Gábor L. Kovács

Effect of oxytocin and vasopressin on memory consolidation: sites of action and catecholaminergic correlates after local microinjection into limbic-midbrain structures

The effects of local postlearning microinjections of arginine-vasopressin (AVP) and oxytocin (OXT) on one-trial learning passive avoidance behavior and the influence of AVP on alpha-MPT-induced disappearance of norepinephrine (NE) and dopamine (DA) in discrete brain regions have been studied in the rat. OXT injected bilaterally in the hippocampal dentate gyrus (25-25 pg) or in the midbrain dorsal raphe nucleus (50 pg) significantly attenuated passive avoidance behavior. Facilitation of passive avoidance behavior was observed when the peptide was injected into the dorsal septal nucleus. AVP facilitated passive avoidance behavior when administered into the hippocampal dentate gyrus, dorsal raphe nucleus or dorsal septal nucleus. Injection of either neuropeptides into the central amygdaloid nucleus appeared to be ineffective. One week after the behavioral experiments a repeated injection of AVP into the hippocampal dentate gyrus increased the disappearance of NE in the dentate gyrus and in the nucleus ruber. An injection into the dorsal septal nuclei decreased the NE disappearance in the dorsal septal nucleus itself and increased it in the nucleus ruber. Injection in the dorsal raphe nucleus led to an increase in the disappearance of DA in the locus coeruleus and in the nucleus ruber. It is concluded that memory consolidation can be oppositely influenced by local application of minute amounts of either OXT or AVP into certain limbic-midbrain structures, suggesting an involvement of these brain regions in the memory effects of these peptides. Modulation of catecholamine turnover in specific brain areas after AVP administration may be related to this behavioral effect.

Neuroleptic activity of the neuropeptide β-LPH62–77 ([Des-Tyr1]γ-endorphin; DTγE)

In contrast to β-endorphin, α-endorphin, β-LPH61–69 and Met-enkephalin which delay extinction of pole-jumping avoidance behavior (De Wied et al., 1978), γ-endorphin given either subcutaneously (30 ng/rat) or intraventricularly (0.3 ng/rat) facilitated extinction. Removal of the N-terminal amino acid residue tyrosine — yielding the neuropeptide [Des-Tyr1]γ-endorphin (DTγE) — which destroys the opiate-like activity as determined on the electrically driven guinea pig ileum, potentiated the facilitating effect of γ-endorphin on pole-jumping avoidance behavior. Observations on passive avoidance behavior gave essentially the same results. Whereas α-endorphin facilitated this behavior. DTγE attenuated passive avoidance behavior. Amounts of γ-endorphin and DTγE which were highly active on extinction of pole-jumping avoidance behavior (0.3 μg s.c. per rat) were without effect on gross behavior in an open field. Much higher amounts (10–50 μg s.c. per rat) also failed to affect the rate of ambulation in an open field. In relatively high doses (20 μg i.v.t. or 50 μg s.c. per rat), γ-endorphin and in particular DTγE were positive in the various “grip tests”. Haloperidol given s.c. (0.03–0.1 μg/rat) facilitated extinction of pole-jumping avoidance behavior and attenuated passive avoidance behavior. The same amounts decreased ambulation in an open field. In higher doses haloperidol was active in the “grip tests” but in addition caused severe immobility, ptosis and extension of the lower limbs. Intraventricularly administered morphine or β-endorphin induced wide open eyes, exophthalmus, rigidity and reduced reflexes, in contrast to γ-endorphin and DTγE which did not produce such effects. These results are interpreted to indicate that DTγE or a closely related peptide is an endogenous neuroleptic. It may be that a reduced availability as a result of an inborn error in the generation of DTγE is an etiological factor in psychopathological states for which neuroleptic drugs are beneficial.

Facilitation of memory consolidation by vasopressin: Mediation by terminals of the dorsal noradrenergic bundle?

Administration of arginine-vasopressin (AVP, 5 micrograms, s.c.) immediately after the learning trial results in a long-term facilitation of a one-trial learning passive avoidance response. This effect of AVP is absent in animals with prior destruction of the ascending dorsal noradrenergic bundle by bilateral microinjection of 6-hydroxydopamine (6-OHDA). Postlearning local microinjection of a minute amount of AVP via chronically implanted cannulae into the locus coeruleus did not influence passive avoidance behavior. Upon injection into the midbrain dorsal raphe nucleus, however AVP facilitated passive avoidance behavior. This effect, however, was absent in rats receiving previous microinjection of 5,6-dihydroxytryptamine (5,6-DHT) or of 6-OHDA into the dorsal raphe nucleus. Bilateral 6-OHDA-induced lesions of the nucleus accumbens or 5,6-DHT-induced destruction of the dorsal raphe nucleus did not prevent the effect of AVP administered subcutaneously. The data suggest that vasopressin facilitates memory consolidation processes by modulating noradrenergic neurotransmission in terminals of the dorsal noradrenergic bundle. The serotoninergic neuronal network originating from the dorsal raphe nucleus has a secondary--norepinephrine-mediated--influence upon these processes.

