Regulation of neuropeptide Y in the rat amygdala following unilateral olfactory bulbectomy

While the mechanisms are not fully understood, olfactory bulbectomy (OBX) is a well-known rat model of depression and depression-related disorders such as anxiety and aggression. Alterations in neuropeptide Y (NPY) levels in the brain have been linked to depression and have been shown to be involved in the response to stress. This study explored the possible regulation of NPY immunoreactivity in specific regions of the amygdala 14 days after OBX in adult male Sprague-Dawley rats (n=6). Unilateral OBX and immunohistochemistry permitted comparisons of NPY in the ipsilateral amygdala with NPY in the contralateral (sham) amygdala. OBX resulted in significant increases (P<0.05) in NPY immunoreactivity in the anterior medial amygdala (threefold) and the posterior medial amygdala (2.5-fold). These regions receive projections from the accessory olfactory bulb (AOB). In contrast, the anterior and posterolateral cortical nuclei of the amygdala receive projections from the main olfactory bulb (MOB). NPY was not increased in these nuclei. These data show that not only does OBX increase NPY immunoreactivity in the amygdala, but also suggest that the AOB plays a prominent role in this regulation.     

Effects of olfactory bulbectomy on NMDA receptor density in the rat brain:

Olfactory bulbectomy (OBX) transects the glutamatergic efferents from the olfactory bulbs, and the changes of glutamatergic N-methyl-D-aspartate (NMDA) receptor-mediated function are though to be involved in the behavioral deficits seen in OBX rats. In the present study, irritability scores in OBX male Wistar rats were correlated with discrete regional effects on NMDA receptor function measured using a [3H] MK-801 binding assay. Irritability scores, measured before and for 2 weeks after OBX, showed a gradual increase in irritability after OBX. A reduction of the NMDA receptor density was observed in the cerebral cortex and amygdala 16 days after OBX, but not in the striatum, olfactory tubercle, entorhinal cortex, and hippocampus. These results demonstrate that OBX causes changes in the NMDA receptor system in certain brain regions and suggest that these changes may be responsible for the behavioral deficits of OBX rats.     

Permanent deficits in serotonergic functioning of olfactory bulbectomized rats: an in vivo microdialysis study.

BACKGROUND: Bilateral removal of the olfactory bulbs (OBX) in rats results in a complex constellation of behavioral, neurochemical, neuroendocrine, and neuroimmune alterations, many of which are also reported in patients with major depressive disorder (MDD). Drawing on clinical findings, there has been considerable interest in the role of serotonin in the mechanism of action of OBX. However, to date, there has been no report of direct measurement of serotonergic functioning of bulbectomized animals using microdialysis. The present study describes the effects of olfactory bulbectomy on functioning of the serotonergic system. METHODS: In vivo microdialysis was performed in conscious rats that underwent OBX or sham surgery. Alterations in the functioning of the serotonergic system were assessed by administration of fluvoxamine, fenfluramine, and 3-hydroxybenzylhydrazine (NSD-1015). Animals were also repeatedly tested in an open field. RESULTS: Bilateral removal of the olfactory bulbs decreased basal extracellular levels by decreasing the releasable pool of serotonin (5-HT) in the basolateral amygdala 2 weeks after surgery and in the dorsal hippocampus 2 weeks and 5 months after surgery. Olfactory bulbectomized animals showed a lower rate of 5-HT synthesis under basal conditions. However, the capacity of the system to synthesize 5-HT was not affected. Olfactory bulbectomized rats were hyperactive in the open field. This hyperactivity remained after successive testing, indicating permanent behavioral changes. CONCLUSIONS: This microdialysis study shows that OBX has profound and long-lasting effects on serotonergic functioning and on activity levels and is therefore considered an intriguing and promising animal model for affective processes in the brain.     

