Hyperphagia and obesity following serotonin depletion by intraventricular p-chlorophenylalanine.

Loss of brain serotonin was associated with overeating and increased body weight. Rats injected with p-chlorophenylalanine intraventricularly began overeating after 3 days and continued to display marked hyperphagia, primarily in the daytime, accompanied by increased body weight for 1 to 2 weeks. The effect was related to drug dose and to the degree and duration of serotonin depletion. Norepinephrine and dopamine levels were not significantly affected. It is concluded that p-chlorophenylalanine disinhibits feeding, as it does a number of other behaviors, by depleting serotonin. This suggests that hypothalamic lesions or dietary deficiencies which selectively and sufficiently deplete serotonin would lead to overeating.

Activation of lordotic responding in female rats by suppression of serotonergic activity.

After systemic administration of several serotonergic antagonists, female rats that had been ovariectomized, adrenalectomized, and estrogen-primed showed lordotic responding. Lordosis could also be elicited after direct placement of serotonergic receptor blockers into hypothalamic sites known to contain serotonergic terminals. None of the treatments activated the soliciting component of the estrous behavior pattern of the female rat. It is postulated that the hypothalamus contains serotonergic terminals which suppress lordotic responding.

The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain.

The present study quantified the cleaved form of the microtubule-associated protein tau (cleaved MAP-tau, C-tau), a previously demonstrated marker of CNS toxicity, following the administration of monoamine-depleting regimens of the psychostimulant drugs amphetamine (AMPH), methamphetamine (METH), +/-3,4-methylenedioxymethamphetamine (MDMA), or para-methoxyamphetamine (PMA) in an attempt to further characterize psychostimulant-induced toxicity. A dopamine (DA)-depleting regimen of AMPH produced an increase in C-tau immunoreactivity in the striatum, while a DA- and serotonin (5-HT)-depleting regimen of METH produced an increase in the number of C-tau immunoreactive cells in the striatum and CA2/CA3 and dentate gyrus regions of the hippocampus. MDMA and PMA, two psychostimulant drugs that produce selective 5-HT depletion in the striatum, had no effect on C-tau immunoreactivity in the striatum or hippocampus. Furthermore, 5,7-dihydroxytryptamine (5,7-DHT), an established 5-HT selective neurotoxin, did not produce an increase in C-tau immunoreactivity. Dual fluorescent immunocytochemistry with antibodies to glial fibrillary acidic protein (GFAP) and C-tau indicated that C-tau immunoreactivity was present in astrocytes, not neurons, suggesting that increased C-tau may be an alternative indicator of reactive gliosis. The present results are consistent with previous findings that the DA-depleting psychostimulants AMPH and METH produce reactive gliosis whereas the 5-HT-depleting drugs MDMA and PMA, as well as the known 5-HT selective neurotoxin 5,7-DHT, do not produce an appreciable glial response.

Relation of clinical symptoms to apomorphine-stimulated growth hormone release in mood-incongruent psychotic patients.

The relationship between dopamine receptor agonist (apomorphine hydrochloride)-stimulated growth hormone (GH) release and psychotic symptoms was examined in 138 schizophrenic or schizoaffective inpatients (Research Diagnostic Criteria) and ten healthy normal volunteers. Patients were divided into three groups: those demonstrating an abnormally large GH response, an average GH response (mean GH response), or an abnormally low GH response. Abnormally large GH responses were associated with higher total psychosis scores. The increased psychosis scores observed in this group were due primarily to an increased incidence of thought disorder. Further analysis revealed a strong, positive correlation between thought disorder and the GH response. The apomorphine-stimulated GH response was also significantly related to duration of illness, an effect independent of age. Consistent with this last result, patients with a diagnosis of a DSM-III schizophreniform disorder demonstrated an elevated GH response.

Growth hormone response to apomorphine and family patterns of illness.

Sixty-five psychotic probands were divided into three groups (low, intermediate, and high) on the basis of the GH response to the dopamine receptor agonist apomorphine. Two hundred and sixty-five first-degree relatives of the probands were diagnosed according to SADS-DSM-III methods, and the relatives of the three groups of probands were compared so as to detect familial differences in the incidence of DSM-III Axis I disorders, schizotypal personality disorder, and antisocial personality. Although the morbid risk of schizophrenic spectrum disorder was only 3.1% in the relatives of the high GH probands, the morbid risk for disorders of the schizophrenic spectrum was 17.0% and 10.7% in the relatives of the intermediate and low GH probands, respectively. These data provide preliminary evidence that there may be a psychotic subtype that is characterized by supersensitivity of the dopamine system that is familially, and perhaps genetically, distinct from the bulk of the schizophrenias.

Growth hormone response to apomorphine and diagnosis: a comparison of three diagnostic systems.