Aldosterone blocks the response to corticosterone in the raphe-hippocampal serotonin system

The accumulation of serotonin induced by the monoamino oxidase inhibitor pargyline was used as an index for 5-HT turnover in the dorsal hippocampus and raphe area. A low dose of corticosterone administered s.c. immediately after adrenalectomy significantly increased serotonin turnover in both regions over the subsequent 1 h interval. The same dose of aldosterone was ineffective, but pretreatment with aldosterone blocked the serotonin response to corticosterone in the acutely adrenalectomized rat. [3H]Corticosterone administered to adrenalectomized rats was not retained by cell nuclei of the raphe area in a limited capacity manner as occurred in the hippocampus. Pretreatment with aldosterone blocked the uptake of [3H]corticosterone in hippocampal cell nuclei. It is concluded that corticosterone triggers a serotonin response and that the specificity of the corticosterone action suggests involvement of the steroid receptor system located postsynaptically to the raphe-hippocampal serotonin projection.

The effects of vasopressin on memory processes: The role of noradrenergic neurotransmission

Publisher Summary Electrophysiological findings indicate an action of vasopressin on the central nervous system: the neuronal activities of the hypothalamus and cortex are influenced by the peptide. With single treatments with the peptide at various time intervals after the single learning trial, the critical period of the effect of vasopressin could be determined. Treatment given immediately after the learning trial appeared to be most effective. The effect of the peptide disappeared 6 h after the trial. As consolidation of memory takes place within the first few hours after learning, the conclusion that vasopressin facilitates memory consolidation was justified. Vasopressin affects not only consolidation, but also retrieval processes. Vasopressin is not the only peptide of the posterior pituitary gland that influences learning and memory processes. The other physiologically secreted neuropeptide, oxytocin facilitates the extinction of an active avoidance reaction and attenuates passive avoidance behavior in various one-trial learning avoidance paradigms; thus, the two neuropeptides, oxytocin and vasopressin, affect behavioral processes in opposite ways. Vasopressin treatment facilitates memory consolidation processes via modulation of the noradrenergic neurotransmission in limbic midbrain terminals of the dorsal noradrenergic bundle.

Facilitation of avoidance behavior by vasopressin fragments microinjected into limbic-midbrain structures

Effects of arginine vasopressin (AVP1-9) and its behaviorally active fragments [Cyt6]AVP5-9 and [Cyt6]AVP5-8 were studied on the retention of one-trial learning passive avoidance behavior in rats. Peptides were microinjected into various limbic and midbrain structures (ventral or dorsal hippocampus or the dorsal raphe nucleus) and were administered either immediately after the learning trial (post-learning treatment) or shortly before the 24 h retention session (pre-retention treatment). Doses for intracerebral microinjections were selected after preliminary experiments with subcutaneous and intracerebroventricular peptide administration. AVP1-9 facilitated passive avoidance behavior when the peptide was microinjected into either brain structure, however, the ventral hippocampus appeared to be the most sensitive. In this limbic region, AVP1-9 facilitated passive avoidance behavior in an amount of 8 pg (bilaterally), both when given as post-learning or pre-retention treatment. [Cyt6]AVP5-9 and [Cyt6]AVP5-8 were more effective than the parent nonapeptide in terms that a lower amount of these peptide fragments facilitated passive avoidance behavior in all brain regions investigated. The ventral hippocampus appeared to be the most sensitive brain site for the behaviorally active vasopressin fragments as well. Following microinjections into the ventral hippocampus, [Cyt6]AVP5-8 was more effective in a post-learning than in a pre-retention treatment schedule. [Cyt6]AVP5-9 on the other hand was more effective when injected shortly before the retention trial. The data indicate that limbic-midbrain structures are sensitive to AVP1-9 and behaviorally active putative metabolites of this neuropeptide. The active fragments selectively influence different phases of information processing upon limbic microinjections.

Hormonally active arginine-vasopressin suppresses endotoxin-induced fever in rats: lack of effect of oxytocin and a behaviorally active vasopressin fragment.

