Rüdiger U. Hasenöhrl

The role of neuropeptides in learning: focus on the neurokinin substance P

The neurokinin substance P (SP) can have neurotrophic as well as memory-promoting effects. The study of its mechanisms may provide new insights into processes underlying learning and neurodegenerative disorders. Our work shows that SP, when applied peripherally (i.p.), promotes memory and is reinforcing 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. 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 SPs effects on memory and reinforcement. In addition, it was found that a single injection of SP into the NBM led to an increase of extracellular DA in the contralateral NAc. This effect of SP was observed only in those animals where SP was reinforcing, providing evidence for a lateralized relationship between reinforcement induced by injection of SP into the NBM and DA activity in the NAc. Furthermore, the outcome of a series of experiments suggests, that SP may not only be considered to have memory-promoting effects in normal animals, but can also improve functional recovery after unilateral 6-OHDA lesion of the substantia nigra and after lesions of the hippocampus, and can counteract age-related performance deficits.

Substance P and its role in neural mechanisms governing learning, anxiety and functional recovery.

The neurokinin Substance P (SP) is widely distributed in the central nervous system and has been extensively studied in various functional aspects. This review focuses on the behavioral relevance of SP. Here we show that SP can have memory-promoting, reinforcing and anxiolytic-like effects when administered systemically or into the nucleus basalis of the ventral pallidum. These effects seem to be mediated via the SP-preferring NK(1)receptor and differentially related to N- versus C-terminal fragments of the undecapeptide. Secondly, SP injection into the ventral pallidum can lead to increases of acetylcholine in frontal cortex and dopamine in nucleus accumbens, suggesting that the hypermnestic, positively reinforcing and anxiolytic effects observed upon basal forebrain injection of SP are mediated by activation of the nucleus accumbens-ventral pallidum circuitry. Furthermore, SP and certain SP-fragments may not only be considered to have beneficial behavioral effects in normal animals, but can also prevent lesion-induced functional deficits and improve the speed of recovery. This indicates that SP agonists might also have a neuroprotective capacity in parallel with recovery-promoting actions.

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

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 SPs effects on memory and reinforcement. 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.

Enhanced maze performance and reduced oxidative stress by combined extracts of zingiber officinale and ginkgo biloba in the aged rat

Here we assessed the effects of i.g. administration of Zingicomb (ZC), a mixture of zingiber officinale and ginkgo biloba extracts, on learning and memory, and on indicators of oxidative stress in aged rats. Effects of ZC (1 and 10 mg/kg) were investigated in 22-24 months old Wistar rats using the Morris water maze, in which they show deficient performance as compared to 3 months old rats in the undrugged state (days 1 and 2). Treatment was administered on days 3 and 4 of training, then over 7 days with training discontinued, and again on days 5 and 6 when training was resumed. Thereafter chronic treatment was maintained over 5 months. 1 mg/kg ZC improved escape learning in the water maze. The two capital indicators of oxidative stress in brain homogenates, the amount of oxidized proteins (assessed as carbonyl group containing proteins) and lipid peroxidation, were significantly reduced in ZC treated animals. Thus, ZC, which had previously been shown to improve inhibitory avoidance learning and to have anxiolytic properties in adult animals, might also facilitate spatial learning in aged animals, and reduces indices of oxidative stress in brain tissue after chronic treatment.

Anxiolytic-like action of neurokinin substance P administered systemically or into the nucleus basalis magnocellularis region

There is evidence that the neurokinin substance P plays a role in neural mechanisms governing learning and reinforcement. Reinforcing and memory-promoting effects of substance P were found after it was injected into several parts of the brain and intraperitoneally. With regard to the close link between anxiety and memory processes for negative reinforcement learning, the aim of the present study was to gauge the effect of substance P on anxiety-related behaviors in the rat elevated plus-maze and social interaction test. Substance P was tested at injection sites where the neurokinin has been shown to promote learning and to serve as a reinforcer, namely in the periphery (after i.p. administration) and after injection into the nucleus basalis magnocellularis region. When administered i.p., substance P had a biphasic dose-response effect on behavior in the plus-maze with an anxiolytic-like action at 50 microg/kg and an anxiogenic-like one at 500 microg/kg. After unilateral microinjection into the nucleus basalis magnocellularis region, substance P (1 ng) was found to exert anxiolytic-like effects, because substance P-treated rats spent more time on the open arms of the plus-maze and showed an increase in time spent in social interaction. Furthermore, the anxiolytic effects of intrabasalis substance P were sequence-specific since injection of a compound with the inverse amino acid sequence of substance P (0.1 to 100 ng) did not influence anxiety parameters. These results show that substance P has anxiolytic-like properties in addition to its known promnestic and reinforcing effects, supporting the hypothesis of a close relationship between anxiety, memory and reinforcement processes.

