Sequence-specific effects of neurokinin substance P on memory, reinforcement, and brain dopamine activity

Abstract

There is ample evidence that the neurokinin substance P (SP) can have neurotrophic as well as memory-promoting effects. This paper outlines a recent series of experiments dealing with the effects of SP and its N- and C-terminal fragments on memory, reinforcement, and brain monoamine metabolism. It was shown that SP, when applied peripherally (IP), promotes memory (inhibitory avoidance learning) and is reinforcing (place preference task) at the same dose of 37 nmol/kg. Most important, however, is the finding that these effects seemed to be encoded by different SP sequences, since the N-terminal SP1-7 (185 nmol/kg) enhanced memory, whereas C-terminal hepta- and hexapeptide sequences of SP proved to be reinforcing in a dose equimolar to SP. These differential behavioral effects were paralleled by selective and site-specific changes in dopamine (DA) activity, as both SP and its C-, but not N-terminus, increased extracellular DA in the nucleus accumbens (NAc), but not in the neostriatum. The neurochemical changes lasted at least 2 h after injection. These results show that the reinforcing action of peripheral administered SP may be mediated by its C-terminal sequence, and that this effect could be related to DA activity in the NAc. Direct application of SP (0.74 pmol) into the region of the nucleus basalis magnocellularis (NBM) was also memory-promoting and reinforcing, and again, these effects were differentially produced by the N-terminus and C-terminus, supporting the proposed structure-activity relationship for SP's effects on memory and reinfrocement. These results may provide a hypothetical link between the memory-modulating and reinforcing effects of SP and the impairment in associative functioning accompanying certain neurodegenerative processes.

Disruption of the neurokinin-3 receptor (NK3) in mice leads to cognitive deficits

“…Based on these data, localization studies, and the pharmacological effects of tachykinin ligands, the NK3 receptor has been suggested to play a role in schizophrenia (Meltzer and Prus 2006), Parkinson's disease (Bannon et al 1995;Chen et al 2004), epilepsy (Roder et al 1994), anxiety (Ribeiro et al 1999;Hasenohrl et al 2000), depression (Panocka et al 2001), and memory and reinforcement related processes Huston et al 1993;Krappmann et al 1994).…”

Effect of drugs on mnestic performance: a methodological approach

“…This interrogation about animal models should not be settled without mentioning 'long-term potentiation' (LTP), considered as a model for studying the molecular mechanisms of memory (Grover and Teyler, 1990;Rksumk, 1991). The immediate question to be addressed is linked to the discovery of the role of all kinds of compounds (calcium, glutamate, arachidonic acid, nitric oxide, tachykinines) (Zhuo et al, 1993;Bekkers, 1993;Huston et al, 1993), which all have their own 'pharmacology' which cannot be evaluated successively in animals and in man within a period of time compatible with the objective of research (Ungerer et al, 1990; Jaffe er al., 1990). It has to be noted that studies on LTP are not recommended by regulations on preclinical drug trials, and therefore are exceptional.…”

Case Study 2: Bioisosteric Replacements for the Neurokinin 1 Receptor (NK1R)

“…Therefore, these antagonists can inhibit biological functions in the central nervous system and act as an anxyolitic, antidepressant, antiemetic, antimigraine, antialcohol addiction, or as a neuroprotector. They can also play a role in analgesic and antiinflammatory functions, preventing liver damage processes and in antivirus proliferation [9][10][11][12][13][14][15][16][17][18][19][20][21]. Regarding cancer, NK 1 receptor antagonists have an antitumor action (inducing tumor cell death by apoptosis), and induce antiangiogenesis and inhibit the migration of tumor cells [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40].…”

“…The neuropeptide SP has been also implicated in pain, inflammation, chemical-driven liver damage, and virus proliferation. The neuropeptide SP also plays an important role in cancer (e.g., tumor cell proliferation, formation of new blood vessels, and migration of tumor cells for invasion and metastasis) [8][9][10][11][12][13][14][15][16]. However, NK 1 receptor antagonists specifically inhibit the above biological functions mediated by the neuropeptide SP.…”