Effects of chronic exercise and imipramine on mRNA for BDNF after olfactory bulbectomy in rat

We examined the effects of chronic activity wheel running and antidepressant treatment on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) in multiple brain regions-hippocampal formation (HF), ventral tegmental area/substantia nigra (VTA/SN), nucleus accumbens (NAc), and piriform cortex (PFx)-after bilateral olfactory bulbectomy (OBX). Male, Long-Evans rats (n=72) underwent either sham or OBX surgery and were randomly divided into eight experimental groups in a 2 (sham vs. OBX) x 2 (sedentary vs. activity wheel)x2 (saline vs. imipramine) factorial design. Animals were killed after 21 days of treatment. Drug x exercise interaction effects were observed for HF (P=0.006-0.023) and VTA/SN (P=0.021); exercise increased BDNF mRNA in the saline treated animals but not in the imipramine treated animals. OBX did not affect BDNF mRNA in the HF or VTA/SN (P>0.05). BDNF mRNA levels in the PFx were not altered by exercise, drug, or OBX (P>0.05). These results suggest that the effect of exercise on BDNF mRNA extends beyond the HF to the mesolimbic ventral tegmental area and that the potentiation of BDNF mRNA by exercise and antidepressant pharmacotherapy, reported by other investigators, is time limited.     

Olfactory bulbectomy increases food intake and hypothalamic neuropeptide Y in obesity-prone but not obesity-resistant rats

Obese individuals often suffer from depression. The olfactory bulbectomy (OBX) model is an animal model of depression that produces behavioral, physiological, and neurochemical alterations resembling clinical depression. The OBX model was employed to assess depression-related changes in food intake in obesity-prone, Osborne–Mendel (OM) rats and obesity-resistant, S5B/Pl rats. OBX increased food intake in OM rats beginning 7 days following surgery, however, OBX did not alter food intake in S5B/Pl rats at any time point. Fourteen days following surgery, OBX significantly increased locomotor activity (total lines crossed and rears) in the openfield test in OM and S5B/Pl rats. Fifteen days following surgery, prepro-neuropeptide Y (NPY) mRNA levels were significantly increased in the hypothalamus of bulbectomized OM rats and in the medial nucleus of the amygdala of bulbectomized OM and S5B/Pl rats. OBX decreased NPY Y2 receptor mRNA levels in the hypothalamus and medial nucleus of the amygdala in OM rats, while increasing NPY Y2 receptor mRNA levels in the medial nucleus of the amygdala of S5B/Pl rats. These data indicate that though both obesity-prone and obesity-resistant strains were susceptible to the locomotor effects of OBX, food intake and hypothalamic prepro-NPY mRNA were only increased in OM rats. Therefore, strain specific alterations in hypothalamic NPY may account for increased food intake in the obesity-prone rats following OBX, and suggests a potential mechanism to explain the comorbidity of obesity and depression.     

Effects of bilateral olfactory bulbectomy on N-methyl-D-aspartate receptor function: autoradiographic and behavioral studies in the rat

Rat bilateral olfactory bulbectomy (OBX) serves as a useful model in the study of depression and the mechanisms of action of antidepressant treatments. Considering the evidence of NMDA receptors involvement in depression, the present study was undertaken in order to investigate the time-course effects of OBX on the NMDA receptor function. Following bilateral olfactory bulbectomy, rats display an increase in locomotor activity and changes in other types of behavior in a novel environment. Autoradiographic experiments using the noncompetitive NMDA antagonist [(125)I]-iodo-MK-801 as the labeling agent showed that this increase in behavioral activities corresponds to a decrease in [(125)I]-iodo-MK-801 binding in a number of brain regions. In most regions, this reduction reached significance by the third week following OBX. However, in some cortical areas-a nucleus of the thalamus (AV) and one of the amygdala (LA)-this reduction was already significant in the first or second week following OBX and lasted throughout the 4 weeks of the study. We also compared the behavioral modifications induced by a challenge injection of MK-801 (0.2 mg/kg i.p.) in OBX and sham-operated rats. This challenge is known to induce hyperlocomotion and a number of stereotypies in naive rats. These effects were drastically reduced in OBX as compared to sham-operated rats. These data are consistent with the above-mentioned decrease in cerebral binding of MK-801 to NMDA receptors.     

