RESUMO
Electrical and chemical stimulation of the dorsal periaqueductal gray matter (dPAG) and the inferior colliculus (IC) induces escape behavior, usually accompanied by autonomic responses and antinociception. Recently, we presented evidence for a tonic inhibitory control exerted by H(2) histamine receptors on defensive behaviors generated in these midbrain tectum sites. Since treatments of these areas that elicit the defensive behavior repertoire frequently also have anxiogenic effects, we here used the elevated plus-maze (EPM) test for assessing the effects of microinjections of histamine (5-40 nmol), dimaprit (5-10 nmol) and ranitidine (10-30 nmol) into either dPAG or IC, which have a relative abundance of histamine-containing cells and histaminergic receptors. Dimaprit is an agonist and ranitidine is an antagonist of H(2) histamine receptors. Immediately after the injections, the animals were submitted to the EPM test. Whereas dPAG injections of dimaprit had no behavioral effects, histamine (40 nmol) caused a significant reduction in exploratory activity. On the other hand, ranitidine alone or following saline had aversive-like effects in both structures, i.e. reduced open arm, but not closed arm, entries. This pattern is usually interpreted as representing an anxiogenic effect. These effects were more pronounced after injection into dPAG than into IC. Freezing, the most prominent effect produced by ranitidine, was significantly inhibited by histamine as well as dimaprit. Thus, H(2) receptor blockade has fear-like action in the midbrain tectum with predominance in the dPAG. Such an action can be understood as a concomitant of defensive behavior, which has been shown to be a consequence of H(2) receptor antagonism in both dPAG and IC. The functional significance of the different effects of H(2) receptor blockade in dPAG and IC is discussed in the light of the probable distinct roles of these structures in the organization of defensive behavior.
Assuntos
Comportamento Animal/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/psicologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Colículos Inferiores/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Animais , Dimaprit/administração & dosagem , Dimaprit/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Histamina/administração & dosagem , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/administração & dosagem , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Masculino , Mesencéfalo/fisiologia , Microinjeções , Ranitidina/administração & dosagem , Ranitidina/farmacologia , Ratos , Ratos WistarRESUMO
Recent findings implicating neurokinins in the expression of anxiety-like behaviors have stimulated interest in the participation of these neuropeptides in the dorsal periaqueductal gray matter (dPAG), one of the main output regions of the brainstem for the expression of defense reaction. Studies on the behavior of rats submitted to the elevated plus-maze test in this laboratory have shown that microinjections of substance P into the dorsal periaqueductal gray produce anxiogenic-like effects. Now, we analyze what portion of the molecule of substance P is responsible for these effects through the examination of the action of its C- and N-terminus fragments (6-11 and 1-7) in the elevated plus-maze. We also investigated whether these effects are influenced by prior treatment with the tachykinin NK(1) receptor antagonist 17-beta-hydroxy-17-alpha-ethynyl-5alpha-androstanol[3,2-b]pyrimido[1,2-a]benzimidazole (WIN51,708). To this end, rats were implanted with a cannula in the dorsal periaqueductal gray and injected 1 week later with equimolar doses (17.5 and 35 pmol) of either C- or N-fragments of substance P and tested in the elevated plus-maze. The results show that the C-terminal fragment has an anxiogenic profile of effects, including reduction in the number of entries and time spent in the open arms of the maze, plus increases in scanning, stretched-attend posture, head dipping and flat-back approach. On the other hand, the N-terminal fragment produced opposite effects, namely, an increase in the number of entries and time spent in the open arms of the maze accompanied by an increase in end-arm activity, rearing and head dipping. The tachykinin NK(1) receptor antagonist WIN51,708 (20 mg/kg, i.p.) inhibited the effects of the carboxy-terminal of substance P while it did not change the effects of the N-terminal fragment. Microinjection of WIN51,708 (20 mg/kg, i.p.), by its own, did not produce any significant effects. Therefore, the results indicate that the anxiogenic effects of substance P injected into the dorsal periaqueductal gray are encoded by its carboxy-terminal sequence and due to its action on tachykinin NK(1) receptors.
