Psychopharmacology (1993) 112: 147-162 Psychopharmacology © Springer-Verlag 1993 Reviews Sequence-specific effects of neurokinin substance P on memory, reinforcement, and brain dopamine activity J.P. Huston, R.U. Hasenfhrl, F. Boix, P. Gerhardt, and R.K.W. Schwarting Institute of Physiological PsychologyI, Heinrich-Heine-University of Diisseldorf, Universit/itsstrasse 1, 40225 Diisseldorf 1, Germany Received January 21, 1993 / Final version April 16, 1993 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, reinforce- ment, and brain monoamine metabolism. It was shown that SP, when applied peripherally (IP), promotes mem- ory (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) ac- tivity, as both SP and its C-, but not N-terminus, in- creased 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 adminis- tered 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 rein- forcement. 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. Key words: Peptides - Tachykinins - Substance P frag- ments - Inhibitory avoidance learning - Conditioned place preference - Nucleus basalis magnocellularis - Dopamine - Neostriatum - Nucleus accumbens - In vivo microdialysis - Neurodegeneration - Alzheimer's disease - Rat Correspondence to: J.P. Huston Substance P (SP) is an undecapeptide that acts as a neurotransmitter and/or modulator in the mammalian peripheral and central nervous system (Pernow 1983; Maggio 1988, for review). SP belongs to a family of neu- ropeptides called tachykinins, defined by their common carboxy (C)-terminal amino acid sequence, Phe-X-Gly- Leu-Met-NH2, where X is either an aromatic (Phe, Tyr) or an aliphatic (Val, Ile) residue (Erspamer 1981). Several tachykinins, known as neurokinins, have been discovered in the mammalian CNS, including man (see Table 1): SP, neurokinin A (NKA; substance K), NKA (3-10), neuro- kinin B (NKB; neuromedin K), neuropeptide K (NPK), and neuropeptide 7 (NPT) (Henry et al. 1987; Escher and Regoli 1989; Helke et al. 1990). SP is found in high concentrations in the brain and in a variety of peripheral organs, particularly in the intestine (Emson 1979; Jessel 1983, for review). In the periphery, SP is a potent hypo- tensive agent, which produces vasodilatation and stimu- lates contraction of smooth muscles (Pernow 1983, for review); these effects are restricted to its C-terminal tachykinin segment, with SP7-11 being the smallest frag- ment to have this activity (Bury and Mashford 1976; Erspamer 1981; Fuxe et al. 1982). In the CNS, SP is present in high concentrations in terminals of sensory afferent nerves in the dorsal horn of spinal cord and in cranial nerve nuclei. Within the brain, SP is concentrated in a major pathway of striatonigral neurones, with local- ly high concentrations also in the hypothalamus, septum, amygdala and in the region of the nucleus basalis mag- nocellularis (ventral globus pallidus/substantia innomi- nata complex) (Ljungdahl et al. 1978a; Cuello et al. 1985, for review). SP may often coexist with other neurokinins in the same neurones, but also commonly coexists or closely interacts with classical neurotransmitters like dopamine (DA), acetylcholine, opiates, serotonin and GABA (Pernow 1983; H6kfelt et al. 1987; Chang 1988). Recently, mammalian tachykinin receptors have been reclassified as NK-1, NK-2, NK-3, and NK-4 receptor subtypes, based on whether their putative endogenous ligand is SP, NPK, NKB, or NKA, respectively (Henry 1987; Iversen 1989). It is likely that all four receptor subtypes exist in the CNS, although only the NK-1 and