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PubMed2003

Nerve growth factor attenuates hippocampal cholinergic deficits and operant learning impairment in rats with entorhinal cortex lesions.

In the present study we investigated whether continuous intraventricular nerve growth factor (NGF) infusion could ameliorate hippocampal cholinergic deficits and learning impairment following entorhinal cortex lesions. Rats with such lesions received continuous intraventricular infusions of NGF or vehicle. Unlesioned rats with a sham operation were studied as controls. After learning sessions, a dialysis probe was implanted in the CA3 hippocampal region. In addition, brain sections were stained for synaptophysin immunoreactivity. In rats undergoing surgical procedures similar to those in the behavioral study, brains were processed for acetylcholinesterase (AChE) histochemistry. NGF-treated rats showed partial amelioration of lesion-associated hippocampal acetylcholine (ACh) efflux deficits and fixed-interval schedule learning impairment compared with vehicle-treated rats. Histochemical, immunohistologic, and microdensitometric analyses confirmed greater density of AChE-positive fibers and synaptophysin immunoreactivity in CA3, in NGF-treated rats relative to vehicle-treated rats, although not as great as in sham-operation rats, indicating partial recovery in NGF-treated rats. These results suggest that enhanced performance of the learning task with NGF treatment was related to improved hippocampal cholinergic function: specifically, increased cholinergic neurotransmission resulting from NGF effects on cholinergic neurons and presynaptic terminals.

Acetylcholine↗

PubMed1992

Intraventricular administration of thyrotrophin-releasing hormone (TRH) suppresses prolactin secretion and synthesis: a possible involvement of dopamine release by TRH from rat hypothalamus.

The administration of thyrotrophin-releasing hormone (TRH) causes a variety of dopamine-related biological events. To understand the specific role of TRH on rat hypothalamic dopamine neurones, we examined the in-vivo effects of intraventricular (i.c.v.) infusion of TRH on the release and synthesis of prolactin in the rat pituitary gland and on the changes in binding of [3H]MeTRH and dopamine turnover rates in rat hypothalamus. We have also examined the in-vitro effects of TRH on the release of [3H]dopamine from dispersed tuberoinfundibular dopamine neurones. Female rats were treated with i.c.v. infusions of 1 mumol TRH/1 daily for 1, 3 and 7 days using Alzet osmotic pumps. Following 7 days of treatment the serum prolactin concentrations were significantly decreased. A reduction in hypothalamic TRH-binding sites (Bmax) was also apparent but the dissociation constant (Kd) was unaffected. Northern blot analysis of total RNA isolated from the pituitary glands of control animals using 32P-labelled prolactin cDNA as a probe indicated the presence of three species of prolactin gene transcripts of approximately 3.7, 2.0 and 1.0 kb in size, and these were decreased by TRH treatment. We examined the turnover rate of dopamine in the rat hypothalamus when TRH was administered i.c.v. for 7 days. There was a significant increase in 3,4-dihydroxyphenylacetic acid/dopamine ratio with TRH treatment. Moreover, exposure to TRH stimulated [3H]dopamine release from rat tuberoinfundibular neurones in a time- and dose-dependent manner. Dopamine receptor antagonists such as SCH23390 and (-)sulpiride, and other neuropeptides such as vasoactive intestinal peptide and oxytocin did not affect TRH-stimulated [3H]dopamine release.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed2003

Locomotor stimulant effects of intraventricular injections of low doses of ethanol in rats: acute and repeated administration.