Vasopressin and oxytocin modulate memory processes which effects are dissociated from the typical peripheral endocrine effects of these neuropeptides. Recently, vasopressin has been implicated in the regulation of body temperature. In view of this, experiments were designed to determine whether the antipyretic effect of vasopressin was related to the action of the neuropeptide on memory processes. Fever was induced in rats by intracerebroventricular (i.c.v.) injection of 10 ng bacterial endotoxin (ET), which resulted in a rapid rise in colonic temperature. A second i.c.v. injection 15 min after ET administration of graded amounts (0.01, 0,1, 1 and 100 ng) or arginine-vasopressin (AVP) suppresses ET-induced fever in a dose-dependent manner, 1 ng being the minimally effective amount. Equivalent amounts of des-9-glycinamide-arginine-vasopressin (DG-AVP) or oxytocin (OXT) were ineffective. Large amounts (1,000 ng) of the latter two peptides, however, transiently mimicked the effect of AVP. On one-trial learning passive avoidance behavior, the neurohypophyseal peptides exerted a completely different pattern of effects. AVP and DG-AVP induced a dose-dependent facilitation, while OXT resulted in a dose-dependent attenuation of passive avoidance behavior. These findings suggest that AVP-induced antipyresis is related to the hormonally active AVP and dissociated from the effects of neurohypophyseal hormones and hormone fragments on other CNS processes-like learning and memory.

Effects of amphetamine and haloperidol on avoidance behavior and exploratory activity

The effect of graded doses of D-amphetamine and haloperidol were tested on retention of a one trial learning passive avoidance response, on extinction of pole-jumping active avoidance behavior and on open-field activity. Low doses of amphetamine (10 microgram/animal) increased passive avoidance latency when given s.c. 1 h prior to the retention test. Higher doses (20 and 1000 microgram/animal) caused a bimodal distribution of avoidance latencies. Haloperidol (0.03 or 1.0 microgram/animal) significantly attenuated passive avoidance behavior. Amphetamine caused a delay of extinction of pole-jumping avoidance behavior in a dose-dependent manner (10, 30 or 90 microgram per rat). Conversely, haloperidol induced a dose-dependent facilitation of extinction (0.03 or 0.1 microgram per rat). Open-field activity was not significantly affected by 30 microgram amphetamine or 0.03 microgram haloperidol; 90 microgram amphetamine significantly increased rearing activity and 0.1 microgram haloperidol decreased ambulation. The data show that passive and active avoidance behavior are sensitive measures to test the activity of psychomotor stimulant and neuroleptic drugs. Exploratory behavior allows more specific behavioral effects to be dissociated from locomotor influences.

Microinjection of arginine8-vasopressin antiserum into the dorsal hippocampus attenuates passive avoidance behavior in rats

Antiserum to arginine8-vasopressin was microinjected bilaterally into the dentate gyrus of the dorsal hippocampus and the effect of passive avoidance behavior was studied. After the single learning trial of a passive avoidance response, immediate bilateral injection of 1 microliter antiserum (diluted to 1/50) attenuated passive avoidance responding 24 hr later. In immunocytochemical control studies with injection of undiluted antiserum into the dentate gyrus a spreading was observed towards the ventral hippocampus and the dorsal septum. Additionally, administration into the lateral ventricle of 2 microliters of 1/50 dilution of the antiserum did not affect the behavior. For an attenuation of passive avoidance behavior via intraventricular injection, 2 microliters of a 1/10 dilution of anti-AVP was required. These data suggest that endogenous vasopressin in the septo-hippocampal system might be involved in memory processes.

Passive avoidance performance correlates with catecholamine turnover in discrete limbic brain regions

Abstract Experimentally naive male rats were sequentially tested for an exploratory (open-field) and a one-trial learning passive avoidance behavior. Subsequently, α-MPT-induced disappearance of noradrenaline (NA) and dopamine (DA) was determined in microdissected brain regions. The animals were classified as good or poor avoiders on the basis of their performance in passive avoidance retention test. Trained controls were subjected to the same training except of electric foot-shock during the learning trial. The rate constant of NA disappearance was higher in the hippocampal dentate gyrus of the good vs. poor avoiders. In the good avoiders, the rate constant of DA disappearance was significantly higher in the central nucleus of the amygdala. The different turnover of catecholamines in the dorsal hippocampus and the amygdala in relation to passive avoidance performance suggests that individual differences in memory and/or learning may correlate with the catecholamine turnover of certain limbic structures.