On the mechanism of neuroleptic induced increase in striatal dopamine release: brain dialysis provides direct evidence for mediation by autoreceptors localized on nerve terminals

The influence of sulpiride on the in vivo release of dopamine and DOPAC from the rat striatum was investigated by microdialysis. Racemic sulpiride was administered systemically (i.p.) to control rats and to rats in which a striatum was pretreated by kainic acid. In addition various concentrations (10(-8) to 10(-5) M) of the two enantiomers of sulpiride were infused into the striatum and the effects on the release of dopamine were recorded. Infusion as well as systemic administration of sulpiride caused a maximal increase in the release of dopamine of about 180-190% of basal values. A similar increase was seen in kainic acid-pretreated rats. The rises in dopamine seen after systemic administration or infusion of sulpiride were not additive, suggesting that similar mechanisms were involved. DOPAC dialysate levels also increased during infusion of the neuroleptic but the rise was significantly less when sulpiride was administered i.p. to kainic acid pretreated rats. It is concluded that the rise in dopamine release seen after neuroleptics is mediated by autoreceptors localized on nerve terminals. This implies that the well-known increase in electrical activity of dopaminergic neurons during neuroleptic treatment, is not responsible for the increased release of the transmitter.     

Interaction between estradiol and prolactin on vasoactive intestinal peptide concentrations in the hypothalamus and in the anterior pituitary of the female rat

To determine whether vasoactive intestinal peptide (VIP) can be regulated by modification of plasma estradiol and prolactin levels, VIP concentrations in various structures of the rat brain and in the pituitary were measured in hyperprolactinemic female rats by means of a specific radioimmunoassay for the peptide. In ovariectomized rats treated with estradiol (E2) implants alone and with both E2 and pituitary grafts to induce an experimental hyperprolactinemia, VIP levels decreased in the anterior and mediobasal hypothalamus and increased in the pituitary as compared to ovariectomized rats. No modification of hypothalamic VIP concentrations was observed in ovariectomized rats with pituitary grafts only, whereas a significant increase was found in the pituitary. These results suggest that, in the female rats, E2 exerts an effect on hypothalamic VIP levels, probably through indirect mechanisms, and that this action can be enhanced by elevated plasma prolactin levels.     

Comparisons between brain dopaminergic neurons of juvenile and aged rats: sex-related differences.

It is known that several aspects of dopaminergic neurotransmission deteriorate with advanced age. In the present report, we have studied the possible existence of sexual differences in these aging-induced changes. Thus, we measured several pre- and postsynaptic biochemical parameters, indicative of the activity of dopaminergic neurons, in striatum, limbic forebrain and hypothalamic-anterior pituitary area of aged (24-26 months) and young (2 months) rats of both sexes. Tyrosine hydroxylase (TH) activity, as well as the number of D2-dopaminergic receptors, decreased in the striatum of aged rats, especially in the males in which the decrease in the number of receptors was associated with an increase in their affinity. In addition, the ratio between dopamine (DA) and its intraneuronal metabolite, L-3,4-dihydroxyphenyl-acetic acid (DOPAC), which can be used as an index of neurotransmitter turnover, was increased in aged females in parallel with a decreased DA content. In the limbic forebrain, TH activity was also decreased during aging, but only in males, whereas the DOPAC/DA ratio was increased in females, although in parallel with an increased DOPAC production. Finally, in the hypothalamic-anterior pituitary area, aging only affected the females, in which increased plasma prolactin levels were observed. This effect might be the result of a low responsiveness of pituitary lactotrophs to DA released from hypothalamic neurons, in spite of high prolactin levels producing a constant, although ineffective, stimulation of the activity of these neurons, as reflected by the high DOPAC content and DOPAC/DA ratio observed in the medial basal hypothalamus. In summary, these data allow us to suggest that the activity of brain dopaminergic neurons is modified with aging and there are significant differences as a function of sex and brain area.     

Age related changes in the control of prolactin secretion in the female rat

The purpose of this investigation was to evaluate the effects of advancing age on the control of pituitary prolactin secretion. The effects of dopaminergic inhibition and estrogen stimulation of pituitary prolactin secretion were tested both in vivo and in vitro. Estrogen stimulated prolactin secretion in both old and young animals, and elevated estrogen levels in old rats may be partially responsible for elevated prolactin levels. Oral L-DOPA administration induced cycles in old rats but had no effect on prolactin levels in either old or young rats. Injections of L-DOPA lowered prolactin in young but not in old rats, while apomorphine reduced prolactin levels in both groups. The pituitaries of young rats secrete more prolactin in vitro than old pituitaries, further supporting a decrease in hypothalamic DA turnover as a cause for elevated prolactin levels in old rats.     