Our study takes a further look at the apomorphine test in the psychoses and affective disorders, with special reference to the use of different diagnostic systems. Patients meeting Research Diagnostic Criteria (RDC) for schizophrenia, schizoaffective disorder, or manic disorder were included. In addition to the RDC, diagnosis was also made using the DSM-III and ICD-9. All patients underwent an evaluation of peak GH response to apomorphine administration. The results show that RDC and ICD-9 are similar, in that for both systems, a high GH response correlates with a schizoaffective disorder and distinguishes those patients significantly from manic patients. The DMS-III brings in some new dimensions, in that schizophreniform disorder (6-month cut-off) is distinguished from schizophrenia. In addition, patients with affective symptoms and mood-incongruent psychoses are more closely related to schizophreniform disorder than to classical manic disorder.

Functional change in the 5-HT presynaptic receptor in spinal cord of aged rats.

The present study assessed the functional integrity of the serotonin (5-HT) presynaptic receptor in the spinal cord of aged (18-20 months) rats. Previous research determined that exogenous 5-HT and 5-HT1B agonists, in adult (3 months) rats, activated the 5-HT presynaptic receptor resulting in a dose-dependent decrease in 3H-5-HT release from spinal cord slices. Contrastively, exogenous 5-HT and the selective 5-HT1B agonist 1-(m-chlorophenyl) piperazine HCl (mCPP) produced a dose-dependent increase in depolarization-evoked 3H-5-HT release from spinal cord of aged rats. The selective 5-HT1A agonist 8-hydroxy-2(di-n-propylamino) tetralin (8-OHDPAT) increased 3H-5-HT release from aged rat spinal cord slices similar to results previously obtained from adult rat spinal cord slices. The inability of 5-HT and mCPP to inhibit 3H-5-HT release from spinal cord of aged rats indicates a functional change in the 5-HT presynaptic receptor in these animals. Possible mechanisms mediating this functional change are discussed.

Growth hormone levels and lithium ratios as predictors of success of lithium therapy in schizophrenia.

The authors previously found a high correlation between lithium response and clinical diagnostic criteria in a subgroup of schizophrenic-like patients who responded favorably to lithium therapy. In the present study the authors extend this research by using biological markers to predict and identify such patients. They examined growth hormone (GH) response to apomorphine administration and the in vitro lithium ratio in 31 patients before and after a 2-week lithium trial. Peak GH levels (greater than or equal to 20 ng/ml) and lithium ratios (greater than or equal to .39) were correlated with a positive response to lithium therapy. The authors discuss 1) the use of these two biological markers to predict the success of lithium therapy in schizophrenia and 2) biological abnormalities characteristic of lithium-responsive schizophrenic patients.

Down-regulation of central dopamine receptors in schizophrenia.

CSF homovanillic acid (HVA) levels reflecting central dopamine release and apomorphine-stimulated human growth hormone (HGH) secretion reflecting central dopamine receptor activity were concomitantly determined in 20 schizophrenic patients. There was a strong negative correlation between HVA and HGH levels: high dopamine release was associated with lower HGH responses to dopamine receptor activation by apomorphine. Studies are reviewed which suggest that the presently observed relationship reflects release-mediated down-regulation of central D2 receptors, the dopamine receptor subtype associated with the antipsychotic properties of neuroleptic medication.

Growth hormone response to edrophonium in Alzheimer's disease.

Neuropathologic data from patients with Alzheimer's disease indicate the presence of neurofibrillary tangles in hypothalamic regions associated with regulation of pituitary hormone release. The authors explored the hypothesis that cholinergic projections to hypothalamic nuclei controlling pituitary growth hormone (GH) release degenerate in Alzheimer's disease. Integrity of cholinergic regulation was tested by assaying the GH response to a presynaptic cholinergic challenge. After administration of the choline esterase inhibitor edrophonium, the peak GH response was 14 ng/ml in healthy elderly control subjects and only 2 ng/ml in Alzheimer's patients. The magnitude of GH blunting was correlated with cognitive and functional deficits. Possible implications of these data for enhanced accuracy in the diagnosis of dementia are discussed.

Selective 5-HT1B agonists identify the 5-HT autoreceptor in lumbar spinal cord of rat.