Organization of the pallium in the fire-bellied toad Bombina orientalis. I: Morphology and axonal projection pattern of neurons revealed by intracellular biocytin labeling

The cytoarchitecture and axonal projection pattern of pallial areas was studied in the fire-bellied toad Bombina orientalis by intracellular injection of biocytin into a total of 326 neurons forming 204 clusters. Five pallial regions were identified, differing in morphology and projection pattern of neurons. The rostral pallium receiving the bulk of dorsal thalamic afferents has reciprocal connections with all other pallial areas and projects to the septum, nucleus accumbens, and anterior dorsal striatum. The medial pallium projects bilaterally to the medial pallium, septum, nucleus accumbens, mediocentral amygdala, and hypothalamus and ipsilaterally to the rostral, dorsal, and lateral pallium. The ventral part of the medial pallium is distinguished by efferents to the eminentia thalami and the absence of contralateral projections. The dorsal pallium has only ipsilateral projections running to the rostral, medial, and lateral pallium; septum; nucleus accumbens; and eminentia thalami. The lateral pallium has ipsilateral projections to the olfactory bulbs and to the rostral, medial, dorsal, and ventral pallium. The ventral pallium including the striatopallial transition area (SPTA) has ipsilateral projections to the olfactory bulbs, rostral and lateral pallium, dorsal striatopallidum, vomeronasal amygdala, and hypothalamus. The medial pallium can be tentatively homologized with the mammalian hippocampal formation, the dorsal pallium with allocortical areas, the lateral pallium rostrally with the piriform and caudally with the entorhinal cortex, the ventral pallium with the accessory olfactory amygdala. The rostral pallium, with its projections to the dorsal and ventral striatopallidum, resembles the mammalian frontal cortex.     

Effects of D2 dopamine receptor agonist and antagonist on brain activity in the rat assessed by functional magnetic resonance imaging

The effects of D₂ dopamine receptor agonist, bromocriptine (BROMO), and antagonist, haloperidol (HPD), on brain activity were investigated in rats by functional magnetic resonance imaging. T2^*-weighted signal intensity was increased in the hypothalamus at 120 min after acute administration of BROMO, and in the ventral posterior and dorsomedial nuclei of the thalamus from 30 to 120 min. In contrast, the signal intensity was decreased in the caudate–putamen at 30 min after acute administration of HPD, in the hypothalamus from 30 to 60 min, and in the perirhinal cortex at 30 min. After chronic (2 weeks) HPD treatment, acute administration of HPD decreased signal intensity in the caudate–putamen at 60 min, in the hypothalamus at 30 min, the perirhinal cortex from 2 to 120 min, the dorsomedial and ventral posterior nuclei of the thalamus from 2 to 120 min, and the medial nucleus of the amygdala from 60 to 120 min. These results suggest that (1) the D₂ receptor agonist increased the activity of the thalamic nuclei and the hypothalamus, while the D₂ receptor antagonist suppressed brain activity in the regions where D₂ receptors were present, (2) the suppression of brain activity in the thalamic nuclei and the perirhinal cortex by acute HPD administration was enhanced by chronic HPD treatment, and (3) the effects of antipsychotic drugs on the thalamus, amygdala, and perirhinal cortex may be related to their therapeutic efficacy, since clinical improvement in schizophrenic patients appears several days after the start of HPD treatment.     

Neuronal localization of cholecystokinin mRNA in the rat brain by using in situ hybridization histochemistry

The distribution of cholecystokinin (CCK) mRNA in the rat brain was determined by means of in situ hybridization histochemistry. Our results demonstrate a widespread distribution of neurons containing CCK mRNA throughout the rat brain. Hybridization-positive neurons were distributed throughout the neocortex, olfactory bulb, claustrum, amygdala, the dentate gyrus and hippocampus proper, and several subnuclei of the thalamus and the hypothalamus. The most abundant and most heavily labeled neurons were found in the endopiriform/piriform cortex, tenia tecta, and the ventral tegmental area. The distribution of neurons positive for CCK mRNA paralleled that of CCK-like immunoreactive neurons. These results detail the distribution of CCK mRNA and clearly identify the existence of CCK-synthesizing neurons in regions such as the paraventricular and supraoptic nuclei of the hypothalamus, where the presence of CCK cell bodies was previously uncertain.     