FSH and testosterone effects in seminiferous tubules of immature hypophysectomized rats

The effects of follicle-stimulating hormone (FSH) and testosterone on the development of the cytosolic germ cell adenylate cyclase and germ cell morphology in rats hypophysectomized at 29 days of age were studied. Following hypophysectomy, the adenylate cyclase content fell to marginal levels and germ cell development ceased at the late pachytene stage. Testosterone treatment led to a moderate increase in the cytosolic enzyme content and to progression of spermatid cell development to stages 8-12. FSH treatment with doses of 80-100 micrograms/day restored enzyme content to levels seen in control rats, as well as progression of germ cell development up to stages 15-16, i.e., to the same stages present in age-matched control (sham-operated) rats. The results indicate that in immature rats FSH is essential for spermatid cell maturation as is evidenced by its ability to stimulate the formation of cytosolic germ cell adenylate cyclase to quantitatively normal levels, as well as to stimulate the development of spermatid cells.     

Mechanism of the onset of puberty, with special reference to the dynamics of the hypothalamic gonadotropin releasing factor and pituitary gonadotropin

In vivo and in vitro studies of the dynamics of hypothalamic FSH-RF, LH-RF, PIF, and anterior pituitary FSH, LH, and prolactin during the process of sexual maturation were carried out in female Wistar-starin rats. Around the time of vaginal opening there was a wide fluctuation of hormonal values. The peak of FSH content in the anterior pituitary was on Day 25 after birth, LH peaked on Day 40, and prolactin on Day 45. Addition of crude HE (hypothalamic extract) of 20-45 day old female rats to the incubation fluid of anterior pituitary glands resulted in a rise of FSH and LH activity in the culture fluid. The greatest increase of FSH activity was seen on the addition of HE of 20-day-old rats. LH increased most on hte addition of HE in 35-day-old rats and prolactin decreased on the addition of HE in 45-day-old rats. The relationship between anterior pituitary FSH, LH, and prolactin contents and hypothalamic RF and IF is suggested.     

Functional retinal input stimulates expression of astroglial elements in the suprachiasmatic nucleus of postnatal developing rat

Astrocytes are abundant in the hypothalamic suprachiasmatic nucleus (SCN), particularly in the retinorecipient region. Using glial fibrillary acidic protein (GFAP) immunocytochemistry, we investigated the effect of light on the development of astrocytes in the SCN housing under light-dark (LD) or constant dark (DD) conditions after birth. GFAP immunoreactivity in the DD group showed lower levels than those in the LD group at P50. However, there was no difference in density of retinohypothalamic tract (RHT) terminals in the SCN between the DD and LD groups. After the adult pattern of GFAP immunoreactivity was established at P30, transferring rats to different LD conditions produced changes in GFAP immunoreactivity evident when rats were sacrificed at P50. We next examined, using a primary culture of hypothalamic astrocytes, whether neurotransmitters of RHT such as glutamate and pituitary adenylate cyclase activating polypeptide (PACAP) can stimulate GFAP expression directly. PACAP-38 increased the length and number of astrocytic processes but glutamate did not. These findings indicate that the functional aspects of RHT such as the light stimulated release of neurotransmitters is important for the development of astrocytes in rat SCN. Dynamic plasticity of astroglial elements in the SCN occurs even after GFAP shows an adult pattern.     

Regulation of pituitary adenylate cyclase activating polypeptide and its receptor type 1 after traumatic brain injury: comparison with brain-derived neurotrophic factor and the induction of neuronal cell death