Assuntos
Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância P/farmacologia , Análise de Variância , Androstanos/farmacologia , Animais , Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Benzimidazóis/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microinjeções , Antagonistas dos Receptores de Neurocinina-1 , Fragmentos de Peptídeos/farmacologia , Substância Cinzenta Periaquedutal/fisiologia , Ratos , Ratos Wistar , Receptores da Neurocinina-1/fisiologia , Substância P/químicaRESUMO
The dorsal periaqueductal gray matter (DPAG), superior and inferior colliculus have been implicated in the control of defense reactions in the midbrain. Electrical and chemical stimulation of these structures induces escape behavior, usually accompanied by autonomic responses and antinociception. GABA, 5-HT, opioids, excitatory amino acids and neuropeptides have been postulated to participate in the organization of such defensive reactions in the midbrain tectum. However, little attention has been given to a possible involvement of histamine in the generation of such behavior. To examine this issue in the present study, we assessed the effects of injections into the midbrain tectum of histamine and the H(1) and H(2) receptor antagonists, chlorpheniramine and ranitidine on the behavioral manifestations of the defense reaction. The effects of these drugs were also examined on antinociception, which has been considered to be an inherent component of the defense reaction. Thus, the animals were submitted to an open field test and after 30 min, antinociceptive behavior was measured with the aid of the tail-flick test. The results show that histamine reduced exploratory activity without causing motor deficit, as evaluated by the rotarod test. Ranitidine led to a dose-dependent behavioral activation, with clear signs of fear, whereas no apparent effect was observed following injections of chlorpheniramine. Antinociception always followed the escape reaction induced by the H(2) receptor blocker ranitidine. The present results suggest that H(2) receptors may be involved in the control of escape behavior and antinociception following activation of the neural substrates of fear in the midbrain tectum.
Assuntos
Reação de Fuga/fisiologia , Inibição Neural/fisiologia , Receptores Histamínicos H2/fisiologia , Teto do Mesencéfalo/fisiologia , Animais , Nível de Alerta/fisiologia , Mapeamento Encefálico , Colículos Inferiores/fisiologia , Masculino , Limiar da Dor/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Ratos , Ratos WistarRESUMO
We examined the effects of chondroitin sulphate C (CSC) on fear and anxiety parameters following injection of the glycosaminoglycan into the dorsal periaqueductal gray. Rats with chronically implanted cannulae were administered CSC (0.4 or 4.0 nmol) or vehicle (saline, 0.2 microl) and exposed to the elevated plus-maze test of emotionality. Intra-periaqueductal gray injection of CSC produced a dose-dependent anxiogenic effect as indicated by reduced entries into and time spent on the open arms, fewer excursions into the end of the open arms and by increased stretched attend posture, flat back approach and closed arm peeping-out behaviour. The behavioural effects of CSC appeared to be anxioselective, since the glycosaminoglycan did not influence measures of general (exploratory) activity, such as number of entries into the enclosed arms and amount of scanning, rearing and grooming. The present results show that CSC can produce an anxiogenic-like profile after injection into the dorsal periaqueductal gray. This is the first such report implicating an endogenous matrix glycosaminoglycan in neural mechanisms governing fear and anxiety.
Assuntos
Ansiedade/induzido quimicamente , Sulfatos de Condroitina/farmacologia , Matriz Extracelular/metabolismo , Medo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Animais , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Relação Dose-Resposta a Droga , Medo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Microinjeções , Modelos Neurológicos , Neurônios/metabolismo , Substância Cinzenta Periaquedutal/metabolismo , Ratos , Ratos WistarRESUMO
Neural circuits in the dorsal periaqueductal gray matter (dPAG) play an important role in the integration of defensive behavior. The neurokinin substance P causes conditioned place aversion when administered into this region. The present study examined whether these effects may be mimicked by its carboxy-terminal amino acid sequence and whether they are influenced by prior treatment with the tachykinin NK1 receptor antagonist WIN51,708. The behavioral testing apparatus is a circular open field consisting of 4 uniform quadrants that are equally preferred by the rats prior to drug treatments. For conditioning, rats received drug injections on three consecutive days and were placed into their assigned quadrant. The carboxy-terminal analog (17.5 pmol/0.2 microl) applied into the dPAG produced place aversion effects with reduced time spent in the drug-paired quadrant on the testing day. The effects of the carboxy-terminal analog was antagonized by pretreatment with WIN51,708 (20 mg/kg, i.p.). Microinjection of WIN51,708 (20 mg/kg, i.p.), by its own, did not produce significant effects. These findings suggest that previous reports showing conditioned place aversion effects of SP injected into the dPAG are encoded by its carboxy-terminal sequence and due to its action on tachykinin NK1 receptors.
