The role of ketamine in major depressive disorders: Effects on parvalbumin-positive interneurons in hippocampus.

Major depressive disorder (MDD) is a complex illness that is arising as a growing public health concern. Although several brain areas are related to this type of disorders, at the cellular level, the parvalbumin-positive cells of the hippocampus interplay a very relevant role. They control pyramidal cell bursts, neuronal networks, basic microcircuit functions, and other complex neuronal tasks involved in mood disorders. In resistant depressions, the efficacy of current antidepressant treatments drops dramatically, so the new rapid-acting antidepressants (RAADs) are being postulated as novel treatments. Ketamine at subanesthetic doses and its derivative metabolites have been proposed as RAADs due to their rapid and sustained action by blocking N-methyl-d-aspartate (NMDA) receptors, which in turn lead to the release of brain-derived neurotrophic factor (BDNF). This mechanism produces a rapid plasticity activation mediated by neurotransmitter homeostasis, synapse recovery, and increased dendritic spines and therefore, it is a promising therapeutic approach to improve cognitive symptoms in MDD.

Prazosin blocks the glutamatergic effects of N-methyl-D-aspartic acid on lordosis behavior and luteinizing hormone secretion in the estrogen-primed female rat.

We have observed that intracerebroventricular (icv) injection of selective N-methyl-D-aspartic acid (NMDA)-type glutamatergic receptor antagonists inhibits lordosis in ovariectomized (OVX), estrogen-primed rats receiving progesterone or luteinizing hormone-releasing hormone (LHRH). When NMDA was injected into OVX estrogen-primed rats, it induced a significant increase in lordosis. The interaction between LHRH and glutamate was previously explored by us and another groups. The noradrenergic systems have a functional role in the regulation of LHRH release. The purpose of the present study was to explore the interaction between glutamatergic and noradrenergic transmission. The action of prazosin, an alpha1- and alpha2b-noradrenergic antagonist, was studied here by injecting it icv (1.75 and 3.5 microg/6 microL) prior to NMDA administration (1 microg/2 microL) in OVX estrogen-primed Sprague-Dawley rats (240-270 g). Rats manually restrained were injected over a period of 2 min, and tested 1.5 h later. The enhancing effect induced by NMDA on the lordosis/mount ratio at high doses (67.06 +/- 3.28, N = 28) when compared to saline controls (6 and 2 microL, 16.59 +/- 3.20, N = 27) was abolished by prazosin administration (17.04 +/- 5.52, N = 17, and 9.33 +/- 3.21, N = 20, P < 0.001 for both doses). Plasma LH levels decreased significantly only with the higher dose of prazosin (1.99 +/- 0.24 ng/mL, N = 18, compared to saline-NMDA effect, 5.96 +/- 2.01 ng/mL, N = 13, P < 0.05). Behavioral effects seem to be more sensitive to the alpha-blockade than hormonal effects. These findings strongly suggest that the facilitatory effects of NMDA on both lordosis and LH secretion in this model are mediated by alpha-noradrenergic transmission.

Cognitive effects of dopaminergic and glutamatergic blockade in nucleus accumbens in pigeons.

In earlier studies it was found that glutamatergic transmission within the nucleus accumbens septi is involved in the performance of a learned visual shape discrimination in pigeons. This study examines what effects several kinds of glutamate and dopamine antagonists have on the same task. Pigeons were trained with the relevant discrimination, bilaterally implanted with cannulas into the nucleus accumbens and tested after various transmission blockers had been administered intracerebrally. SCH-23390, a D1 dopamine antagonist, at the dose used, had no effect, and Spiperone, a D2-dopamine and 5HT2a-serotonine antagonist, significantly decreased the error repeat trials. CNQX, a non-NMDA glutamate receptor antagonist, and Cycloleucine, an antagonist of the glycine allosteric site of NMDA receptors, had no effect. CGS-19755, a selective competitive NMDA antagonist, significantly impaired performance by significantly decreasing the percent correct trials and increasing the error repeat trials. CPPG, a II/III metabotropic glutamate antagonist, remarkably improved performance. MMPG, a III/II metabotropic glutamate antagonist, at the dose used, did not have any significant effect. The preparation employed may be a useful animal model of perceptual disturbances in schizophrenia.