Serotonin neurons of the midbrain raphe: ascending projections.

The ascending projections of serotonin neurons of the midbrain raphe were analyzed in the rat using the autoradiographic tracing method. Axons of raphe serotonin neurons ascend in the ventral tegmental area and enter the medial forebrain bundle. A number of fibers leave the major group to ascend along the fasciculus retroflexus. Some fibers enter the habenula but the majority turn rostrally in the internal medullary lamina of the thalamus to innervate dorsal thalamus. Two additional large projections leave the medial forebrain bundle in the hypothalamus; the ansa peduncularis-ventral amygdaloid bundle system turns laterally through the internal capsule into the striatal complex, amygdala and the external capsule to reach lateral and posterior cortex, and another system of fibers turns medially to innervate medial hypothalamus and median eminence and form a contrelateral projection via the supraoptic commissures. Rostrally the major group in the medial forebrain bundle divides into several components: fibers entering the stria medullaris to terminate in thalamus; fibers entering the stria terminalis to terminate in the amygdala; fibers traversing the fornix to the hippocampus; fibers running through septum to enter the cingulum and terminate in dorsal and medial cortex and in hippocampus; fibers entering the external capsule to innervate rostral and lateral cortex; and fibers continuing forward in the medial olfactory stria to terminate in the anterior olfactory nucleus and olfactory bulb.     

Connectivity and cytoarchitecture of the ventral telencephalon in the salamander Plethodon shermani

The cytoarchitecture and axonal connection pattern of centers in the ventral telencephalon of the salamander Plethodon shermani were studied using biocytin for anterograde and retrograde labeling of cell groups, as well as by intracellular injections. Application of biocytin to the main and accessory olfactory bulbs identified the olfactory pallial regions and the vomeronasal portion of the amygdala, respectively. According to our results, the amygdala of Plethodon is divided into (1) a rostral part projecting to visceral and limbic centers and receiving afferents from the dorsal thalamus, and (2) a caudal part receiving accessory olfactory input. The striatopallial transition area (SPTA) lies rostrodorsally to the caudal (vomeronasal) amygdala and is similar in connections and possibly in function. The rostral striatum has few descending projections to the medulla, whereas the intermediate striatum sends strong projections to the tegmentum and medulla. The caudal striatum has strong ascending projections to the striatum and descending projections to the ventral hypothalamus. The dendritic trees of neurons labeled below the striatum and in the SPTA spread laterally from the soma, whereas dendrites of striatal neurons converge into the laterally situated striatal neuropil. In the caudal amygdala, three distinct types of neurons are found differing in dendritic arborization. It is concluded that, hodologically, the rostral part of the urodele amygdala corresponds to the central and basolateral amygdala and the caudal part to the cortical/medial amygdala of mammals. The urodele striatum is divided into a rostral striatum proper, an intermediate dorsal pallidum, and a caudal part, with distinct connections described here for the first time in a vertebrate.     

The regional distribution of cadmium in the brains of orally exposed adult rats

Cadmium (Cd) levels were measured in 13 dissected brain regions of adult male rats from 3 treatment groups. Rats (approximately 200 g each) were each fed 10 g/day of diets containing either 20 or 100 micrograms/g (ppm) Cd or control diet to which no Cd was added but contained approximately 0.35 ppm Cd. After 67 days of treatment, the brain of each rat was removed and each was dissected into 13 anatomical regions including olfactory bulbs, frontal cortex, rest of cortex, corpus callosum, hippocampus, amygdalae, corpus striatum, colliculum, tegmentum, thalamus, hypothalamus, pons-medulla, and cerebellum. Cd residues (dry weight) in each sample were determined by flameless atomic absorption spectrophotometry. With exception of the thalamus and olfactory bulbs, each of the brain regions of the 100 ppm Cd rats had more Cd than did those from either the 20 ppm Cd rats or controls which did not differ. There was evidence of selective accumulation of Cd within the olfactory bulbs of control and treated animals. This selective accumulation may be related to anosmia reported in workers with industrial exposure to Cd.     

