The neurokinin (NK) system is one of the most studied peptide systems in the CNS. Three NK receptors exist, each with a preferred ligand: substance P (SP) binds with greatest affinity to NK1, neurokinin A prefers NK2, and neurokinin B

has preferential binding to NK3. The NK system has been implicated in a wide range of functions including nociception, emetic response/vomiting, inflammatory conditions, asthma, irritable bowel syndrome, migraine, anxiety, and depression. SP and the NKi receptor are broadly distributed in the amygdala, locus ceruleus, hypothalamus, substantia nigra, peduncular nuclei, caudate putamen, nucleus accumbens, raphe nuclei, and lamina I of the spinal cord. The distribution of the receptor in limbic regions (amygdala, hypothalamus) overlaps with neurotransmitter systems known to be involved in the regulation of mood (e.g., 5HT, NE). Thus, the SP-NK receptor system has been hypothesized to play an important role in affective behaviors (i.e., anxiety and depression).162

Preclinical studies showed that SP delivered to the lateral septal nucleus, the medial amygdala, or into the intracerebral ventricles increased time spent in the closed arms of the EPM, an anxiogenic response. Furthermore, noxious stimuli and acute and chronic stress produce SP release in the brain. Specifically, maternal separation in the guinea pig and immobilization stress elevate SP levels in amygdala. Given these data NK1 receptors would be anticipated to have anxiolytic activity. Thus, the NK1 receptor knockout mouse has a phenotype that resembles mice treated with anxiolytics. Compared to wild-type controls, NK1 receptor knockout mice display fewer vocalizations in the maternal separation test, spend more time in the open arms of the EPM, and show increased exploratory behavior in the open field.

A variety of NK1 receptor antagonists (Figure 13) have been developed, primarily as analgesics, and produce anxiolytic effects in a variety of animal models162: CP-96345 is effective in the mouse light-dark shuttle box; NKP-608 increases social interaction in rat and in gerbil; L-733060, L-760735, MK-869, CP-99994, and GR-205171 attenuate guinea pig vocalizations in the maternal separation test; and GR-205171 and RP-67580 block marble burying in mice. In the EPM RP-67580 increased open arm activity in mouse with FK-888 causing similar effects in rat and mice and MK-869, L-742694, L-7330360, and CP-99994 are efficacious in the gerbil. The anxiolytic actions of these compounds occur in the absence of motor impairment or sedation.

Free Yourself from Panic Attacks

Free Yourself from Panic Attacks

With all the stresses and strains of modern living, panic attacks are become a common problem for many people. Panic attacks occur when the pressure we are living under starts to creep up and overwhelm us. Often it's a result of running on the treadmill of life and forgetting to watch the signs and symptoms of the effects of excessive stress on our bodies. Thankfully panic attacks are very treatable. Often it is just a matter of learning to recognize the symptoms and learn simple but effective techniques that help you release yourself from the crippling effects a panic attack can bring.

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