Kurt L. Hoffman

Neuroendocrine regulation of estrous behavior in the rabbit: Similarities and differences with the rat

In this review, we compare the neuroendocrine control of estrous behavior in the rabbit, a reflex ovulator, and the rat, a more commonly studied spontaneous ovulator. Although the hormonal control of estrous behavior in both species is similar, notable differences include the absence of a stimulatory effect of progesterone (P) on sexual behavior in the rabbit and the retention of sexual behavior in a substantial proportion of female rabbits after ovariectomy. The ventrolateral component of the ventromedial hypothalamus (VMH) and an adjacent region caudal to it appear to be critical estrogen (E)-responsive regions for lordosis in the rat and rabbit, respectively. In both species the effects of E and P are largely mediated by the genomic action of their receptors (ER and PR), and in both species E similarly regulates the expression of these receptors. The prolonged, E-stimulated estrous of the rabbit is terminated after mating by unknown mechanisms, while the brief estrous of the rat is triggered by the proestrous peak of P and terminated by both the decline in P and the downregulation of hypothalamic PR. In both species, P most likely inhibits estrous behavior during pregnancy, and postpartum estrous may be triggered by a stimulatory effect of E coinciding with the withdrawal of P-mediated inhibition. Estrous behavior is inhibited in both species during lactation, most likely by the suckling-induced inhibition of gonadotropin secretion. This comparative approach can reveal neuroendocrine mechanisms underlying estrous behavior that are common to all mammals, while highlighting evolutionary adaptations unique to each species.

FACILITATION OF ESTROUS BEHAVIOR BY VAGINAL CERVICAL STIMULATION IN FEMALE RATS INVOLVES α1-ADRENERGIC RECEPTOR ACTIVATION OF THE NITRIC OXIDE PATHWAY

In estrogen-primed female rats, vaginal cervical stimulation (VCS) provided by male intromissions or by an experimenter enhances estrous behaviors exhibited by females during subsequent mating with a male. We tested the hypothesis that alpha(1)-adrenergic receptors, acting via the nitric oxide-cGMP-protein kinase G pathway, mediate VCS-induced facilitation of female reproductive behaviors. Ovariectomized, estradiol-primed rats received intracerebroventricular (icv) infusions of vehicle or pharmacological antagonists 15 or 60min before VCS. Estrous behaviors (lordosis and proceptivity) in the presence of a male were recorded immediately (0min), and 120min following VCS. First we verified that VCS, but not manual flank stimulation alone, enhanced estrous behaviors when females received icv infusion of the vehicles used to administer drugs. Increased estrous behavior was apparent immediately following VCS and persisted for 120min. We then infused prazosin, phenoxybenzamine (alpha(1)-adrenergic receptor antagonists), yohimbine, idaxozan (alpha(2)-adrenergic receptor antagonists), or propranolol (beta-adrenergic receptor antagonist) 15min prior to the application of VCS in females primed with 5mug estradiol benzoate. Only alpha(1)-adrenergic antagonists inhibited VCS facilitation of estrous behavior, apparent 120min after VCS. Finally, we administered specific inhibitors of soluble guanylyl cyclase, nitric oxide synthase or protein kinase G icv 15 or 60min before VCS. All three agents significantly attenuated VCS facilitation of estrous behavior. These data support the hypothesis that endogenously released norepinephrine, acting via alpha(1)-adrenergic receptors, mediates the facilitation of lordosis by VCS, and are consistent with a mechanism involving alpha(1)-adrenergic activation of the nitric oxide/cGMP/protein kinase G pathway.

Animal models of obsessive compulsive disorder: recent findings and future directions

Introduction: Obsessive compulsive disorder (OCD) is a debilitating condition with limited treatment options. OCD is heterogeneous with respect to the content of obsessions and compulsions and their underlying motivation, among other characteristics. Animal models have provided important insights into the pathophysiology of OCD. Areas covered: The phenomenology of OCD is discussed, with emphasis on clinically-relevant subgroups. The paper also discusses the advantages and limitations of animals as models of OCD, along with considerations on assessing their validity. A PubMed database search using the terms ‘animal model’ and ‘obsessive compulsive disorder’ revealed ongoing studies in several models, including stereotypy in the deer mouse, quinpirole-induced checking, spontaneous alternation, compulsive lever pressing, genetic models, pathogenic models and models involving normal compulsive-like behavioral patterns. These models are presented with respect to their similarity to specific features of OCD and the information gained from them. Studies in many of these models point to the participation of corticostriatal thalamocortical circuitry and corticostriatal glutamate neurotransmission in the pathophysiology of compulsive-like behavior. Expert opinion: The use of animal models takes us beyond simple serotonin- or dopamine-based models of OCD that are founded on the often limited, and still unexplained, response of OCD symptoms to serotonin reuptake inhibitors or antipsychotic therapy. Pharmacological challenges that selectively target neurochemical systems that modulate either corticostriatal glutamate or striatal dopamine neurotransmission, or indeed both, should be investigated in animal models of compulsive-like behavior. Such systems include metabotropic glutamate, adenosine and endocannabinoid receptors, among others.

