena result from non-specific behavioral or pharmacological effects, rather than from a specific inhibition of plasticity. To review the literature in order to explore whether the effects of NMDA receptor antagonists on opiate-induced changes in behavior are best accounted for by an inhibition of neural and behavioral plasticity, or if alternative explanations might better account for the results. The effects of NMDA receptor antagonists on the development of tolerance to opiate analgesia and the development of opiate physical dependence do not appear to be due to confounding behavioral effects produced by high doses of NMDA receptor antagonists, "side-effects" of a particular drug or drug class, blockade of associative learning processes, or state-dependency. Results on tolerance and sensitization to the locomotor effects of morphine are more mixed and controversial; however, there is evidence suggesting that NMDA receptor antagonists may inhibit these phenomena in a similar manner. NMDA receptor antagonists appear to inhibit the neural plasticity underlying some forms of opiate tolerance, sensitization and physical dependence, suggesting that NMDA receptors are involved in the development of these drug-induced changes in behavior. Further research will help to determine the neural mechanisms responsible for these phenomena, and the therapeutic potential for drugs acting on the NMDA receptor complex in the treatment of pain and addiction.

Olfactory bulbectomy temporarily impairs Morris maze performance: An ACTH(4–9) analog accellerates return of function

Rats with a bilateral lesion of the olfactory bulb are permanently anosmic. However, this lesion also produces nonspecific behavioral effects that recover over time. In this study olfactory bulb-lesioned animals are given a spatial orientation task—the Morris maze—which supposedly relies on visual and not olfactory cues. In exp. 1 this assumption was verified by subjecting animals with peripherally induced anosmia to the Morris maze (olfactory neurons in the nasal mucosae were destroyed by flushing the nose with ZnSO4). Anosmia did not affect the acquisition rate of the animals. In exp. 2 anosmia was produced by a central lesion to the bulbus olfactorius. Two weeks after lesioning the Morris maze performance is severely impaired. Interestingly, chronic administration (10μg/48 h/rat, during these 14 days, SC) of the ACTH(4–9) analog ORG 2766 diminished the impairment in performance. In exp. 3 olfactory bulb-lesioned animals were allowed 6 wk to recover before Morris maze testing began, to investigate if spontaneous recovery of performance occurred. No difference was seen in the acquisition performance of lesioned animals when compared to sham animals at this timepoint. The effect of the peptide is discussed in the context of an accelleration of the recovery of nonspecific consequences of brain lesioning.

The effects of 5-HT receptor blockade on memory formation in the chick: Possible interactions between β-adrenergic, and serotonergic systems

An antagonist, 21-009, with high affinity for 5-HT 1B receptors and some for β-adrenergic receptors, induces amnesia in the domestic chick when given centrally before training, using a one-trial passive avoidance task. Nonspecific behavioral effects, or effects upon performance at test, almost certainly do not causethe observed amnesia. The 5-HT 2 antagonist ketanserin and the 5-HT 3 antagonist ICS 205-930, did not have any effects when given before training at the same dose as that at which 21-009 was effective. The unusual pattern of action of 21-009 (sensitivity only at, or around the time of learning, combined with very delayed memory loss) resembles that of certain β-antagonists, but not others. The results are discussed in terms of both direct action on 5-HT systems involved in memory formation and possible interactions between 5-HT and β-adrenergic systems.

Effects of the peripheral 5-HT2 antagonist xylamidine on consummatory behaviors

It has been reported that xylamidine, a specific peripheral 5-HT2 antagonist, attenuates, but does not completely block, 5-HT-induced anorexia, and that this effect may be mediated by both 5-HT2 and non-5-HT2 receptor subtypes. To determine whether this incomplete antagonism was a consequence of xylamidine’s being given at suboptimal doses, the dose-response characteristics of xylamidine on the anorexia induced by a dose of 5 mg/kg of 5-HT was investigated; the asymptote of the dose-response curve began at about 0.75 mg/kg. A second reason for the incomplete attenuation of 5-HT-induced anorexia would be that xylamidine has confounding nonspecific behavioral and/or ingestive effects. Xylamidine was found not to alter gross drinking behavior, and in a 2-bottle test, it did not, unlike lithium chloride, produce a conditioned taste aversion. The effects of xylamidine on drinking behavior and conditioning cannot account for the previously reported failure of xylamidine to completely block peripheral 5-HT-induced anorexia, and the possibility of non-5-HT2 receptors’ being partially responsible for the mediation of this anorectic effect remains open.