RATIONALE: Low doses of ethanol stimulate locomotion in mice, but in rats the typical response to peripheral ethanol administration is a dose-dependent suppression of locomotion. Moreover, chronic ethanol administration fails to produce signs of locomotor sensitization in rats. OBJECTIVE: The present study was undertaken to determine whether intraventricular (i.c.v.) infusions of low doses of ethanol (as determined by comparisons with systemic doses, and by analyses of brain extract ethanol levels) could increase locomotor activity in rats after acute or repeated administration. METHODS: Male rats received acute doses of ethanol i.p. (0.0, 0.25, 0.5, 1.0, or 2.0 g/kg) or i.c.v. (0.0, 0.7, 1.4, or 2.8 micromol) and were tested for motor activity. In a third experiment, repeated i.c.v. vehicle or ethanol (2.8 micromol) was administered for 15 sessions over a 30-day period, and motor activity was recorded. This phase was followed by a single challenge session, in which a low dose of ethanol (0.7 micromol) was injected i.c.v. to both groups of rats. RESULTS: Rats injected with i.p. ethanol showed no increase in activity at low doses, with higher doses suppressing activity. In contrast, i.c.v. injections of low doses of ethanol increased motor activity. After repeated administration, ethanol-treated rats were more sensitive than control-treated rats to the locomotor stimulant effect of ethanol. CONCLUSIONS: These results demonstrate that central administration of low doses of ethanol can increase locomotor activity in rats and suggest that i.c.v. ethanol can produce some signs of motor sensitization, a characteristic that has been related to the potential addictive properties of many drugs.

Animals↗

PubMed2003

Behavioral effects of intraventricular injections of low doses of ethanol, acetaldehyde, and acetate in rats: studies with low and high rate operant schedules.

Although ethanol is typically classed as a sedative-hypnotic, low doses of ethanol have been shown to stimulate locomotor activity in mice. However, in rats the typical response to peripheral administration of ethanol is a dose-dependent suppression of motor activity and operant responding. The present study was undertaken to determine the effects of intraventricular (ICV) infusions of ethanol, acetaldehyde, and acetate on operant performance in rats. ICV injections of ethanol, acetaldehyde, or acetate were given to rats previously trained on either a differential-reinforcement-of-low-rates-of-responding (DRL) 30-s schedule, which generates low rates of responding, or a fixed ratio 5 (FR5) schedule, which generates relatively high rates. Ethanol, acetaldehyde, and acetate all produced a rate-increasing effect in rats on the DRL 30-s schedule at moderate doses (2.8 and 1.4 micromol, respectively). Acetate also produced a rate-decreasing effect on the DRL 30-s schedule at a larger dose (8.8 micromol). Performance on the FR5 schedule was unaltered by ethanol and acetaldehyde, even at doses as high as 17.6 micromol. However, acetate produced a rate-decreasing effect on the FR5 schedule at doses of 4.4, 5.6, and 8.8 micromol. Central administration of low doses of ethanol and its metabolites can increase operant responding on some schedules in rats. Acetate is the substance that is most potent for producing rate-suppressing effects. These results indicate that the major metabolites of ethanol are pharmacologically active when injected into the brain, and suggest that acetate may mediate some of the rate-suppressing effects of ethanol, such as sedation, ataxia or motor slowing.

Acetaldehyde↗

PubMed1978

Continuity between the ventricular and subarachnoid cerebrospinal fluid in an amphibian, Rana pipiens.

Continuity between the ventricular and subarachnoid cerebrospinal fluid has been investigated in Rana pipiens. The structure of the posterior tela, a deficient membrane situated at the extreme caudal end of the roof of the fourth ventricle, has been studied using whole membrane mounts and by light microscopy of resin embedded tissue. The ependymal component consists of columnar and rounded cells which form a regular 'syncytium' enclosing round and oval fenestrations. Small fenestrations are covered on the subarachnoid side by elongated pial cells and thus do not give total continuity between the fourth ventricle and the subarachnoid space. Large fenestrations, on the other hand, are accompanied by equivalent pial fenestrations giving direct access between the fluid compartments. Towards the caudal end the fenestrations break up and the numbers of ependymal and pial cells decrease, the caudal end itself being characterised by a small remaining clump of ependyma and pia or of pia alone. Flow through the tela has been studied using fluorescein-labelled dextran placed in the intraventricular space. Infusion into the lateral ventricle and subsequent localisation by fluorescence microscopy shows the marker to be in the fourth ventricle, in the fenestrations of the posterior tela and in the subarachnoid space overlying the tela. Infusion of the marker followed by freezing and examination of the cut heads on a freezing microtome, shows fluorescence throughout the ventricular system, in the subarachnoid space adjacent to the posterior tela and also along the dorsal subarachnoid space of the spinal cord.