Neurotrophic factors are known to promote neuronal survival during development and after acute brain injury. Recent data suggest that some neuropeptides also exhibit neurotrophic activities, as shown for the pituitary adenylate cyclase activating polypeptide, which increases the survival of various neuronal populations in culture. Employing in situ hybridization techniques, we have studied the regulation of messenger RNA for pituitary adenylate cyclase activating polypeptide and its receptor type 1 after a moderate traumatic brain injury to rat brain cortex. We have further compared their messenger RNA expression to that of brain-derived neurotrophic factor and to the amount of cell death occurring in the brain at various times after the brain injury. Levels of brain-derived neurotrophic factor messenger RNA increased rapidly within 2 h after trauma in cortex and hippocampus, and returned to control levels thereafter. The levels of messenger RNA for pituitary adenylate cyclase activating polypeptide also increased with time in the injured brains and reached maximal expression at 72 h, i.e. the end of the observation period. The alterations in pituitary adenylate cyclase activating polypeptide messenger RNA levels were particularly pronounced in the perifocal region and in the ipsilateral dentate gyrus of the brain injury. In contrast, the messenger RNA levels encoding pituitary adenylate cyclase activating polypeptide receptor type 1 first decreased after trauma and were then normalized in the dentate gyrus. There was a large increase in the number of cells labelled for DNA breaks at 12 h post-trauma, indicative of enhanced cell death. The number of labelled cells, however, decreased at later stages concomitant with an increase in the expression of pituitary adenylate cyclase activating polypeptide messenger RNA. Pituitary adenylate cyclase activating polypeptide rescued cortical neurons in cultures against ionomycin-induced cell death, supporting the concept of a neuroprotective effect for the peptide. These results demonstrate a differential regulation of messenger RNA for brain-derived neurotrophic factor and the pituitary adenylate cyclase activating polypeptide and its receptor after brain trauma. The data also suggest that pituitary adenylate cyclase activating polypeptide might have a beneficial effect in brain injury by counteracting neuronal cell death.     

Oestradiol increases baseline growth hormone levels in the male rat: possible direct action on the pituitary*

The effect of oestradiol treatment on the secretion of growth hormone (GH) was investigated in normal unrestrained male rats with chronic i. v. cannulae and in hypophysectomized male rats with autotransplanted pituitaries. The effect of gonadectomy of normal rats on the plasma GH secretory pattern was also evaluated. Baseline plasma GH levels were elevated following estradiol treatment of normal male rats (1.5 mg kg^-1 per 15 days). Gonadectomy of male rats also resulted in increased baseline GH levels, although the effect was less apparent than after oestradiol administration. The pulse height was not influenced by gonadectomy or oestradiol administration. In male rats with the pituitary autotransplanted to the kidney capsule, oestradiol caused a dose-dependent increase in plasma GH levels, while there was no such effect of testosterone. These results suggest that the stimulatory influence of oestradiol on baseline GH levels is, at least partly, due to a direct effect on the pituitary. Plasma prolactin levels were elevated in rats with pituitary transplants receiving oestradiol. It is concluded that oestrogen administration to normal male rats increases baseline plasma GH levels, possibly by an effect exerted directly at the pituitary level.     

Decreased tuberoinfundibular and pituitary dopamine and dihydroxyphenylacetic acid concentrations in rats with estrogen-induced pituitary tumors

The majority of pituitary adenomas are prolactin (PRL)-secreting, but it is still uncertain whether their pathogenesis results from a central nervous system (CNS) disturbance or autonomous lactotroph growth and function. We have measured dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) concentrations in rats bearing estradiol-induced PRL-secreting pituitary tumors. Female rats, injected at 3-week intervals with 2 mg estradiol valerate (EV), had increased plasma prolactin concentrations, up to 3 micrograms/ml, at 31 weeks. Inversely, there was a reduction of DA and DOPAC in the median eminence and arcuate nucleus as well as a decreased DOPAC/DA ratio in the arcuate nucleus. DA-containing nuclei in the other parts of the brain were not affected. Anterior pituitary weight increased while its DA concentration decreased during estradiol treatment. In the neurohypophysis, DA concentrations were unchanged while DOPAC and the ratio DOPAC/DA decreased following the estrogen treatment. Our data suggest that rats with primary estrogen-induced PRL-secreting tumors have a defect in the CNS-DA neurotransmission.     

Sex differences in vasoactive intestinal peptide (VIP) concentrations in the anterior pituitary and hypothalamus of rats

Recent evidence suggests that vasoactive intestinal peptide (VIP), a putative prolactin (PRL)-releasing factor, is both synthesized and released by anterior pituitary cells, to act as a paracrine or autocrine factor. We have investigated the hypothesis that hypothalamic or pituitary VIP levels differ in male and female rats, since neuroendocrine control of PRL is sexually differentiated. Opposite sex differences were found in the hypothalamus and anterior pituitary. Random-cycle female rats had one-third higher VIP levels in the hypothalamus than males. In contrast, anterior pituitary VIP levels were 3 times as high in male rats as in females. Median eminence VIP levels were similarly low in both sexes. These results support a possible role of VIP in the sexually dimorphic regulatory mechanisms of PRL secretion. Moreover, demonstration that hypothalamic and pituitary VIP levels vary in opposite directions suggests that VIP is differentially regulated at the two sites.     