Morphology and axonal projection pattern of neurons in the telencephalon of the fire-bellied toad Bombina orientalis: an anterograde, retrograde, and intracellular biocytin labeling study

The connectivity and cytoarchitecture of telencephalic centers except dorsal and medial pallium were studied in the fire-bellied toad Bombina orientalis by anterograde and retrograde biocytin labeling and intracellular biocytin injection (total of 148 intracellularly labeled neurons or neuron clusters). Our findings suggest the following telencephalic divisions: (1) a central amygdala-bed nucleus of the stria terminalis in the caudal midventral telencephalon, connected to visceral-autonomic centers; (2) a vomeronasal amygdala in the caudolateral ventral telencephalon receiving input from the accessory olfactory bulb and projecting mainly to the preoptic region/hypothalamus; (3) an olfactory amygdala in the caudal pole of the telencephalon lateral to the vomeronasal amygdala receiving input from the main olfactory bulb and projecting to the hypothalamus; (4) a medial amygdala receiving input from the anterior dorsal thalamus and projecting to the medial pallium, septum, and hypothalamus; (5) a ventromedial column formed by a nucleus accumbens and a ventral pallidum projecting to the central amygdala, hypothalamus, and posterior tubercle; (6) a lateral column constituting the dorsal striatum proper rostrally and the dorsal pallidum caudally, and a ventrolateral column constituting the ventral striatum. We conclude that the caudal mediolateral complex consisting of the extended central, vomeronasal, and olfactory amygdala of anurans represents the ancestral condition of the amygdaloid complex. During the evolution of the mammalian telencephalon this complex was shifted medially and involuted. The mammalian basolateral amygdala apparently is an evolutionary new structure, but the medial portion of the amygdalar complex of anurans reveals similarities in input and output with this structure and may serve similar functions.     

THE TOPOGRAPHY OF PLAQUES AND TANGLES IN DOWN''S SYNDROME PATIENTS OF DIFFERENT AGES

The topographical distribution of senile plaques and neurofibrillary tangles has been investigated in 12 patients with Down's syndrome ranging from 31 to 65 years of age. No plaques or tangles whatsoever were seen in the brain of the 31-year-old patient. The nine patients over 53 years of age, showed a similar pathological picture in which there were numerous mature plaques in all areas of cerebral cortex, hippocampus and amygdala and numerous tangles in these areas and in subcortical structures such as nucleus basalis, locus caeruleus, dorsal raphe, ventral tegmental area, substantia nigra, olfactory bulb and tracts. In the other two patients aged 37 and 51 years, an intermediate pathological picture was seen in which primitive plaques predominated within the cortex, with numerous mature plaques in hippocampus and amygdala. In the 37-year-old patient, tangles were numerous in the entorhinal cortex, but much less common in hippocampus and amygdala, rare in cerebral cortex and absent in the subcortical areas, olfactory bulbs and tracts. A similar pattern was seen in the 51-year-old patient though here some cells in the subcortex were also affected. These observations suggest that the primary focus of plaque and tangle formation in Down's syndrome may be in amygdala, entorhinal cortex and hippocampus, with a 'spreading out' to subsequently involve all areas of cortex, certain subcortical regions and the olfactory bulbs and tracts. It appears unlikely that the olfactory bulbs and tracts provide a portal of entry for any pathogenic agent that may be responsible for inducing plaque and tangle formation within the rest of the brain.     