The anxiolytic effect of allopregnanolone is associated with gonadal hormonal status in female rats.

The behavioural display in the plus-maze, an established experimental model of anxiety, was studied in rats injected into the lateral brain ventricle (i.c.v.) with the neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone). Female rats under different gonadal hormonal status were chosen. Allopregnanolone enhanced exploration of the open arms in both estrous rats and ovariectomized estrogen and progesterone primed rats. No effect was observed in diestrous 1 and ovariectomized not-primed rats. In all cases, the plus-maze locomotor-exploratory behaviour was not affected by allopregnanolone. The GABA(A) receptor antagonist, bicuculline (9.8 microM i.c.v.) reversed the allopregnanolone action in the ovariectomized primed rats. When bicuculline was injected i.c.v. in conjunction with allopregnanolone, the anxiogenic effect of bicuculline was reversed by the highest dose (25 microM) of allopregnanolone only. These results suggest that allopregnanolone exerts an anxiolytic action interacting with the GABA(A) receptor in an estrogen-dependent manner.

Interaction between glutamate and luteinizing hormone-releasing hormone (LHRH) in lordosis behavior and luteinizing hormone release (LH): further studies on NMDA receptor mediation.

The present studies examine the effects of the glutamate agonist N-Methyl-D-Aspartic acid on lordosis responsiveness and LH release in estrogen-primed, ovariectomized rats. Groups of rats previously cannulated in the 3rd ventricle of the brain (IVT) were challenged with saline, NMDA and LHRH. A clear increase in lordosis-to-mount quotients (LQ) after IVT administration of 0.5, 0.75 and 1 microgram NMDA was found. LHRH (150 ng IVT) also enhanced LQ. High plasma LH levels were present in both cases. Intraventricular administration of the selective LHRH antagonist [D-p-Glu1, D-Phe2, D-Trp3,6]-LHRH (100 ng) was unable to prevent NMDA action on lordosis behavior. In contrast, it blunted LHRH enhancement of LQ. LH release evoked by either NMDA and LHRH was blocked by the LHRH antagonist. Present results support our previous view suggesting that glutamate, through NMDA receptors, participates in the regulation of lordosis behavior. Glutamate seems to exert its actions in the behavioral and endocrine patterns through different mechanisms; the first seems not to be mediated by LHRH, but the endocrine effect operates via LHRH release.

Inhibition by N-methyl-D-aspartic acid (NMDA) receptor antagonist of lordosis behavior induced by estrogen followed by progesterone or luteinizing hormone-releasing hormone (LHRH) in the rat.

The effects of glutamate receptor antagonists on sexual receptivity induced by progesterone and LHRH were examined in ovariectomized, estradiol-primed rats (OVX-EB). Enhancement of lordosis/mounts quotient (L/M) by progesterone (0.5 mg) or LH-RH (150 ng; third ventricle, IVT) in OVX-EB rats was significantly decreased by IVT injection of (+) 2-amino-7-phosphonoheptanoic acid a competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist. On the contrary, there were no changes in L/M quotient after IVT injection of 6,7-dinitroquinoxaline-2,3,dione at two dose levels, a Non-NMDA receptor antagonist. The NMDA antagonist did not modify lordosis behavior in OVX-EB rats. The results indicate that the NMDA type of glutamate receptors appears to mediate progesterone and LHRH facilitatory actions and suggest that glutamatergic synapses may be involved in lordosis-facilitating neural mechanisms.

Visual discrimination in pigeons impaired by glutamatergic blockade of nucleus accumbens.

The nucleus accumbens septi (Acc) is thought to be involved in the control of cognitive processes and to be implicated in the pathophysiology of schizophrenia. Because perceptual-cognitive distortions are a core symptom in schizophrenia, any evidence that the Acc intervenes in a sensory recognition task in an animal species would be of interest. Pigeons were instrumentally trained to discriminate visual shapes. The acute effects of drug microinjections into the Acc on the discrimination of the training shapes, on the correction responding after errors, and on the generalisation to different shapes were examined. The effects of conduction blockade with lidocaine, glutamatergic blockade with 7-aminophosphonoheptanoic acid, and dopaminergic stimulation with apomorphine on behavioural performance were tested. No effects were observed with lidocaine and apomorphine. A significant and reversible performance disruption to near chance levels was obtained after aminophosphonoheptanoic acid injections into the Acc. It appears that a glutamatergic blockade of the Acc interferes with the visual discrimination processes of pigeons.

