Neuropeptides in learning and memory processes with focus on galanin.

Neuropeptides represent by far the most common signalling molecules in the central nervous system. They are involved in a wide range of physiological functions and can act as neurotransmitters, neuromodulators or hormones in the central nervous system and in the periphery. Accumulating evidence during the past 40 years has implicated a number of neuropeptides in various cognitive functions including learning and memory. A major focus has been on the possibility that neuropeptides, by coexisting with classical neurotransmitters, can modulate classical transmitter function of importance for cognition. It has become increasingly clear that most transmitter systems in the brain can release a cocktail of signalling molecules including classical transmitters and several neuropeptides. However, the neuropeptides seem to come into action mainly under conditions of severe stress or aversive events, which have linked their action also to regulation of affective components of behaviour. This paper summarises some of the results of three neuropeptides, which can impact on hippocampal cognition by intrinsic (dynorphins, nociceptin) or extrinsic (galanin) modulation. The results obtained with these neuropeptides in rodent studies indicate that they are important for various aspects of hippocampal learning and memory as well as hippocampal plasticity. Recent studies in humans have also shown that dysregulation of these neuropeptides may be of importance for both neurodegenerative and neuropsychiatric disorders associated with cognitive impairments. It is concluded that compounds acting on neuropeptide receptor subtypes will represent novel targets for a number of disorders, which involve cognitive deficiencies.

5-HT(1A) and NMDA receptors interact in the rat medial septum and modulate hippocampal-dependent spatial learning.

Cholinergic and GABAergic neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB) projecting to the hippocampus, constitute the septohippocampal projection, which is important for hippocampal-dependent learning and memory. There is also evidence for an extrinsic as well as an intrinsic glutamatergic network within the MS/vDB. GABAergic and cholinergic septohippocampal neurons express the serotonergic 5-HT(1A) receptor and most likely also glutamatergic NMDA receptors. The aim of the present study was to examine whether septal 5-HT(1A) receptors are important for hippocampal-dependent long-term memory and whether these receptors interact with glutamatergic NMDA receptor transmission in a manner important for hippocampal-dependent spatial memory. Intraseptal infusion of the 5-HT(1A) receptor agonist (R)-8-OH-DPAT (1 or 4 microg/rat) did not affect spatial learning in the water maze task but impaired emotional memory in the passive avoidance task at the higher dose tested (4 microg/rat). While intraseptal administration of (R)-8-OH-DPAT (4 microg) combined with a subthreshold dose of the NMDA receptor antagonist D-AP5 (1 microg) only marginally affected spatial acquisition, it produced a profound impairment in spatial memory. In conclusion, septal 5-HT(1A) receptors appears to play a more prominent role in emotional than in spatial memory. Importantly, septal 5-HT(1A) and NMDA receptors appear to interact in a manner, which is particularly critical for the expression or retrieval of hippocampal-dependent long-term spatial memory. It is proposed that NMDA receptor hypofunction in the septal area may unmask a negative effect of 5-HT(1A) receptor activation on memory, which may be clinically relevant.

Blockade of 5-HT 1B receptors facilitates contextual aversive learning in mice by disinhibition of cholinergic and glutamatergic neurotransmission.

Serotonergic (5-HT) neurotransmission plays a role in learning and memory processes, but the physiological role of various receptor subtypes is not well characterised. Among these, 5-HT(1B) receptors are located as autoreceptors on 5-HT axons and heteroreceptors on non-serotonergic terminals. This study examined the role of the 5-HT(1B) receptor in one-trial aversive contextual learning using the passive avoidance (PA) task in NMRI mice. Subcutaneous administration of the 5-HT(1B) receptor agonist anpirtoline (0.1-1.0mg/kg) before PA training impaired retention performance 24h later. Combined administration of anpirtoline with the selective 5-HT(1B) receptor antagonist NAS-181 (0.1-1.0mg/kg) fully blocked the impairments. Administration of NAS-181 alone dose-dependently improved PA retention performance. This facilitatory effect was blocked by subthreshold doses of both the muscarinic antagonist scopolamine (0.03 mg/kg) and the NMDA receptor antagonist MK-801 (0.03 mg/kg). NAS-181 also fully blocked the PA impairments induced by an amnesic dose of scopolamine (0.1mg/kg), when administered prior to, but not after, scopolamine. In addition, NAS-181 attenuated PA impairments induced by MK-801 (0.3mg/kg). These findings indicate that 5-HT(1B) receptors are activated at basal levels of 5-HT transmission. The facilitatory effect of NAS-181 involved alleviation of an inhibitory 5-HT tone mediated via 5-HT(1B) receptors on cholinergic and glutamatergic transmission. This disinhibition is expected to occur in neuronal circuits involved in contextual learning including the hippocampus and interconnected cortico-limbic regions. Blockade of brain 5-HT(1B) heteroreceptors may represent a novel therapeutic strategy for restoration of deficient cholinergic and glutamatergic neurotransmission contributing to memory disorders.