Assuntos
Androstanos/farmacologia , Benzimidazóis/farmacologia , Condicionamento Operante/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Receptores da Neurocinina-1/fisiologia , Substância P/farmacologia , Androstanos/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Benzimidazóis/administração & dosagem , Relação Dose-Resposta a Droga , Interações Medicamentosas , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Microinjeções/métodos , Antagonistas dos Receptores de Neurocinina-1 , Fragmentos de Peptídeos/administração & dosagem , Substância Cinzenta Periaquedutal/anatomia & histologia , Substância Cinzenta Periaquedutal/metabolismo , Ratos , Ratos Wistar , Substância P/administração & dosagem , Substância P/análogos & derivados , Substância P/fisiologia , Fatores de TempoRESUMO
The elevated T-maze was combined with a free exploration protocol, which, in contrast to the conventional procedure, dispenses with handling of the animals during the experimental sessions. This allows measurement of fear indexes derived from the elevated plus-maze as well as assessment of acquisition of open arm avoidance and open arm escape in one continuous session. Retention of the different fear-responses is measured 72 h later without drug treatment. In order to assess the effects of two known anxiolytics in this paradigm, rats received an IP injection of diazepam (1 to 4 mg/kg), substance P (5 to 500 microg/kg) or vehicle (1 ml/kg) and were tested on the T-maze for 5 min. Diazepam elevated open arm activity, indicative of an anxiolytic effect. The drug also increased the latency to escape from the open arms, but did not significantly affect acquisition of open arm avoidance. During the retention trial, diazepam in higher doses impaired the performance of both fear-responses, suggestive of an anterograde amnesic effect. Substance P did not influence acquisition and retention of open arm avoidance and escape. However, in high doses, the peptide increased the sojourn time in the central arena of the maze, indicating reduced fear and, hence, a dissociation between anxiolytic and amnesic effects. The present findings demonstrate that the elevated T-maze free exploration paradigm is sensitive to anxiolytic and memory-modulating effects of drugs.
Assuntos
Ansiolíticos/farmacologia , Diazepam/farmacologia , Medo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Substância P/química , Substância P/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar , Fatores de TempoRESUMO
In order to further validate the recently developed marmoset (Callithrix penicillata) predator confrontation model of fear and anxiety, we investigated the behavioral effects of buspirone with this method. The apparatus consisted of three parallel arms connected at each end to a perpendicular arm, forming a figure-eight continuous maze. A taxidermized wild oncilla cat (Felis tigrina) was positioned facing a corner of the parallel arms, alternating between the left or right side of the maze among animals tested. All subjects were first submitted to seven 30-min maze habituation trials (HTs) in the absence of the predator, and then to five randomly assigned treatment trials (TTs) in the presence of the predator: three buspirone sessions (0.1, 0.5 and 1.0 mg/kg), saline and sham injection controls. Twenty minutes after treatment administration, the animal was released into the maze and had free access to the apparatus for 30 min. All trials were taped for later behavioral analysis. Buspirone significantly decreased the frequency of scent marking, while increasing the time spent in proximity to the 'predator' stimulus, indicating an anxiolytic effect. Neither locomotor activity, exposure to a novel environment, stimulus location and habituation, nor gender influenced the effects of the drug treatments. These results further validate this method and demonstrate the potential usefulness of this ethologically based paradigm to test anxiety and fear-induced avoidance in nonhuman primates and its susceptibility to anxiolytic pharmacological manipulations.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Buspirona/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Animais , Ansiolíticos/uso terapêutico , Ansiedade/psicologia , Buspirona/uso terapêutico , Callithrix , Comportamento Exploratório/fisiologia , Medo/fisiologia , Medo/psicologia , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologiaRESUMO
In this study, we evaluated the goldfish model of hemilabyrinthectomy for investigating potential recovery-promoting drugs. In this lesion model, the unilateral removal of the labyrinth induces a postural imbalance in response to light (Dorsal Light Reflex), from which the animals can recover over time. The behavioral effects of two neuropeptides were tested--namely, of substance P and ACTH4-10, both of which are known to promote functional recovery in several other lesion models. Furthermore, the effect of MK-801, an antagonist of the glutamatergic NMDA-receptor subtype, was tested because this substance has also been shown to exert a neuroprotective effect. After lesion of the right labyrinth, the animals (n = 12) were treated intraperitoneally daily either with vehicle (n = 12), substance P (n = 11), ACTH4-10 (n = 12), or MK-801 (n = 12). Another group (n = 11), which served as a non-lesion control, did not receive hemilabyrinthectomy or systemic injections. The lesion group, treated post-operatively with vehicle, did not recover from the postural deviation over the 24-d testing period. In contrast, all three test substances accelerated the functional recovery after unilateral labyrinthectomy. The decrease of the dorsal light reflex persisted even after cessation of drug treatment after 20 d. The results indicate that using the dorsal light reflex in the model of hemilabyrinthectomy in goldfish provides a useful approach to studying the ability of potential new neurotrophic or neuroprotective drugs to promote functional recovery.