Is inhibition by diazepam and beta-carbolines of estrogen-induced luteinizing hormone secretion related to sedative effects?

The effects of diazepam (DZ) and the beta-carbolines ZK-91296 and ZK-93423 on luteinizing hormone (LH) release evoked by beta-estradiol were studied in estradiol-primed ovariectomized rats. Acute treatment with 2.5, 5 and 10 mg/kg DZ and ZK-91296 significantly blunted the LH response. ZK-93423 (1, 5 and 10 mg/kg) produced a similar effect. The inverse agonist DMCM (2 mg/kg) was unable to modify plasma LH levels in estrogen-primed, ovariectomized rats. Sedative effects were observed with doses of DZ (1 mg/kg) ineffective to blunt the LH response. In contrast, ZK-91296 (5 mg/kg) produced inhibition of LH surges in nonsedative doses. These results indicate that diazepam and beta-carboline agonists prevent the LH surge evoked by estrogen. They suggest, in addition, that the actions on LH release and their sedative effects are not directly related.

Luteinizing hormone releasing hormone (LHRH) in the periaqueductal gray substance increases some subcategories of grooming behavior in male rats.

Locomotion, holeboard exploration and grooming behavior were measured in male rats after injection of LHRH or cerebrospinal fluid (CSF) into the mesencephalic periaqueductal gray substance (PGS). LHRH injection at doses of 75 ng did not alter locomotion and rearing but decreased significantly the scores of head dipping and defecation. Several subcategories of grooming responses were evaluated in a home cage-like environment. Head, body and genital grooming increased significantly after injection of 75 ng LHRH. The frequency of gnawing and head shakes increased as well. Lower doses (50 ng) also raised the scores of head and body grooming and produced a tendency for genital grooming increase. Higher doses (100 ng) did not affect genital grooming responses and produced drowsiness in most of animals. These results demonstrate that some motor activities are selectively modified by the localized administration of LHRH in the PGS.

Thyrotropin releasing hormone injected into the nucleus accumbens septi selectively increases face grooming in rats.

The effect of unilateral injection of peptides into the nucleus accumbens septi (NAS) on subcategories of grooming behavior was studied in male rats. The peptides used were: thyrotropin releasing hormone (TRH), luteinizing hormone releasing hormone (LHRH) and corticotropin releasing hormone (CRH). Male rats (Holtzman strain, 240-270 g body weight) injected with progressive doses of TRH (100, 200 and 400 ng) at 5-day intervals were compared with the control state (injection of artificial cerebrospinal fluid, CSF). A selective increase in face grooming was observed with the 100 ng (49.78 +/- 6.11, N = 18) and 200 ng (50.29 +/- 7.72, N = 17) doses of TRH (P < 0.05 vs CSF injection, 26.94 +/- 3.64, N = 18). Face grooming increased further with the 400 ng dose (55.19 +/- 8.26, N = 16, P < 0.01), but a dose-response curve could not be obtained at the dose range used. Flank scratching, head, body and genital grooming were not altered by the TRH injection, but the rearing behavior was inhibited (10.33 +/- 1.56; N = 18; 10.76 +/- 1.77, N = 17; 12 +/- 2.06, N = 16) (P < 0.05 for all doses vs controls, 20.61 +/- 2.81, N = 18). The rats that received LHRH (75 ng, N = 16) and CRH (100 ng, N = 14) did not show behavioral changes when compared with their control states. The results show that injection of TRH into the NAS, but not the injection of LHRH or CRH, selectively increases face grooming without affecting other subcategories of grooming at the doses used, and appears to link this peptide with the neural substrate of stereotyped behavior.

Distinct grooming patterns induced by intracerebroventricular injection of CRH, TRH and LHRH in male rats.