Tryptophan ingestion by pregnant rats induces pituitary and mammary tumours in the adult female offspring.

The present study was designed to evaluate the long-term consequences of tryptophan treatment on the central serotonergic activity in the female offspring of rats, and particularly on serotonin-controlled hormone release. During the second half of gestation, tryptophan (200 mg/kg/day) was given daily by stomach intubation to pregnant rats and the brain concentrations of serotonin and 5-hydroxyindole acetic acid and the plasma concentrations of prolactin, progesterone, oestradiol and luteinizing hormone were quantified in the adult female offspring. The offspring showed an increase in hypothalamic serotonin and serum progesterone and prolactin. In addition, maternal ingestion of tryptophan induced a marked rise in 665-day-old offspring in the incidence of both pituitary prolactinomas (62%) and mammary adenomas (49%). Present data suggest that tryptophan regulates serotonergic differentiation during early development. A transitory modification of the tryptophan concentration in the fetal brain induces a permanent increase in hypothalamic serotonin level and, in addition to modifying the release of prolactin, increases the incidence of tumours in the hypophysis and mammary gland.     

Dopamine release in the nucleus accumbens of freely moving rats determined by on-line dialysis: effects of apomorphine and the neuroleptic-like peptide desenkephalin-gamma-endorphin

This study examined the effects of apomorphine, sulpiride, desenkephalin-gamma-endorphin (DE gamma E) and a combination of DE gamma E with apomorphine on the release of dopamine (DA) and its main metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens of freely moving rats. A fully automated on-line brain dialysis system was used. A small dose of s.c. administered apomorphine induced a decrease in the output of DA and DOPAC. Sulpiride, infused into the nucleus accumbens, induced a 2-fold increase in the output of DA, DOPAC and HVA. DE gamma E hardly modified either the basal release of DA, DOPAC and HVA or the apomorphine-induced attenuation of the release of DA and DOPAC. These results indicate a dissociation between the behavioural effects of DE gamma E and its effect on the release of DA in vivo.     

Galanin stimulates the release of vasoactive intestinal polypeptide from perifused hypothalamic fragments in vitro and from periventricular structures into the cerebrospinal fluid in vivo in the rat

Intracerebroventricular injection of galanin (2 micrograms/rat) raised plasma prolactin (PRL) levels in the rat, which was accompanied by an increase in immunoreactive vasoactive intestinal polypeptide (VIP) in the cerebrospinal fluid (CSF). Immunoreactive VIP release from superfused rat hypothalamic fragments in vitro was dose-relatedly stimulated by galanin (10(-7) and 10(-8) M). PRL release from superfused rat anterior pituitary cells was stimulated by TRH (10(-8) M) but not affected by galanin (10(-7) to 10(-5) M). These findings indicate that central galanin has a stimulating role in the release of hypothalamic VIP, which results in pituitary PRL secretion in the rat.     

Hyperprolactinaemia in hypophysectomized or intact male rats and the development of adjuvant arthritis.