Olfactory bulb removal decreases androgen receptor binding in amygdala and hypothalamus and disrupts masculine sexual behavior

In these experiments we examined the relationship between olfactory bulb removal, limbic system androgen receptor binding and male copulatory behavior. Sexually experienced male rats were castrated, and implanted with two 10 mm testosterone-filled silastic capsules. Animals then underwent either bilateral olfactory bulb removal (BOB) or sham surgery (Sham). Beginning 1-2 days postoperatively both BOB and Sham operates were given 4 tests for male copulation on alternate days. Less than 40% of BOB males ejaculated. In contrast, 80-100% of sham operates continued to ejaculate throughout the 4 postoperative tests. Cell nuclear androgen receptor binding was assessed in amygdala, hypothalamus, preoptic area and septum 1-2 and 8-9 days after either bulbectomy or sham surgery. We found that olfactory bulbectomy significantly reduces androgen receptor binding in amygdala and hypothalamus. The reduction in androgen receptor binding in amygdala occurs within 1-2 days following olfactory bulb removal and is correlated with the disruption of ejaculatory activity. These data suggest that the neuromodulation by olfactory bulb input to androgen-concentrating neurons in the amygdala and hypothalamus is necessary for effective copulation in male rats.     

Herpes virus-mediated preproenkephalin gene transfer in the ventral striatum mimics behavioral changes produced by olfactory bulbectomy in rats

The syndrome of behavioral, physiological, and neurochemical changes caused by ablation of the olfactory bulbs (OBX) in rats serves as a reliable and well-validated model of depression. Previous experiments have demonstrated that OBX leads to increased expression of the preproenkephalin (ENK) gene in the olfactory tubercle (OT) portion of the ventral striatum in rats. The aim of the present experiments was to investigate the role of OBX-induced ENK overexpression in the OT in the behavioral abnormalities exhibited by bulbectomized rats. A recombinant herpes virus carrying human preproENK cDNA was used to manipulate ENK gene expression in the OT of bulbectomized and sham-operated rats. Motivational deficits were assessed by the sucrose preference test, and 'agitation-like' behaviors were measured with the novel open field and footshock-induced freezing tests. ENK gene transfer in sham-operated rats mimicked some of the effects of OBX; it decreased freezing behavior in response to mild footshock and produced behavioral activation in the open field. In another experiment, virally mediated ENK gene transfer into the OT of intact rats decreased footshock-induced freezing, and this effect was reversed by naltrexone administration. PreproENK gene transfer into the OT did not produce analgesic effects in the tail-flick test. No effects on freezing behavior were observed following preproENK gene transfer into the frontal cortex. An additional experiment revealed that naltrexone administration attenuated the OBX-induced abnormality in freezing behavior. The results indicate that overexpression of the preproENK gene in the ventral striatum may mediate the 'agitation-like' behavior exhibited by bulbectomized rats.     

Hemispheric disconnection and rotational behaviour

Several studies have demonstrated the existence of crossed pathways interconnecting the bilateral extrapyramidal system. The present study has evaluated the role of the thalamus in the interhemispheric control of nigrostriatal function by observing the effect of midsagittal thalamic transection on amphetamine-induced rotation in rats. The effect of thalamic transection on net rotational asymmetry did not differ from the effects of sham operations. Also, the transection did not affect the rotational asymmetry induced by subsequent lesioning of the dominant hemisphere substantia nigra. The failure to affect the rotation asymmetry by the transection suggests either that the inter-hemispheric pathway does not control extrapyramidal asymmetry or that the crossing takes place outside the thalamus. In an additional group of rats, thalamic transection did not interrupt retrograde labeling of somata in the substantia nigra and ventral tegmental area by horseradish peroxidase injected in the contralateral caudate. Thus, the crossed nigrostriatal projection does not decussate via the thalamus. It is suggested that this pathway decussates in the ventral mesencephalon.     

