Systemic or intra-prelimbic cortex infusion of prazosin impairs fear memory reconsolidation.

The alpha-1 adrenergic antagonist prazosin has been used to alleviate the symptoms of PTSD, but the mechanism remains unclear. One possibility is that prazosin may disrupt fear memory reconsolidation, leading to attenuation of fear responses. To test this hypothesis, we administered a single systemic injection of prazosin during the reconsolidation of olfactory fear conditioning in rats. We found that a post-retrieval injection of prazosin disrupted subsequent retrieval of fear. Similarly, intra-prelimbic cortex infusion of prazosin during the reconsolidation period also disrupted subsequent retrieval of fear. These findings suggest that fear memory undergoes reconsolidation through activation of alpha-1 adrenergic receptors in the prelimbic cortex.

Neuroanatomy of anxiety.

The evolutionary approach to human anxiety is based on the defensive responses that nonhuman animals show to fear-provoking stimuli. Studies performed mostly on rodents have related areas such as the medial prefrontal cortex, amygdaloid and hypothalamic nuclei, hipoccampal formation, and midbrain central gray to these responses. It is clear, however, that animals show different and sometimes opposite responses according to the threatening stimulus. These responses include immediate reactions such as freezing or flight, behavioral inhibition or avoidance, which are organized by at least partially distinct brain systems. As discussed in this chapter, several pieces of evidence indicate that these brain systems are similar in rodents and primates. In addition, recent neuroimaging studies also suggest dysfunctions in these systems are probably related to anxiety disorders in humans.

Frequency of climbing behavior as a predictor of altered motor activity in rat forced swimming test.

Previous work has shown that the frequency of climbing behavior in rats submitted to the forced swimming test (FST) correlated to the section's crosses in the open field test, which suggest it might be taken as a predictor of motor activity in rat FST. To investigate this proposal, the frequency, duration, as well as the ratio duration/frequency for each behavior expressed in the FST (immobility, swimming and climbing) were compared in animals treated with a motor stimulant, caffeine (CAF), and the antidepressant, clomipramine (CLM). Male Wistar rats were submitted to 15min of forced swimming (pre-test) and 24h later received saline (SAL, 1ml/kg, i.p.) or CAF (6.5mg/kg, i.p.) 30min prior a 5-min session (test) of FST. To validate experimental procedures, an additional group of rats received three injections of SAL (1ml/kg, i.p.) or clomipramine (CLM, 10mg/kg, i.p.) between the pre-test and test sessions. The results of the present study showed that both drugs, CLM and CAF, significantly reduced the duration of immobility and significantly increased the duration of swimming. In addition, CAF significantly decreased the ratio of immobility, and CLM significantly increased the ratio of swimming and climbing. Moreover, CLM significantly increased the duration of climbing but only CAF increased the frequency of climbing. Thus, it seems that the frequency of climbing could be a predictor of altered motor activity scored directly in the FST. Further, we believe that this parameter could be useful for fast and reliable discrimination between antidepressant drugs and stimulants of motor activity.

Anxiolytic effect of spermine microinjected into the dorsal periaqueductal grey in rats / Efeito ansiolítico da espermina microinjetada na substância cinzenta periaquedutal dorsal de ratos

Investigamos o possível efeito das espermina e receptores das poliaminas na substância cinzenta periaquedutal dorsal, sobre a ansiedade. Grupos de ratos receberam microinjeções de espermina (2,5 nmol) no interior da matéria cinzenta periaquedutal dorsal e foram testados no labirinto em cruz elevado. Os resultados indicam um aumento significativo na porcentagem de entradas e no tempo de permanência nos braços abertos. Outro experimento mostra que o efeito ansiolítico obtido após microinjeção de espermina (2,5 nmol) no interior da matéria cinzenta periaquedutal dorsal, foi bloqueado pela microinjeção prévia dos antagonistas das poliaminas, arcaina (4 nmol) ou ifenprodil (5 nmol), neste sítio. Estes resultados indicam que o receptor da espermina interage na modulação da ansiedade em ratos expostos ao labirinto em cruz elevado. Considerando que as poliaminas são encontradas normalmente no cérebro, estes resultados sugerem que o sistema de poliaminas na matéria cinzenta periaquedutal dorsal possuem um importante papel na ansiedade