This paper reports the effects on grooming, related behaviors and levels of anxiety induced by the hypophysiotropic peptides corticotropin-releasing hormone (CRH, 1 microgram, 0.2 nmol, icv), thyrotropin-releasing hormone (TRH, 100 micrograms, 275 nmol, icv) and luteinizing hormone-releasing hormone (LHRH, 1.5 micrograms, 1.3 nmol, icv) administered into the lateral ventricle of the brain (icv) of adult male rats of a Holtzman-derived colony (N = 15, each group). CRH induced an increase in total grooming scores, whereas LHRH, TRH and vehicle had no effect. CRH strongly increased face and head grooming and induced head shakes. The time spent in rearing and gnawing was significantly decreased. In the plus-maze, CRH reduced the time of exploration in the open arm. TRH increased face grooming and induced body shakes. LHRH had no effect on grooming or rearing behavior. No body or head shakes were observed after LHRH administration. Scoring of individual grooming elements demonstrated differences in action of the three peptides. Although both CRH and TRH increased face grooming, only CRH induced head grooming. Furthermore, CRH induced predominantly head shakes while TRH increased body shake activity. In contrast, CRH was anxiogenic and TRH appeared to induce stereotyped behavior. From the characterization of grooming elements and related responses, we conclude that each hypophysiotropic peptide induces a specific behavioral pattern.

[Experimental approaches to perceptual dysfunction in schizophrenia]. / Aproximaciones experimentales a la disfunción perceptual en la esquizofrenia.

METHOD: Starting from the studies of Conrad on early schizophrenia, we quantified the gestaltic alteration that he has described using a visual-motor gestaltic test (Bender test) in acute and chronic schizophrenic patients. We observed that rotations and distortions were significantly higher in chronic patients, and perseverations in acute patients. Global scores and time employed showed significant differences in both groups when compared with controls. Time is classically considered a compensation in the failure. We observed that the Bender gestaltic test allows quantification of perceptual alterations due to the loss of the objective structure of the perception in schizophrenic patients. Aiming to reproduce these findings in an animal model, we proposed a study of pharmacological modification of nucleus accumbens septi (Acc) neurotransmission, traditionally linked with physiopathology of schizophrenia. In this way, we developed a discrimination shape model in a skinner box in trained pigeons, bilaterally implanted in Acc by stereotaxic surgery. CONCLUSIONS: The antagonists of N-methyl-D-aspartic acid (NMDA) glutamatergic receptor induced a significant decrease in performance in the discrimination task, and a significant increase in correcting trials. The last parameter was considered a perseveration, manifestation of a behavioral inflexibility in relationship with environmental changes. The glutamatergic blockade of Acc in rats using a passive avoidance task induced a disturbance in acquisition, and the same procedure in the plus maze test led to a significant decrease in anxiety levels, suggesting additional homologies with schizophrenic psychoses.

Evaluating spatial memory function in mice: a within-subjects comparison between the water maze test and its adaptation to dry land.

The Morris water maze (WM) is a common spatial memory test in rats. It has been adapted for evaluating genetic manipulations in mice. One major acknowledged problem of this cross-species translation is floating. We investigated here in mice the feasibility and practicality of an alternative paradigm-the cheeseboard (CB), which is a dry version of the WM, in a within-subject design allowing direct comparison with the conventional WM. Under identical task demands (reference or working memory), mice learned in the CB as efficiently as in the WM. Furthermore, individual differences in learning rate correlated between the two reference memory tests conducted separately in the two mazes. However, no such correlation was found with respect to reference memory retention or working memory performance. This study demonstrated that the CB is an effective alternative to the WM as spatial cognition test. Additional tests in the CB confirmed that the mice relied on extra maze cues in their spatial search. We would recommend the CB as a valuable addition to, rather than a replacement of the WM in phenotyping transgenic mice, because the two apparatus might diverge in the ability to detect individual differences in various domains of mnemonic functions.

Glutamatergic ionotropic blockade within accumbens disrupts working memory and might alter the endocytic machinery in rat accumbens and prefrontal cortex.