Region-specific dysregulation of allopregnanolone brain content in the olfactory bulbectomized rat model of depression

Allopregnanolone (ALLO) is one of the most potent positive endogenous allosteric modulators of the type A γ-aminobutyric acid (GABA_A) receptors. While the robust anxiolytic profile of ALLO has been extensively characterized in rodents and its antidepressant-like effect was recently demonstrated in mice, there have been only few reports on alterations of brain ALLO levels in putative animal models of depression and anxiety. Removal of the olfactory bulbs of rats produces one of the most predictive animal models with which to screen for drugs with potential antidepressant activity following repeated treatment. We therefore investigated whether the olfactory bulbectomized (OB) rat model of depression may be associated with alterations of ALLO levels in whole brain tissue and in different brain regions. We determined ALLO levels in whole brain, amygdala, frontal cortex, hippocampus, and whole cerebral cortex of OB or sham-operated rats at 7, 14, or 28 days following bulbectomy or sham surgery. We observed a significant increase of whole brain ALLO content at 7 and 28 days post-surgery in the OB rats. At days 7 and 14 following olfactory bulb removal, ALLO levels were significantly decreased in amygdala and frontal cortex and significantly increased in whole cerebral cortex. In the hippocampus we observed only a tendency for decreased ALLO levels at day 14. Our data indicates a strong region-specific dysregulation of ALLO homeostasis in brains of OB rats which may contribute to the formation of the bulbectomy syndrome via a sustained reduction in physiological GABA-ergic tone in amygdala and frontal cortex.     

Endocannabinoid modulation of amphetamine sensitization is disrupted in a rodent model of lesion‐induced dopamine dysregulation

We tested the hypothesis that increased dopaminergic sensitivity induced by olfactory bulbectomy is mediated by dysregulation of endocannabinoid signaling. Bilateral olfactory bulbectomy induces behavioral and neurobiological symptomatology related to increased dopaminergic sensitivity. Rats underwent olfactory bulbectomy or sham operations and were assessed 2 weeks later in two tests of hyperdopaminergic responsivity: locomotor response to novelty and locomotor sensitization to amphetamine. Amphetamine (1 mg/kg i.p.) was administered to rats once daily for 8 consecutive days to induce locomotor sensitization. URB597, an inhibitor of the anandamide hydrolyzing enzyme fatty‐acid amide hydrolase (FAAH), was administered daily (0.3 mg/kg i.p.) to sham and olfactory bulbectomized (OBX) rats to investigate the impact of FAAH inhibition on locomotor sensitization to amphetamine. Pharmacological specificity was evaluated with the CB₁ antagonist/inverse agonist rimonabant (1 mg/kg i.p). OBX rats exhibited heightened locomotor activity in response to exposure either to a novel open field or to amphetamine administration relative to sham‐operated rats. URB597 produced a CB₁‐mediated attenuation of amphetamine‐induced locomotor sensitization in sham‐operated rats. By contrast, URB597 failed to inhibit amphetamine sensitization in OBX rats. The present results demonstrate that enhanced endocannabinoid transmission attenuates development of amphetamine sensitization in intact animals but not in animals with OBX‐induced dopaminergic dysfunction. Our data collectively suggest that the endocannabinoid system is compromised in olfactory bulbectomized rats. Synapse 63:941–950, 2009. © 2009 Wiley‐Liss, Inc.     

Regional changes in brain norepinephrine content in relation to mouse-killing behavior by rats

Three separate series of experiments were conducted as follows: isolation housing, bilateral olfactory bulbectomy, and Δ⁹-tetrahydrocannabinol (THC) administration. All three experimental manipulations produced an increase in the incidence of mouse-killing behavior. In order to elucidate the possible neural mechanisms mediating the killing response, norepinephrine (NE) content was measured in 6 discrete areas of the brain (the cortex, striatum, amygdala, midbrain, hypothalamus, and pons plus medulla oblongata). Following isolation housing, no significant difference in NE levels of any of the brain areas was demonstrated between the aggregated and isolated rats, nor between the killer and nonkiller rats. The rats with olfactory bulbectomy exhibited high NE content in the hypothalamus as compared with the intact or sham-operated rats, but there was no significant difference between the killer and nonkiller rats. After injection of THC, NE content in both the hypothalamus and pons plus medulla oblongata was decreased independent of the manifestation of killing response. The evidence indicates no regional change in brain NE levels specific to the killing response and suggests that brain NE may not participate in the mediation of mouse-killing behavior.