Animals↗

PubMed1997

Ameliorative influence of a nootropic drug on motor activity of rats after bilateral carotid artery occlusion.

The effects of the peptidergic nootropic drug Cerebrolysin on spatial memory and motor activity were examined in intact and ischemic rats. Ischemic-hypoxic damage was induced by injection of Na-cyanide followed by bilateral occlusion of common carotid arteries. Immediately afterwards Cerebrolysin or saline was administered, either by continuous intraventricular (i.v.) infusion or by daily intraperitoneal (i.p.) injection. Rats were tested for spatial memory and motor activity in the Morris water maze on days 3 and 4 post-surgery. The best dose of the substance for i.p. administration was known from previous studies. Therefore we had to investigate the dose-response-relationship and tolerability of the drug after i.v. administration in intact rats. Infusion (i.v.) of a high dose of Cerebrolysin (0.57 mg/day) decreased motor activity and spatial memory of intact rats (p < 0.01 and p < 0.05, respectively) but low dose of Cerebrolysin was well tolerated in the intact animals. Ischemia led to deterioration of motor activity in control rats (p < 0.01). Cerebrolysin significantly counteracted deleterious motor changes due to ischemia up to the level of intact controls after both i.v. infusion (0.0057 mg/day) and daily i.p. drug administration (100 mg/kg bw and day) indicating an accelerating recovery after ischemia.

Amino Acids↗

PubMed1996

Intraventricular administration of estradiol modulates rat prolactin secretion and synthesis.

The effect of estradiol (E2) on rat tuberoinfundibular dopaminergic (TIDA) neurons was examined in vivo, employing chronic intraventricular (i.c.v.) infusion technique using an osmotic mini-pump. The activity of TIDA neurons was assessed by the release and synthesis of prolactin (PRL) in the rat pituitary gland and by the changes in the 3, 4-dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) levels and in the DOPAC/DA ratio in the rat hypothalamus. We also examined the [3H] E2 binding in the rat hypothalamus. Ovariectomized female Wistar rats with E2 replacement were treated with daily i.c.v. infusion of 1 microM of E2 or saline vehicle for 1, 3, and 7 days using the Alzet osmotic mini-pump and brain infusion kit. At 1 day of i.c.v. infusion of E2, the serum PRL level was significantly decreased compared with that in the vehicle group. Northern blot analysis of the total RNA isolated from the pituitary glands demonstrated a decrease in the PRL gene transcript level in the E2 group. At 3 days of E2 treatment, however, the serum PRL level was significantly increased compared with that of the vehicle-injected group and Northern blot analysis also demonstrated that the PRL gene transcript level was increased in the E2 group. At 7 days of E2 administration, there were no significant differences between the E2 and vehicle groups in either serum PRL or PRL gene transcript levels. There was a significant increase in the DOPAC/DA ratio after 1 day in the E2 group. However, no significant effects of E2 on this ratio were observed at 3 and 7 days of treatment. The DOPAC concentration in the E2 group was significantly increased at day 1 and significantly decreased at day 3, compared with that of the respective time in vehicle group. At day 7 there was no significant change in DOPAC concentration in either groups. The DA concentrations in the hypothalamus was not changed on any day in either group. Specific [3H] E2 binding was observed in the rat hypothalamus. These data suggest that E2 may have a biphasic effect on the accumulation of PRL gene transcripts and on the PRL secretion in the rat pituitary by first stimulating and then inhibiting the TIDA neuronal activity.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1982

Immunohistochemical studies of intrahypothalamic somatostatin-containing neurons in rat.