In rats, complete Freund's adjuvant (CFA), injected at the base of the tail, induced a hyperactivation of cellular immune functions and triggered the development of adjuvant arthritis (AA). Before onset of arthritis (Days 9-10 upon CFA), the positive control rats showed significant increases of pituitary prolactin (Prl) mRNA accumulation (Days 3-5). On the other hand, production of pituitary growth hormone (GH) mRNA was significantly reduced from Day 3 onwards. During this early latent period, plasma Prl levels were transiently increased (at least on Day 4), while GH levels were reduced within 8 days (and onwards). Pituitary proopiomelanocortin (POMC) mRNA content progressively decreased with a nadir between Days 6 and 8, accompanied by a loss of the adrenocortical ornithine decarboxylase (ODC) circadian rhythm of activity and a transient reduction of plasma corticosterone (CS) levels (Days 3-6, obvious during the dark phase). At onset of arthritis, the POMC mRNA accumulation and adrenocortical ODC activity increased over their respective baselines. Elevation of plasma CS levels (obvious during the light phase) and important CS-induced thymolysis occurred. Further, hypophysectomized rats did not develop AA. However, hypophysectomized male rats carrying pituitary grafts under the kidney capsule had mild hyperprolactinaemia and developed a worsened arthritic response to CFA, compared to sham-operated controls. On the other hand, intact hyperprolactinaemic male rats showed a delay in the onset and a reduction in the severity of AA. This difference might be due to stimulation of the adrenal cortex in intact pituitary-grafted rats. Such rats showed increased baselines of pituitary POMC mRNA production, adrenocortical ODC activity and plasma CS levels. In addition, during the latent period after CFA, POMC mRNA accumulation, adrenocortical ODC activity and plasma CS levels were only partially suppressed, less than in sham-operated rats. Extensive thymolysis occurred after CFA in these animals--as in the sham-operated rats--but not in the hypophysectomized pituitary-implanted rats. This suggested that in the presence of adrenocortical deficiency, Prl released by the pituitary graft can freely act on the immune system, without being counter-regulated by CS.     

Changes in Hormone Sensitivity of the Adenylate Cyclase Signaling System in the Testicular Tissue of Rats with Neonatal Streptozotocin-Induced Diabetes

Activity of the adenylate cyclase signaling system was evaluated in the testicular tissue of rats with neonatal streptozotocin-induced diabetes (120 and 180 days duration). This state is similar to type 2 diabetes in humans. The regulation of this system by polypeptide hormones and biogenic amines was studied. Sensitivity of the adenylate cyclase signaling system to the regulatory effect of human chorionic gonadotropin and PACAP (pituitary adenylyl cyclaseactivating polypeptide) was significantly reduced. The effects of these agents are realized via stimulatory G proteins. Somatostatin, acting through inhibitory G proteins, produced less pronounced effect on the adenylate cyclase signaling system. The increase in the duration of diabetes was accompanied by a decrease in the stimulatory effects of human chorionic gonadotropin and PACAP on adenylate cyclase. Sensitivity of the adenylate cyclase signaling system to biogenic amines remained unchanged (serotonin) or increased under these conditions (epinephrine). Our results indicate that changes in hormonal regulation of the adenylate cyclase signaling system and functional activity of cAMP-dependent signaling cascades are important factors for dysfunction of spermatogenesis and steroidogenesis during insulinindependent diabetes.     

Effects of pergolide on diethylstilbestrol-induced rat pituitary hyperplasia.

Hyperplastic anterior pituitary glands were produced in female rats by treatment with 10 mg of diethylstilbestrol in Silastic tubing. This led to increased numbers of immunoreactive prolactin cells and increased serum prolactin levels. After 6 weeks of diethylstilbestrol treatment, one group of rats was treated with daily injections of pergolide for 3 weeks. Pergolide produced a significant decrease in pituitary gland weight and in serum prolactin levels but did not change the percentage of prolactin cells significantly, compared with that of control rats. Ultrastructural studies showed a significant increase in the numbers of prolactin secretory granules and numerous large intracellular bodies with associated secretory granules in pituitaries from rats treated with pergolide. In one group of rats in which the diethylstilbestrol was discontinued for 3 weeks after 6 weeks of treatment there was a significant decrease in pituitary gland weight and serum prolactin and a significant decrease in the percentage of prolactin cells, compared with values in the rats treated with diethylstilbestrol for 9 weeks. These results indicate that pergolide causes decreased release of prolactin from secretory granules in anterior pituitary prolactin cells and an increase in the numbers of PRL secretory granules per cell but does not change the percentage of prolactin-producing pituitary cells after 3 weeks of treatment.     