The role of 5-HT(1A) receptors in learning and memory.

The ascending serotonin (5-HT) neurons innervate the cerebral cortex, hippocampus, septum and amygdala, all representing brain regions associated with various domains of cognition. The 5-HT innervation is diffuse and extensively arborized with few synaptic contacts, which indicates that 5-HT can affect a large number of neurons in a paracrine mode. Serotonin signaling is mediated by 14 receptor subtypes with different functional and transductional properties. The 5-HT(1A) subtype is of particular interest, since it is one of the main mediators of the action of 5-HT. Moreover, the 5-HT(1A) receptor regulates the activity of 5-HT neurons via autoreceptors, and it regulates the function of several neurotransmitter systems via postsynaptic receptors (heteroreceptors). This review assesses the pharmacological and genetic evidence that implicates the 5-HT(1A) receptor in learning and memory. The 5-HT(1A) receptors are in the position to influence the activity of glutamatergic, cholinergic and possibly GABAergic neurons in the cerebral cortex, hippocampus and in the septohippocampal projection, thereby affecting declarative and non-declarative memory functions. Moreover, the 5-HT(1A) receptor regulates several transduction mechanisms such as kinases and immediate early genes implicated in memory formation. Based on studies in rodents the stimulation of 5-HT(1A) receptors generally produces learning impairments by interfering with memory-encoding mechanisms. In contrast, antagonists of 5-HT(1A) receptors facilitate certain types of memory by enhancing hippocampal/cortical cholinergic and/or glutamatergic neurotransmission. Some data also support a potential role for the 5-HT(1A) receptor in memory consolidation. Available results also implicate the 5-HT(1A) receptor in the retrieval of aversive or emotional memories, supporting an involvement in reconsolidation. The contribution of 5-HT(1A) receptors in cognitive impairments in various psychiatric disorders is still unclear. However, there is evidence that 5-HT(1A) receptors may play differential roles in normal brain function and in psychopathological states. Taken together, the evidence indicates that the 5-HT(1A) receptor is a target for novel therapeutic advances in several neuropsychiatric disorders characterized by various cognitive deficits.

The neuropeptide galanin as an in vivo modulator of brain 5-HT1A receptors: possible relevance for affective disorders.

The neuropeptide galanin is widely distributed throughout the central nervous system with multiple and diverse biological functions mediated by different receptor subtypes. In the rat, galanin-like immunoreactivity is expressed in a population of 5-hydroxytryptamine (5-HT, serotonin) neurons in the dorsal raphe with extensive projections to the forebrain areas, e.g., hippocampus. This review summarizes results from experimental studies in rodents showing that in vivo galanin is a potent modulator of brain 5-HT transmission, and in particular 5-HT1A receptor-mediated functions. Galanin, given intracerebroventricular (i.c.v.), was demonstrated to have strong inhibitory interactions with 5-HT1A receptor functions, particularly in the dorsal raphe but also in the hippocampus. Since pre- and postsynaptic 5-HT1A receptors in the dorsal raphe and hippocampus are implicated in the action of antidepressant drugs and in depressive disorders, it is suggested that galanin receptors may be an important target for development of novel antidepressant drugs. This view is supported by a recent study in the rat showing that the galanin antagonist M35, given i.c.v., could block the depression-like behavior in the forced swim test induced by galanin, while M35 produced an antidepressant-like effect on its own.