Intrahypothalamic somatostatin-containing neurons were investigated immunohistochemically. In intact rats, immunoreactive cell bodies appeared in the rostral periventricular area, and immunoreactive beaded fibers were observed to terminate in the median eminence and to form delicate networks surrounding immunonegative cell bodies within the medial preoptic, suprachiasmatic, arcuate, ventromedial and premammillary nuclei. Intraventricular colchicine infusion resulted in the appearance of immunoreactive cell bodies in the arcuate, ventromedial and suprachiasmatic nuclei, and an increase in the number of cell bodies seen in the periventricular area. Complete deafferentation of the medial-basal hypothalamus excluding the rostral periventricular area caused the immunoreactive structures in the median eminence to disappear and enhanced the staining of periventricular cell bodies. In the arcuate and ventromedial nuclei, the immunoreactive fiber networks were left intact and the immunoreactive cell bodies were occasionally recognized. Horizontal knife cut between the arcuate nuclei and median eminence did not alter immunoreactivity in either region. Neonatal administration of MSG caused only the disappearance of arcuate nuclei. The results indicate that two kinds of somatostatin neuronal systems exist in rat hypothalamus: one is involved in the production of hormonal somatostatin and the other serves for the regulation of neuronal activities in restricted hypothalamic nuclei.

Animals↗

PubMed1990

NGF-induced remodeling of mature uninjured axon collaterals.

Accumulation of nerve growth factor (NGF) within the rat hippocampus following septal denervation is thought to contribute to sympathetic axon ingrowth. However, intraventricular NGF infusion, which results in elevated hippocampal NGF, fails to elicit such sprouting, although it increases innervation of the extracerebral vasculature. To determine whether or not NGF would stimulate sympathohippocampal sprouting, we infused NGF after sprouting was initiated. Surprisingly, NGF reduced the amount of hippocampal sprouting and, when infused at the time of lesion, delayed its onset while, at the same time, stimulating perivascular sprouting. Since NGF did not prevent ingrowth into the hippocampus from transplanted sympathetic ganglia, the reduction in sympathetic hippocampal fibers from intact ganglia appears to result from the proliferation of vascular fibers. Thus, changes in trophic support (NGF levels) appear to be sufficient to produce remodeling of mature, uninjured sympathetic arbors. Such trophomorphism may underlie collateral elimination during normal development and injury-induced neuronal rearrangements.

Animals↗

PubMed1989

Norepinephrine stimulates behavioral activation in rats following depletion of nucleus accumbens dopamine.

Intraventricular (ICV) infusion of norepinephrine (NE) produces locomotor activation in rats that is greatly potentiated by prior depletion of whole brain catecholamines by ICV injection of 6-hydroxydopamine (6OHDA). In a series of experiments, the neural substrates of this potentiated locomotor response were examined. One group of animals received ICV infusion of 6OHDA to deplete whole brain catecholamines. Other rats were pretreated with desmethylimipramine (DMI) and then received 6OHDA infusions into the nucleus accumbens (NAC) to selectively deplete dopamine (DA) from this region. One week later, all animals were tested for their locomotor response to ICV infusion of NE. Both groups of rats exhibited a greatly potentiated locomotor response to ICV NE compared to corresponding sham-lesioned animals. Both ICV and NAC 6OHDA-injected animals also exhibited a supersensitive locomotor response to the DA receptor agonist apomorphine. These results suggest that NE-induced locomotor activation in ICV 6OHDA-treated rats results from the actions of NE on supersensitive NAC DA receptors.

Animals↗

PubMed1994

Dopaminergic and muscarinic regulation of striatal enkephalin and substance P messenger RNAs following striatal dopamine denervation: effects of systemic and central administration of quinpirole and scopolamine.