D1 and D2 dopamine receptor antagonists decrease behavioral bout duration, without altering the bout's repeated behavioral components, in a naturalistic model of repetitive and compulsive behavior.

Nest building behavior in the pregnant female rabbit (Oryctolagus cuniculus) is a model for compulsive behavior in Obsessive Compulsive Disorder (OCD). This behavior comprises a cycle of repeated, stereotyped components (collecting straw, entering nest box and depositing the straw there, returning to collect more straw), which itself is repeated 80+ times in a single bout that lasts approximately 50min. The bout, in turn, is repeated if necessary, according to the rabbits perception of whether or not the nest is finished. We administered SCH23390 (5-100μg/kg; D1/D5 antagonist) or raclopride (0.05-1.0mg/kg; D2/D3 antagonist), subcutaneously to day 28 pregnant female rabbits, 30 or 60min before placing straw inside their home cage. At doses that minimally affected ambulatory behavior in open field (5-12.5μg/kg SCH23390, 0.5-1.0mg/kg raclopride), both antagonists dramatically reduced bout duration while not significantly affecting the initiation of straw carrying behavior, the sequential performance of the individual cycle components, maximum cycle frequency, or the total number of bouts performed. These results point to an important role for dopamine neurotransmission for the prolonged expression of a normal, repetitive and compulsive-like behavior. Moreover, the finding that dopamine receptor antagonists decrease the time spent engaged in repetitive behavior (without significantly altering the form of the repetitive behavior itself) suggests a possible explanation for why neuroleptics can be clinically effective for treating OCD.

Rat dorsal prostate is necessary for vaginal adhesion of the seminal plug and sperm motility in the uterine horns

The rat prostate comprises dorsal, ventral and lateral lobes that are morphologically and biochemically distinct. Lesions to these structures are expected to affect the quality of the ejaculate and male fertility. In experiment 1, we analyzed ejaculate parameters of males that had chemical lesions of the dorsal or ventral lobes. At pre-lesion and at 5 and 20 days post-lesion males were mated, and after ejaculation, seminal fluid and seminal plug were obtained from the mated females. In experiment 2, the ventral lobes were ablated, and the ejaculate was analyzed. In experiment 3, the fertility of males with chemically-lesioned dorsal lobes or ablation of the ventral lobes was evaluated. Chemical lesion of the dorsal lobe prevented the adhesion of the seminal plug to vaginal walls. When these males were tested at 5-days postlesion, no sperm were found in uterus, and at 20-days post-lesion, the few sperm encountered showed slow progressive motility. None of the females that mated with dorsal lobe-lesioned males became pregnant. However, chemical lesion or ablation of the ventral lobes did not affect ejaculate or fertility. Our results indicate that the dorsal prostatic lobes are indispensable for reproductive success in males, and define parameters of ejaculate with which fertility can be estimated.

Histological correlates of N40 auditory evoked potentials in adult rats after neonatal ventral hippocampal lesion: animal model of schizophrenia

The neonatal ventral hippocampal lesion (NVHL) is an established neurodevelopmental rat model of schizophrenia. Rats with NVHL exhibit several behavioral, molecular and physiological abnormalities that are similar to those found in schizophrenics. Schizophrenia is a severe psychiatric illness characterized by profound disturbances of mental functions including neurophysiological deficits in brain information processing. These deficits can be assessed by auditory evoked potentials (AEPs), where schizophrenics exhibit abnormalities in amplitude, duration and latency of such AEPs. The aim of the present study was to compare the density of cells in the temporal cerebral cortex and the N40-AEP of adult NVHL rats versus adult sham rats. We found that rats with NVHL exhibit significant lower amplitude of the N40-AEP and a significant lower number of cells in bilateral regions of the temporal cerebral cortex compared to sham rats. Because the AEP recordings were obtained from anesthetized rats, we suggest that NVHL leads to inappropriate innervation in thalamic-cortical pathways in the adult rat, leading to altered function of cortical networks involved in processing of primary auditory information.

Clozapine and glycinamide prevent MK-801-induced deficits in the novel object recognition (NOR) test in the domestic rabbit (Oryctolagus cuniculus).