Histamine and the hypothalamus

The chemical tools that could be used to examine the function of histamine in the brain are considered together with the evidence linking histamine specifically with the hypothalamus. The distribution of histamine and the enzymes responsible for its synthesis and metabolism is consistent with there being both mast cells and histaminergic nerve terminals within the hypothalamus. Iontophoresis, mepyramine binding and histamine-stimulated adenylate cyclase studies suggest that both histamine H1- and H2- receptors are present in the hypothalamus. In addition, intracerebroventricularly injected histamine receptor agonists and antagonists affect many functions associated with the hypothalamus such as cardiovascular control, food intake, body temperature control, and pituitary hormones whose release is mediated via the hypothalamus, such as corticotropin, growth hormone, thyroid stimulating hormone, prolactin, gonadotropins and vasopressin. However, only in the case of thyroliberin release, prolactin release, body fluid control and blood pressure control is there evidence yet that such effects are mediated via histamine receptors actually in the hypothalamus. The effects of enzyme inhibitors suggest endogenous histamine may be involved in the physiological control of thyroid stimulating hormone, growth hormone and blood pressure, and the effects of receptor antagonists support a role for endogenous histamine in prolactin control. Otherwise, there is little evidence for a physiological role for endogenous, as against exogenous, histamine whether it be from histaminergic terminals or mast cells. In addition, few studies have tried to distinguish possible effects on presynaptic receptors, postsynaptic receptors, hypothalamic blood vessels or the hypophyseal portal blood vessels. It is concluded that although there is good evidence now linking histamine and the hypothalamus more specific studies are required, for instance using microinjection or in vitro techniques and the more specific chemical tools now available, to enable a clearer understanding of the physiological role of histamine in the hypothalamus.     

Adenylate cyclase-cyclic AMP-phosphodiesterase system in microdissected brain areas of normotensive and spontaneously hypertensive rats

The topographical distribution of the adenylate-cyclase-cyclic adenosine monophosphate-phosphodiesterase system was investigated in specific brain areas of rats, and compared with spontaneously hypertensive rats. In normotensive animals, brain cyclic adenosine monophosphate levels were quite uniform (between 7.14 and 13.04 pmol/mg protein) with highest concentrations in catecholamine-containing cell groups. In contrast, the distribution of basal adenylate cyclase and phosphodiesterase activity is not uniform. The unstimulated adenylate cyclase activity was very low in the striatum and catecholamine-containing cell groups in the medulla oblongata (A1C1-cell groups) and very high in the central gray matter and the cerebellum, where the lowest phosphodiesterase activities were measured. In spontaneously hypertensive rats, altered cyclic adenosine monophosphate levels were found in 17 of 36 brain areas investigated in comparison to those of normotensive rats. Increased concentrations were found in regions which are known to participate in the central regulation of blood pressure (nucleus of the solitary tract, A1C1 catecholaminergic cell groups in the ventrolateral medulla oblongata, locus coeruleus) and in the periaqueductal central gray matter, the hippocampus and the cingulate cortex. Lower levels were measured only in hypothalamic nuclei, especially in the paraventricular and dorsomedial nucleus. No significant differences in basal adenylate cyclase activity were found in spontaneously hypertensive rats compared with Wistar-Kyoto control rats, while phosphodiesterase activity was generally higher in spontaneously hypertensive rats, most significantly in the medulla oblongata. Present data show that characterization of the adenylate cyclase-cyclic adenosine monophosphate-phosphodiesterase system helps to localize structural and/or functional differences between the spontaneously hypertensive rat and its normotensive control rat and indicate that more than one functional system is affected in spontaneous hypertension.     

Pituitary adenylate cyclase activating polypeptide reduces A-type K+ currents and caspase activity in cultured adult mouse olfactory neurons

Pituitary adenylate cyclase activating polypeptide has been shown to reduce apoptosis in neonatal cerebellar and olfactory receptor neurons, however the underlying mechanisms have not been elucidated. In addition, the neuroprotective effects of pituitary adenylate cyclase activating polypeptide have not been examined in adult tissues. To study the effects of pituitary adenylate cyclase activating polypeptide on neurons in apoptosis, we measured caspase activation in adult olfactory receptor neurons in vitro. Interestingly, we found that the protective effects of pituitary adenylate cyclase activating polypeptide were related to the absence of a 4-aminopyridine (IC50=144 microM) sensitive rapidly inactivating potassium current often referred to as A-type current. In the presence of 40 nM pituitary adenylate cyclase activating polypeptide 38, both A-type current and activated caspases were significantly reduced. A-type current reduction by pituitary adenylate cyclase activating polypeptide was blocked by inhibiting the phospholipase C pathway, but not the adenylyl cyclase pathway. Our observation that 5 mM 4-aminopyridine mimicked the caspase inhibiting effects of pituitary adenylate cyclase activating polypeptide indicates that A-type current is involved in apoptosis. This work contributes to our growing understanding that potassium currents are involved with the activation of caspases to affect the balance between cell life and death.