Striatal dopamine depletion produces an increase in enkephalin and a decrease in substance P messenger RNAs. Subsequent systemic administration of either the D2 dopamine agonist, quinpirole, or the muscarinic antagonist, scopolamine, results in the reduction of the lesion-induced elevation in striatal enkephalin messenger RNA. These changes in enkephalin messenger RNA levels may be mediated solely within the striatum or through trans-synaptic circuits involving the striatum. To dissociate these possibilities, we have compared the effects of systemic and central administration of quinpirole and scopolamine on striatal enkephalin and substance P messenger RNAs using in situ hybridization histochemistry. Systemic administration of both quinpirole and scopolamine blocked the elevation of striatal enkephalin messenger RNA normally observed in 6-hydroxydopamine-lesioned rats. In addition, high doses of systemic scopolamine (25 and 50 mg/kg per day) prevented the lesion-induced decrease in striatal substance P messenger RNA levels. In order to determine whether the effects of these drugs are mediated directly within the striatum, central administration of quinpirole and scopolamine were compared. In contrast to systemic administration, intraventricular and intrastriatal infusion of quinpirole but not scopolamine prevented the lesion-induced change in striatal enkephalin messenger RNA. However, neither quinpirole nor scopolamine administered centrally affected the level of substance P messenger RNA in the striatum of 6-hydroxydopamine-induced lesioned animals. Together, these data suggest that changes in D2 receptor activation directly in the striatum are responsible for the effects of quinpirole on enkephalin messenger RNA. In contrast, the effect of systemic scopolamine on striatal enkephalin and substance P messenger RNAs may not be mediated within the striatum.

Animals↗

PubMed2016

Characterization of a novel adeno-associated viral vector with preferential oligodendrocyte tropism.

No adeno-associated virus (AAV) capsid has been described in the literature to exhibit a primary oligodendrocyte tropism when a constitutive promoter drives gene expression, which is a significant barrier for efficient in vivo oligodendrocyte gene transfer. The vast majority of AAV vectors, such as AAV1, 2, 5, 6, 8 or 9, exhibit a dominant neuronal tropism in the central nervous system. However, a novel AAV capsid (Olig001) generated using capsid shuffling and directed evolution was recovered after rat intravenous delivery and subsequent capsid clone rescue, which exhibited a >95% tropism for striatal oligodendrocytes after rat intracranial infusion where a constitutive promoter drove gene expression. Olig001 contains a chimeric mixture of AAV1, 2, 6, 8 and 9, but unlike these parental serotypes after intravenous administration Olig001 has very low affinity for peripheral organs, especially the liver. Furthermore, in mixed glial cell cultures, Olig001 exhibits a 9-fold greater binding when compared with AAV8. This novel oligodendrocyte-preferring AAV vector exhibits characteristics that are a marked departure from previously described AAV serotypes.

Animals↗

PubMed1989

Neuronotrophic factors in cellular functional and cognitive repair of adult brain.

Neuronotrophic factors (NTFs) are special proteins that control survival, growth and functional competence of selected neuronal populations during their development. A recently articulated CNS neuronotrophic hypothesis proposes that adult central neurons continue to be dependent on endogenous supplies of their NTFs for maintenance, function and repair capabilities. The hypothesis has important implications in two major neurologic areas:i) involutive and degenerative processes and ii) CNS regeneration. Strong evidence favoring this general hypothesis has come from the recently observed effects of Nerve Growth Factor (NGF) on the forebrain cholinergic neurons in adult rats. Medial septum cholinergic (MSC) neuros project to the hippocampal formation largely via the fimbria-fornix tract. Transection of the fimbria-fornix interrupts the retrograde delivery of hippocampal NGF to the MSC neuronal somata, leading to reduction in their cholinergic enzyme and, possibly, progressive cellular atrophy. Intraventricular administration of exogenous NGF compensates for the loss of endogenous NGF supply and can reverse as well as protect against the neuronal damage. In a second model, intraventricular NGF infusions were applied to 2-year old (aged) rats displaying a deficient cognitive behavior. Four-weeks administration resulted in i) a correction of the cognitive deficit and ii) a increased body size of basal forebrain cholinergic neurons Cholinergic deficits are known to accompany cognitive deficits both in the brain aging process and Alzheimer's disease. The NGF effects on aged rats, therefore, strongly encourage the possibility of future clinical application in both such cases of brain dysfunction.