Effects of blocking N-methyl-D-aspartic acid (NMDA) and non-NMDA glutamatergic receptors on performance in the hole board test was studied in male rats bilaterally cannulated into the nucleus accumbens (Acc). Rats, divided into 5 groups, received either 1 microl injections of saline, (+/-) 2-amino-7-phosphonoheptanoic acid (AP-7) (0.5 or 1 microg) or 2,3-dioxo-6-nitro-1,2,3,4,tetrahydrobenzo-(f)quinoxaline-7-sulphonamide disodium (NBQX, 0.5 or 1 microg) 10 min before testing. An increase by AP-7 was observed in ambulatory movements (0.5 microg; p < 0.05), non-ambulatory movements and number of movements (1 microg; p < 0.05); sniffing and total exploration (1 microg; p < 0.01). When holes were considered in order from the first to the fifth by the number of explorations, the most visited holes (first and second) of the AP-7 group were significantly higher than the corresponding holes of saline group (p < 0.05 for 0.5 microg and p < 0.001 for 1 microg). When the second hole was compared with the first of his group, a difference was only observed in the AP-7 1 microg group (p < 0.001). Increasing differences between the other holes and the first were observed by drug treatment. At molecular level, it was observed that AP-7 induced an increase of the coat protein AP-2 expression in Acc, but not AP-180 neither the synaptic protein synaptophysin. The increase of AP-2 was also observed in the medial prefrontal cortex by the action of AP-7 but not NBQX. We conclude that NMDA glutamatergic blockade might induce an activation of the endocytic machinery into the Acc, leading to stereotypies and perseverations, lacking cortical intentional direction.

[Visual and motor functions in schizophrenic patients]. / Objetivación de la función visomotriz en la esquizofrenia.

In the present work, visual and motor functions have been explored in 26 chronic schizophrenic patients, and 7 acute schizophrenic patients, compared with 26 normal controls, by means of the Bender-Gestalt Test. Parameters under consideration were: Form distortion, rotation, integration, perseveration, use of space, subtle motricity, score (global parameter), and time employed. As regards distortion and rotation there have been highly significant differences between chronic patients and control group. Among acute patients, it was observed that perseveration was also highly significant. Conversely, integration and use of space did not differ significantly among the three groups involved. The global score, resulting from all the above mentioned parameters showed important differences between both patient groups on the one hand, and control group on the other hand. Taking into account that patients were being administered neuroleptic drugs, it can safely be said, however, that the Bender-Gestalt Test allows to recognize alteration in perceptual closure consistent with a loss of the objective structure of perceived phenomena, in both chronic and acute patients.

Effects of anxiety and memory of systemic and intra-amygdala injection of 5-HT3 receptor antagonist BRL 46470A.

This study deals with the effects of the 5-HT3 receptor antagonist, BRL 46470A, on memory and anxiety, using the elevated T-maze. This method is useful for investigating the effects of anxiolytic drugs on memory, and the relationships between neural subsystems involved in emotionally related behaviors and in processes underlying learning. After the drug was either injected peripherally or microinjected into the amygdala, the animals were tested on the elevated T-maze (30 or 15 min later, respectively). Two kinds of aversively motivated behaviors, inhibitory avoidance and one-way escape, were recorded. These behaviors may reflect different types of fear/anxiety, namely, anticipatory anxiety and innate fear. Three days later, memory for these tasks was assessed by reexposing the subjects to the maze. The compound had an anxiolytic effect on the inhibitory avoidance response when given systemically, but an anxiogenic effect when injected into the amygdala. It had an anxiolytic action on the escape response when given either systemically or into the amygdala. The compound had no adverse effects on memory for either task. These results suggest that this new 5-HT3 antagonist may be useful in the treatment of certain types of anxiety disorders, especially those related to unconditioned fear, e.g. phobic or panic disorders, with the likelihood of having no side effects on memory processes. The contrasting results obtained with different measures of anxiety may also account for the inconsistencies found in the experimental literature dealing with compounds of this nature.

Prazosin blocks the glutamatergic effects of N-methyl-D-aspartic acid on lordosis behavior and luteinizing hormone secretion in the estrogen-primed female rat