Facilitation of learning after lesions of the tuberomammillary nucleus region in adult and aged rats

Abstract The tuberomammillary nucleus (TM) located in the posterior part of the hypothalamus is the main source of neuronal histamine in the central nervous system. Recent work from our laboratories has indicated an involvement of the TM region in neuronal plasticity and reinforcement processes. In the present study, we investigated the effects of TM lesions on the performance of adult and aged Wistar rats in a set of learning tasks, which differed in terms of complexity and reward contingencies (habituation learning, inhibitory avoidance, discrimination learning, Morris water maze). An improvement was found in every test applied, indicating that TM lesions seem to generally enhance learning and memory capacities independent of the special demands of a given task. Age-related learning deficits were strongly diminished. Immunohistochemistry revealed that the excitotoxic lesions used to destroy the TM region led to a marked decrease in the number of histamine-positive neurons in the vicinity of the injection site, indicating an involvement of the brain histaminergic system in the observed behavioral changes.

Anxiolytic-like effect of combined extracts of Zingiber officinale and Ginkgo biloba in the elevated plus-maze

The effects of the known anxiolytic compound diazepam (DZ) on the behavior of rats in the elevated plus-maze were compared with those of zingicomb (ZC) (registered trademark of Mattern et Partner), a combination preparation of standardized extracts of Ginkgo biloba and Zingiber officinale. DZ was administered intraperitoneally (IP) in a reference dosage of 1 mg/kg 30 min before the rats were tested on the elevated plus-maze for 5 min. The treatment with DZ elevated the time spent on the open arms and excursions into the end of the open arms, increased scanning over the edge of an open arm, and decreased risk-assessment from an enclosed arm. ZC was administered intragastrically (IG) in four doses ranging between 0.5 and 100 mg/kg 60 min prior to plus-maze testing. The treatment with 0.5 mg/kg ZC elevated the time spent on the open arms and excursions into the end of the open arms; at the high dosage of 100 mg/kg, ZC led to fewer excursions to and less scanning of the open arms. Injection of 1 or 10 mg/kg ZC had no significant effect on the behavior in the maze. These data provide evidence that ZC has anxiolytic effects in the elevated plus-maze comparable to those of DZ, but that in high dosage the phytopharmacon may also have anxiogenic properties. The anxiolytic-like effects of ZC are discussed with regard to the known antiserotonergic action of ginger and Ginkgo biloba.

Reinforcing effects of neurokinin substance P in the ventral pallidum : Mediation by the tachykinin NK1 receptor

The neurokinin substance P has reinforcing effects when administered into the nucleus basalis of the rats ventral pallidum and these effects are encoded by its carboxy-terminal amino acid sequence. The present study examined the effect of prior treatment with the tachykinin NK1 receptor antagonist WIN51,708 on the conditioned place preference produced by intrabasalis injection of substance P and its carboxy-terminal heptapeptide analog dimethyl-C7. Pretreatment with WIN51,708 (10 and 20 mg/kg, i.p.) dose-dependently reversed the place preference produced by intrabasalis substance P (0.74 pmol). The carboxy-terminal analog dimethyl-C7 (0.74 pmol) was also found to act as a reinforcer following injection into the nucleus basalis region, but unlike for substance P, the behavioral effects of dimethyl-C7 could not be completely antagonized by joint administration of the NK1 antagonist. When injected alone, WIN51,708 did not influence the preference behavior. These findings suggest that the reinforcing effects of substance P in the nucleus basalis region might be mediated via NK receptive sites. The failure of WIN51,708 to completely antagonize the behavioral effects of dimethyl-C7 is interesting in the light of evidence, indicating that the carboxy-terminal substance P analog shows higher affinity for the tachykinin NK3 than for the NK1 receptor subtype.

Anxiolytic-like behavior after lesion of the tuberomammillary nucleus E2-region

Abstract The tuberomammillary nucleus (TM), located in the posterior hypothalamic region, consists of five subgroups and is the only known source of brain histamine. In the present experiment, rats received bilateral ibotenic acid or sham lesions in the rostroventral part of the TM (E2-region). Three weeks later they were tested on the elevated plus-maze test of fear and anxiety. Lesions in the tuberomammillary E2-region elevated the time spent on the open arms, as well as excursions into the end of the open arms, increased scanning over the edge of an open arm, and decreased risk-assessment from an enclosed arm. Thus, partial destruction of TM intrinsic neurons can induce anxiolytic-like effects which are possibly related to a lesion-induced reduction of histaminergic activity.

Reinforcing properties of substance P in the region of the nucleus basalis magnocellularis in rats

The conditioned place preference paradigm was used to assess the reinforcing properties of substance P, injected unilaterally into the region of the nucleus basalis magnocellularis of rats. Over three baseline trials the rats spent more time in either the black (in most cases) or white compartment of the test box (i.e. preferred one compartment). On Day 4 the animals were injected with substance P (1 ng, 100 ng) or vehicle (0.5 microliter) and placed into their non-preferred compartment for 10 min. On Day 5 the positive reinforcing effect of 1 ng substance P was reflected by an increase in the amount of time spent in the compartment in which substance P was administered, as well as by a reversal of the place preference shown during baseline trials. Thus, the injection of substance P into the region of the nucleus basalis may have reinforcing properties in addition to its memory promoting effects that were reported previously.