Aging↗

PubMed1989

NGF Amplifies Expression of NGF Receptor Messenger RNA in Forebrain Cholinergic Neurons of Rats.

In order to study the ligand-mediated regulation of NGF receptors in vivo, we assessed NGF receptor mRNA in the septal area of both neonatal and adult rats following intraventricular NGF administration. In neonatal rats NGF treatment, in comparison with cytochrome c, elicited a pronounced augmentation in the level of NGF receptor mRNA. A similar effect was also observed following continuous intraventricular NGF infusion in young adult rats. In addition, in this latter case, the increase in NGF receptor mRNA was associated with an increase in NGF receptor-related immunoreactivity, most likely associated with the cholinergic neurons, in the septal area. These results show that NGF itself may regulate expression of NGF receptor mRNA and corresponding protein levels in forebrain cholinergic neurons and suggest that NGF effects in the CNS may be mediated by an up-regulation of NGF receptors.

Journal Article↗

PubMed1992

Recent developments in peptide drug delivery to the brain.

Peptide-based therapeutics are highly water-soluble compounds that do not readily enter brain from blood owing to poor transport through the brain capillary endothelial wall, i.e., the blood-brain barrier (BBB). Strategies available for peptide drug delivery to brain include: (a) neurosurgical-based (intraventricular drug infusion, hyperosmotic opening of the BBB); (b) pharmacological-based (peptide lipidization, liposomes); and (c) physiological-based (biochemical opening of the BBB, chimeric peptides). Chimeric peptides are formed by the covalent coupling of a pharmaceutical peptide (that is normally not transported through the BBB) to a brain transport vector that undergoes absorptive-mediated or receptor-mediated transcytosis through the BBB. The most efficient brain transport vector known to date is a monoclonal antibody to the transferrin receptor, and this vector achieves a brain volume of distribution approximately 18-fold greater than the plasma space by 5 hr after a single intravenous injection of antibody. The chimeric peptides are formed generally with chemical-based linkers. However, avidin/biotin-based linkers allow for high yield coupling of drug to vector, and for the release of biologically-active peptide following cleavage of the chimeric peptide linker. These strategies may also be used for the delivery of antisense oligonucleotide-based therapeutics to brain. In conclusion, the development of efficacious neuropharmaceuticals in the future will require the development of both drug delivery and drug discovery strategies that operate in parallel.

Animals↗

PubMed1983

Hemodynamic mechanisms in CNS-induced natriuresis in the conscious rat.

These experiments were designed to determine 1) the effects of increased CSF sodium concentration on renal hemodynamics in the conscious rat, and 2) the role of the periventricular tissue surrounding the anteroventral third ventricle (AV3V) in the natriuretic and hemodynamic responses during this treatment. After electrolytic lesions of AV3V periventricular tissue or control surgery, blood pressure, glomerular filtration rate, effective renal blood flow, urine volume, and sodium and potassium excretion were measured before and during intraventricular (IVT) infusion of either isotonic or hypertonic saline solutions in conscious hydrated rats. Blood pressure, glomerular filtration rate, and sodium and potassium excretion increased during IVT infusion of concentrated sodium solutions in control rats but not in animals with lesions in the AV3V region. These data support the hypothesis that the natriuretic response to increased CSF sodium concentration in the rat is due to a pressor response and/or increased glomerular filtration rate and demonstrate that ablation of AV3V periventricular tissue blunts the natriuretic response, possibly through diminished central pressor mechanisms and/or decreased central control of glomerular filtration rate.

Animals↗

PubMed1986

1,25-Dihydroxyvitamin D3 treatment results in increased choline acetyltransferase activity in specific brain nuclei.