Studies in humans indicate that acute administration of sub-anesthetic doses of ketamine, an NMDA receptor antagonist, provokes schizophrenic-like symptoms in healthy volunteers, and exacerbates existing symptoms in individuals with schizophrenia. These and other findings suggest that NMDA receptor hypofunction might participate in the pathophysiology of schizophrenia, and have prompted the development of rodent pharmacological models for this disorder based on acute or subchronic treatment with NMDA receptor antagonists, as well as the development of novel pharmacotherapies based on increasing extrasynaptic glycine concentrations. In the present study, we tested whether acute hyperlocomotory behavior and/or deficits in the novel object recognition (NOR) task, induced in male rabbits by the acute subcutaneous (s.c.) administration of MK-801 (0.025 and 0.037 mg/kg s.c., respectively), were prevented by prior administration of the atypcial antipsychotic, clozapine (0.2mg/kg, s.c.), or the glycine pro-drug glycinamide (56 mg/kg, s.c.). We found that clozapine fully prevented the MK-801-induced hyperlocomotion, and both clozapine and glycinamide prevented MK-801-induced deficits in the NOR task. The present results show that MK-801-induced hyperlocomotion and deficits in the NOR task in the domestic rabbit demonstrate predictive validity as an alternative animal model for symptoms of schizophrenia. Moreover, these results indicate that glycinamide should be investigated in pre-clinical models of neuropsychiatric disorders such as schizophrenia, obsessive compulsive disorder and anxiety disorders, where augmentation of extrasynaptic glycine concentrations may have therapeutic utility.

Activation of the orbitofrontal and anterior cingulate cortices during the expression of a naturalistic compulsive-like behavior in the rabbit

HighlightsMaternal nest building in the rabbit is a potential model for compulsive behavior.Pregnancy changes the behavioral and neural responses to nest material (straw).Pregnancy is associated with compulsive‐like collecting and carrying of straw.Straw carrying activates orbitofrontal, anterior cingulate, and piriform cortices.Nest building behavior may be homologous to compulsive behavior in OCD. ABSTRACT We propose that maternal nest building in the female laboratory rabbit is a useful model for compulsions in obsessive‐compulsive disorder (OCD). This repetitive behavior comprises collecting straw, depositing it into the nest box, and then returning to collect more straw. We reasoned that if “straw carrying” behavior is homologous to compulsive behavior, then it should be associated with activation of prefrontal regions associated with OCD, namely, the orbitofrontal and anterior cingulate cortices (OFC and ACC, respectively). In the present study, we quantified c‐FOS immunoreactivity in the ACC, OFC, premotor (PM), infralimbic (IL), prelimbic (PL), and piriform (PI) cortices of: (1) pregnant female rabbits that were given straw (PREG + STRAW); (2) pregnant rabbits that were not given straw (PREG); (3) estrous rabbits that were given straw (ESTROUS + STRAW); (4) estrous rabbits that were not given straw (ESTROUS). After 1 h, all females were sacrificed and processed for brain c‐FOS immunoreactivity. We found that pregnant rabbits showed lower latencies to interact with the straw than estrous rabbits, and that pregnant rabbits displayed straw carrying, while estrous rabbits did not. c‐FOS expression was increased in the OFC, ACC, and PI in the PREG + STRAW compared to all other groups. By contrast, c‐FOS expression in all other regions was greater in PREG + STRAW compared to PREG, but not different from ESTROUS + STRAW. These results point to an important role for the OFC, ACC, and PI in initiating repetitive straw‐carrying behavior, and further support the proposal that this behavior can serve as a model for compulsions in OCD.

Glycinamide prevents MK-801-induced hyperactivity and deficits in object recognition memory in an animal model of positive and cognitive symptoms of schizophrenia

Fig. 1. Effects of MK-801 and Gly on novel object exploration and locomotory behavior in open field. a) Total exploration time of the familiar and novel object during the test phase (3 min) of the NOR test. Exploration time (sec) of familiar and novel objects is shown as median ± interquartile range (n = 7 or 8 rats per group). b) Discrimination ratios (DRs), an index of novel object discrimination, are shown as median ± interquartile range (n = 7 or 8 rats per group). c) Locomotion (number of line crossings during 3 min) in the open field test is expressed as median ± interquartile range (n = 8 rats per group). For between-group comparisons (i.e., data shown in panels b and c), the Kruskal–Wallis test indicated significant between-group differences (p b 0.05). Asterisks denote statistically significant post-hoc comparisons (Wilcoxon or Mann–Whitney test): p b 0.001 (***), p b 0.01 (**) and p b 0.05 (*). Theta (panel b) denotes significantly different from the hypothetical null value of 0 (no discrimination; Wilcoxon test, p b 0.05). Dear Editors,

1.02 – Female Sexual Behavior in Rodents, Lagomorphs, and Goats

Female sexual behavior is the result of a complex interaction between hormones, receptors, and cellular mechanisms that interact in different brain circuits to induce behavior. The present chapter describes molecular, cellular, physiological, and behavioral aspects that are important for the expression of female sexual behavior. In previous editions of this series, the primary focus was on female sexual behavior of rats. In the present edition, we expand this focus to encompass lagomorphs and goats, in addition to rodents. Our aim is to emphasize both the diversity in female sexual behavior and the interspecies similarities in underlying biological mechanisms.