We have observed that intracerebroventricular (icv) injection of selective N-methyl-D-aspartic acid (NMDA)-type glutamatergic receptor antagonists inhibits lordosis in ovariectomized (OVX), estrogen-primed rats receiving progesterone or luteinizing hormone-releasing hormone (LHRH). When NMDA was injected into OVX estrogen-primed rats, it induced a significant increase in lordosis. The interaction between LHRH and glutamate was previously explored by us and another groups. The noradrenergic systems have a functional role in the regulation of LHRH release. The purpose of the present study was to explore the interaction between glutamatergic and noradrenergic transmission. The action of prazosin, an alpha1- and alpha2b-noradrenergic antagonist, was studied here by injecting it icv (1.75 and 3.5 µg/6 µL) prior to NMDA administration (1 µg/2 µL) in OVX estrogen-primed Sprague-Dawley rats (240-270 g). Rats manually restrained were injected over a period of 2 min, and tested 1.5 h later. The enhancing effect induced by NMDA on the lordosis/mount ratio at high doses (67.06 ± 3.28, N = 28) when compared to saline controls (6 and 2 µL, 16.59 ± 3.20, N = 27) was abolished by prazosin administration (17.04 ± 5.52, N = 17, and 9.33 ± 3.21, N = 20, P < 0.001 for both doses). Plasma LH levels decreased significantly only with the higher dose of prazosin (1.99 ± 0.24 ng/mL, N = 18, compared to saline-NMDA effect, 5.96 ± 2.01 ng/mL, N = 13, P < 0.05). Behavioral effects seem to be more sensitive to the alpha-blockade than hormonal effects. These findings strongly suggest that the facilitatory effects of NMDA on both lordosis and LH secretion in this model are mediated by alpha-noradrenergic transmission.

Thyrotropin releasing hormone injected into the nucleus accumbens septi selectively increases face grooming in rats

The effect of unilateral injection of peptides into the nucleus accumbens septi (NAS) on subcategories of grooming behavior was studied in male rats. The peptides used were: thyrotropin releasing hormone (TRH), luteinizing hormone releasing hormone (LHRH) and corticotropin releasing hormone (CRH). Male rats (Holtzman strain, 240-270 g body weight) injected with progressive doses of TRH (100, 200 and 400 ng) at 5-day intervals were compared with the control state (injection of artificial cerebrospinal fluid CSF). A selective increase in face grooming was observed with the 100 ng (49.78 + 6.11, N = 18) and 200 ng (50.29 + 7.72, N = 17) doses of TRH (P<0.05 vs CSF injection 26.94 + 3.64, N = 18). Face grooming increased further with the 400 ng dose (55.19 + 8.26, N = 16, P<0.01), but a dose-response curve could not be obtained at the dose range used. Flank scratching, head, body and genital grooming were not altered by the TRH injection, but the rearing behavior was inhibited (10.33 + 1.56; N = 18; 10.76 + 1.77, N = 17; 12 + 2.06, N = 16) (P<0.05 for all doses vs controls, 20.61 + 2.81, N = 18). The rats that received LHRH (75 ng, N = 16) and CRH (100 ng, N = 14) did not show behavioral changes when compared with their control states. The results show that injection on TRH into the NAS, but not the injection of LHRH or CRH, selectively increases face grooming without affecting other subcategories of grooming at the doses used, and appears to link this peptide with the neural substrate of stereotyped behavior.

Distinct grooming patterns induced by intracerebroventricular injection of CRH, TRH and LHRH in male rats

This paper reports the effects on grooming, related behaviors and levels of anxiety induced by the hypophysiotropic peptides corticotropin-releasing hormone (CRH, 1 mug, 0.2 nmol, icv), thyrotropin-releasing hormone (TRH, 100 mug, 275 nmol, icv) and luteinizing hormone-releasing hormone (LHRH, 1.5 mug, 1.3 nmol, icv) administered into the lateral ventricle of the brain (icv) of adult male rats of a Holtzman-derived colony (N = 15, each group). CRH induced an increase in total grooming scores, whereas LHRH, TRH and vehicle had no effect. CRH strongly increased face and head grooming and induced head shakes. The time spent in rearing and gnawing was significantly decreased. In the plus-maze, CRH reduced the time of exploration in the open arm. TRH increased face grooming and induced body shakes. LHRH had no effect on grooming or rearing behavior. No body or head shakes were observed after LHRH administration. Scoring of individual grooming elements demonstrated differences in action of the three peptides. Although both CRH and TRH increased face grooming, only CRH induced head grooming. Furthermore, CRH induced predominantly head shakes while TRH increased body shake activity. In contrast, CRH was anxiogenic and TRH appeared to induce stereotyped behavior. From the characterization of grooming elements and related responses, we conclude that each hypophysiotropic peptide induces a specific behavioral pattern.