To better understand the role of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in brain function, the level of calcium-binding protein (CaBP) and the activities of choline acetyltransferase (CAT) and monoamine oxidase were measured in discrete brain nuclei of vitamin D-deficient and -replete male rats. The nuclei sampled were those in which receptors for 1,25-(OH)2D3 and/or vitamin D-dependent CaBP have been localized. Significant elevations in CAT activity were found in the arcuatemedian eminence and in the bed nucleus of the stria terminalis of rats made vitamin D replete by eight daily ip injections of 100 or 200 ng 1,25-(OH)2D3 as well as by constant intraventricular (ivi) infusion of 25 ng 1,25-(OH)2D3 for 7 days. The percent increase ranged from 12-45% and was related to the ip dose administered. Constant ivi of 2 mM CA2+ or 125 ng 25-hydroxyvitamin D3/day for 7 days did not alter CAT activity. No significant changes in monoamine oxidase or CaBP in discrete brain nuclei were observed with vitamin D repletion. Since the arcuate-median eminence of the hypothalamus is an important regulatory site in the neuroendocrine control of reproduction, serum testosterone was measured. Serum testosterone levels were abnormally low in the vitamin D-deficient animals, but increased 2- to 5-fold to normal values in those rats made vitamin D replete by constant ivi of 25 ng 1,25-(OH)2D3 or by ip injection of 100 or 200 ng 1,25-(OH)2D3. Patterns of serum LH paralleled those for testosterone. Our results suggest that 1,25-(OH)2D3 effects cholinergic activity in several discrete brain regions and may play a role in the neuroendocrine regulation of certain aspects of anterior pituitary gland function.

Animals↗

PubMed1993

Intraventricular administration of histidyl-proline-diketopiperazine [Cyclo(His-Pro)] suppresses prolactin secretion and synthesis: a possible role of Cyclo(His-Pro) as dopamine uptake blocker in rat hypothalamus.

Histidyl-proline-diketopiperazine [Cyclo (His-Pro) (CHP)] was discovered to be one of the metabolites of TRH. To understand the specific role of CHP in rat hypothalamic dopamine neurons, we examined the in vivo effects of intraventricular (icv) infusion of CHP on the release and synthesis of PRL in the rat pituitary and the 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine ratio in the rat hypothalamus. We also examined the in vitro effects of CHP on the release of [3H]dopamine from dispersed tuberoinfundibular dopamine neurons, [3H]dopamine reuptake in hypothalamic membrane fractions, and PRL release from rat pituitary cultured cells. Female rats were treated by icv infusion of 1 microM CHP daily for 1, 3, and 7 days, using Alzet osmotic pumps. After 1 day of treatment, the serum PRL concentration was significantly decreased. Northern blot analysis of the total RNA isolated from the pituitary glands of control animals using 32P-labeled PRL cDNA as a probe indicated the presence of PRL gene transcript, 1.0 kilobase in size, and its amount was decreased by CHP treatment. CHP did not affect [3H]dopamine release from dispersed tuberoinfundibular dopaminergic neurons at any concentration up to 1 microM. CHP did not inhibit PRL release from cultured pituitary cells at low concentrations (1-100 nM), but it stimulated PRL release at high concentrations (1 and 10 microM). We also examined the concentrations of dopamine and DOPAC in the rat hypothalamus when CHP was administered icv for 1 or 7 days. There was a significant decrease in the DOPAC/dopamine ratio after CHP treatment for 1 day. Furthermore, CHP caused dose-dependent inhibition of [3H]dopamine uptake by the rat hypothalamus similar to other dopamine uptake blockers, such as benztropine and GBR12909. These data suggest that icv administration of CHP might decrease both PRL secretion and accumulation of PRL gene transcripts in the pituitary by decreasing the DOPAC/dopamine ratio and inhibiting dopamine reuptake in the rat hypothalamus.

3,4-Dihydroxyphenylacetic Acid↗