A comparison of PCP-like compounds for NMDA antagonism in two [formula omitted] models

The PCP-like compounds ketamine and dexoxadrol were evaluated in two behavioral test procedures known to be sensitive to competitive N-methyl-D-aspartate (NMDA) receptor antagonists. In the NMDA-induced convulsion test in mice, ketamine and dexoxadrol blocked convulsant activity only at doses that also induced nonspecific effects of PCP-like behaviors, thereby confounding the interpretation of results. These compounds also blocked NMDA-induced discriminative stimuli in rats; however, this effect was produced at doses lower than those which induced the nonspecific behavioral effects. These results provide evidence that in behavioral procedures, PCP-like compounds may block excitatory amino acid receptor stimulation by NMDA. The NMDA discrimination identifies these interactions without the influence of motor deficit or other behavioral motor effects.

Suppression of receptive and proceptive behavior in ovariectomized, estrogen-progesterone-primed rats by intraventricular beta-endorphin: studies of behavioral specificity.

Intraventricular (i.c.v.) administration of beta-endorphin (beta-END) has been shown to suppress lordosis behavior in ovariectomized (OVX) estrogen-progesterone (EP) primed rats, but the behavioral specificity of this effect is not known. Using OVX EP-primed rats, the present study assessed the effect of i.c.v. beta-END on proceptive behavior as well as on lordosis (receptive) behavior, and attempted to discern whether the sexual effects were secondary to generalized nonspecific behavioral effects. Doses of 0.5-4 micrograms beta-END (human) significantly suppressed lordosis behavior. Doses of 1 and 4 micrograms were used in experiments which measured proceptive behaviors (presentations and ear wiggling), and both doses abolished or nearly abolished the display of these behaviors. Administration of inactive peptide (a protein digest) had no effect on sexual behavior. Neither 1 nor 4 micrograms beta-END elicited measurable catalepsy. In a series of tests for responsiveness to general somatosensory stimuli, 1 microgram had no effect on responsiveness while 4 micrograms had minor effects, even though sexual activity was severely diminished after both doses. Blood pressure was unaltered by infusion of beta-END (1 microgram), although there was a significant reduction in heart rate. When open field behavior was tested in conjunction with sexual behavior, ambulation and rearing were significantly decreased after beta-END treatment as compared with saline treatment. However, simple linear correlation tests showed a lack of correlation between the changes in open field behavior and the changes in sexual behavior, indicating that the effects of beta-END on the two types of behavior may be unrelated.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of norepinephrine-elicited feeding by neurotensin: evidence for behavioral, anatomical and pharmacological specificity.

Neurotensin (NT) injected into the paraventricular hypothalamic nucleus (PVN) has been shown to suppress feeding behavior. To investigate whether this suppression generalizes to feeding elicited by norepinephrine injection, rats with bilateral PVN cannulas were injected with NT (3.0 nmol/cannula) or vehicle followed by norepinephrine (20.0 nmol/cannula). Pretreatment with NT caused a 48% reduction in feeding elicited by norepinephrine. To determine whether NT's effect resulted from non-specific behavioral effects or leakage into the periphery, NT (0.25, 1.25 or 6.0 nmol) was injected ipsilateral or contralateral to a unilateral norepinephrine (40.0 nmol) injection. Ipsilateral NT produced a dose-dependent suppression of norepinephrine-elicited feeding which was significantly greater than the effect of contralateral NT, suggesting that NT's effect was at least partially behaviorally and anatomically specific. To investigate the pharmacological specificity of the suppression, rats that ate in response to PVN norepinephrine (40.0 nmol) were given prior injections of NT or one of six NT fragments at 0.25, 1.25, 6.0 or 30.0 nmol. NT and the C-terminal fragments 3-13 and 6-13 caused a dose-dependent suppression of feeding. In contrast, none of the N-terminal fragments (i.e. 1-8, 1-11 or 1-12) were effective. This specificity rules out non-specific changes in parameters such as pH or osmotic pressure and suggests that the anorectic effect may have been mediated by NT receptors.