To investigate a possible effect of the spermine and its polyamins receptors in the dorsal periaqueductal grey (DPAG) in anxiety. Groups of rats received microinjections of spermine (2.5 nmol) into DPAG and were tested in the elevated plus-maze apparatus. Results indicated an overall significant increase in the percentage of entries and in the time spent in open arms. In another experiment the anxiolytic effect obtained after the microinjection of spermine (2.5 nmol) into DPAG was block by previous microinjection of polyamines antagonists, arcaine (4 nmol) or ifenprodil (5 nmol) into the same site. These results indicate that the spermine receptor interaction in the modulation of anxiety in rats exposed to the elevated plus-maze. Considering that polyamines are natural component of the brain, these results suggest that polyamine system within DPAG may play a role in aversion and anxiety

Transmissäo pelo glutamato como alvo molecular na ansiedade / Glutamatergic neurotransmission as molecular target in anxiety

O glutamato (GLU) é o principal neurotransmissor excitatório do cérebro de mamíferos. Os receptores do GLU säo classificados em ionotrópicos ou metabotrópicos. A interferência do GLU no desenvolvimento neural, na plasticidade sináptica, no aprendizado e na memória, na epilepsia, na isquemia neural, na tolerância e na dependência a drogas, na dor neuropática, na ansiedade e na depressäo tem limitado o uso de compostos que agem nos receptores de GLU, quando existe a necessidade de açöes mais seletivas dessas drogas. Dados pré-clínicos em roedores e humanos têm mostrado que compostos que reduzem a ativaçäo do GLU, pelo bloqueio dos seus receptores ou através da reduçäo da sua liberaçäo dos terminais, produzem um perfil ansiolítico em modelos de ansiedade. A aplicaçäo desses compostos em áreas específicas do cérebro, envolvidas na mediaçäo do comportamento defensivo, tal como a substância cinzenta periaquedutal dorsal, também reproduzem o mesmo perfil ansiolítico de açäo. O conhecimento crescente acerca da neurotransmissäo pelo GLU e o desenvolvimento de compostos mais seletivos atuantes nesta neurotransmissäo, renovaram a atençäo para esse sistema neurotransmissor como alvo molecular possível para uma nova classe de drogas no tratamento de condiçöes neuropsiquiátricas. Embora incompleta, esta revisäo tenta atrair a atençäo para a importância de estudos colaborativos entre clínicos e pesquisadores de ciências básicas na geraçäo de idéias para alvos potenciais no desenvolvimento de novos compostos ansiolíticos. e desta maneira contribuir para a compreensäo das bases biológicas da ansiedade

[Glutamatergic neurotransmission as molecular target in anxiety]. / Transmissão pelo glutamato como alvo molecular na ansiedade.

Glutamate (GLU) is the main excitatory neurotransmitter in the mammalian brain. GLU receptors are classified as ionotropic (iGLUR) or metabotropic (mGLUR). The GLU interference with neural development, synaptic plasticity, learning and memory, epilepsy, neural ischemia, drug addiction, tolerance, neuropathic pain, anxiety and depression, has limited the use of compounds acting on GLU synapses, when there is a need for a selective effect for these drugs. Pre-clinical data in rodents and humans subjects has shown that compounds that reduce GLU activation either by blocking its receptors or by reducing its release from terminals elicit an anxiolytic profile of action in models of anxiety. When applied to specific brain areas involved in the mediation of defensive behavior, such as the periaqueductal gray matter, these compounds also replicate the same anxiolytic-like profile. The increasing knowledge about GLU neurotransmission and the development of more selective GLU-acting compounds have renewed attention towards this neurotransmismiting system as a possible target for new classes of drugs for the treatment of neuropsychiatric conditions. Although not complete this review tried to draw attention to collaborative studies between clinicians and basic researchers that have provided insight for potential targets in the development of new anxiolytic compounds thus contributing for the understanding of the biological basis of anxiety.