Assuntos
Hormônio Adrenocorticotrópico/farmacologia , Maleato de Dizocilpina/farmacologia , Orelha Interna/fisiologia , Fragmentos de Peptídeos/farmacologia , Reflexo/fisiologia , Substância P/farmacologia , Análise de Variância , Animais , Lateralidade Funcional , Carpa Dourada , Luz , Modelos Animais , Membrana dos Otólitos/fisiologia , Postura , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Reflexo/efeitos dos fármacosRESUMO
The dorsal periaqueductal gray matter (DPAG) is one of the main output regions of the brainstem for the expression of defense reaction. Recent findings implicating neurokinins in the expression of fear or anxiety-like behaviors, have stimulated interest in the participation of these neuropeptides in the generation of aversive states in the dorsal periaqueductal gray matter. Analyses of traditional measures of the behavior of rats submitted to the elevated plus-maze test in this laboratory have shown that microinjections of substance P (SP) into the DPAG produce anxiogenic-like effects. The present study employs an ethological analysis of the behavior of animals in this test to investigate the involvement of substance P (SP) and its C- and N- fragments (7-11 and 1-7) in the expression of the different aspects of fear upon injection into the DPAG. To this end, rats were implanted with a cannula in the DPAG and injected one week later with 35 and 70 pmol of either substance P, or C- or N- SP fragments and tested immediately afterwards in the elevated plus-maze. The results show that SP and its C terminal fragment, produced increases in scanning, stretched attend posture, head dipping and flat-back approach, whereas the fragment N terminal produced only an increase in rearing. Therefore, the effects of SP and its C terminal fragment were associated to risk assessment behavior, whereas those of N terminal fragment were related to vertical exploratory activity. The results indicate that SP produces anxiogenic effects through activation of neural substrates of aversion in the DPAG and that this effect is probably related to its C terminal fragment.
Assuntos
Ansiedade/induzido quimicamente , Fragmentos de Peptídeos/administração & dosagem , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância P/administração & dosagem , Animais , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Masculino , Substância Cinzenta Periaquedutal/anatomia & histologia , Substância Cinzenta Periaquedutal/fisiologia , Ratos , Ratos Wistar , Substância P/fisiologiaRESUMO
There has been an increasing interest in the role of neuropeptides in the integration of brain functions. Besides the well-known positive-reinforcing effects of Substance P (SP) in prosencephalic regions, a role of this neuropeptide in the generation of aversive states in mesencephalic structures has also been envisaged. Evidence from a previous study suggests an involvement of SP in the neural substrates of aversion in the dorsal periaqueductal gray matter (DPAG). In the present study, we investigate whether N- and C-terminal fragments of Substance P are responsible for the effects produced by microinjections of SP into the dorsal periaqueductal gray. The results show that SP and its C-terminal fragment SP(7-11) produced a behavioral activation with increases in locomotor activity, grooming, and rearings, while the N-terminal fragment SP(1-7) produced only an increase in vertical exploratory activity. The effects were more pronounced with intermediate doses of SP and its C-fragment, confirming the characteristic bell-shaped dose-effect function of this neuropeptide. The proaversive effects observed with DPAG microinjections of these neuropeptides in the present study gain further relevance when combined with previous reports showing unconditioned and conditioned aversive effects following DPAG microinjections of SP in the place aversion and the elevated plus maze tests, two widely used animal models of anxiety. These results confirm previous data showing that SP has a modulatory role in the DPAG and that its effects are probably due to its C-terminal fragment.