The purpose of the present study was to characterize the 5-HT autoreceptor in the lumbar spinal cord of the rat. The effect of selective 5-HT1A and 5-HT1B agonists on K+-evoked release of [3H]5-HT and the binding of [3H]5-HT were examined. The 5-HT1B compounds, mCPP and quipazine were more potent than exogenous 5-HT at decreasing K+-evoked release of [3H]5-HT in slices of spinal cord. The pEC40 values of 5-HT agonists tested, determined from release assays, significantly correlated with the relative affinities (pKD's) of these compounds for the binding of [3H]5-HT to the 5-HT1B receptor subtype in the presence of 2 microM 8-OHDPAT, as determined from radioligand binding studies (r = 0.98, P = 0.003). Conversely, the potencies of the 5-HT1A agonists 5-MeODMT and 8-OHDPAT, at the 5-HT autoreceptor, were negatively correlated (r = -0.77, P less than 0.10) with their potencies at displacing [3H]5-HT from the 5-HT1A subsite (binding of [3H]5-HT in the presence of 1 microM mCPP). Thus, the 5-HT autoreceptor in spinal cord appears to bear a significant pharmacological similarity to the 5-HT1B binding site. Further testing of the present results requires the development of new 5-HT1 agonists which are selective (1000-fold difference) for the 5-HT1A and 5-HT1B subsites.

Selective serotonin1A/1B agonists differentially affect spinal nociceptive reflexes.

The purpose of the present experiments was to determine whether serotonin-1A (5-HT1A) and serotonin-1B (5-HT1B) binding sites, recently characterized in the spinal cord of the rat, mediate differential effects of 5-HT on spinal nociceptive processing. Several days after spinal transection at T10, rats were injected intraperitoneally at 20 min intervals, with increasing doses (0, 0.1, 0.4, 2.0, 9.0 mg/kg) of either a 5-HT1A selective agonist (8-OH-DPAT, buspirone) or a 5-HT1B agonist (mCPP, TFMPP). Nociceptive sensitivity was determined by quantifying, in cm2, changes from baseline in the receptive field areas of three spinal nociceptive withdrawal reflexes after noxious (greater than 400 mmHg) levels of mechanical stimulation. The 5-HT1A agonist 8-OH-DPAT and buspirone, significantly increased in a dose-dependent manner the receptive field areas of the three reflexes, with the following log ED50 values (nmol/kg): ventroflexion reflex--buspirone (2.75), 8-OH-DPAT (2.70); dorsiflexion reflex--buspirone (2.91), 8-OH-DPAT (2.67); lateral flexion reflex--buspirone (3.51), 8-OH-DPAT (2.77). The hypersensitivity of the reflexes after pretreatment with buspirone was effectively blocked by the 5-HT1A selective antagonist spiperone, at all doses (0.001, 0.01, 0.1 and 1.0 mg/kg) tested. The 5-HT1B selective agonists mCPP and TFMPP significantly decreased the receptive field are of the ventroflexion reflex (log ED50 values: mCPP, 3.79 nmol/kg; TFMPP, 3.61 nmol/kg) with no significant effect on the dorsiflexion or lateral flexion reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantification and localization of kainic acid-induced neurotoxicity employing a new biomarker of cell death: cleaved microtubule-associated protein-tau (C-tau).

Previous studies of neuronal degeneration induced by the neurotoxin, kainic acid, employed silver stain techniques that are non-quantitative or ELISA measurement of the non-neuronal protein, glial fibrillary acidic protein. As previous studies employed biomarkers that were either non-quantitative or non-neuronal, the present study employed a new neuronally localized biomaker of neuronal damage, cleaved microtubule-associated protein (MAP)-tau (C-tau). The time course of kainate neurotoxicity was quantitatively determined in several brain regions in the present study employing a C-tau specific ELISA. Differences in ELISA determined regional brain levels of C-tau were compared with the density of somatodendritic C-tau labeling qualitatively determined in immunohistochemical anatomical mapping studies of kainic acid-treated animals. Immunoblot studies revealed that the C-tau antibodies employed in the present study were highly specific for proteolytic cleaved C-tau. Immunolabeling of 45 kD-50 kD C-tau proteins was observed only in brain samples from kainic acid-treated but not vehicle-treated rats. Time course studies revealed that C-tau levels determined by ELISA were maximal 3 days after kainic acid with C-tau levels increasing 26-fold in hippocampus, 16-fold in cortex and four-fold in both striatum and hypothalamus. These statistical differences in maximal C-tau levels observed in the ELISA studies were similar to differences qualitatively observed in C-tau immunohistochemical studies. C-tau immunohistochemistry revealed extensive damage in hippocampal regions CA1 and 3, moderate damage in several cortical regions and mild damage in striatum and hypothalamus. Similar cleavage of rat MAP-tau to C-tau has been reported after neuronal degeneration induced by neurotoxic doses of methamphetamine and neuronal degeneration resulting from bacterial meningitis. In humans, C-tau proteolysis has been demonstrated to be a reliable biomarker of neuronal damage in traumatic brain injury and stroke where cerebrospinal C-tau levels are correlated with patient clinical outcome. These data suggest that C-tau proteolysis may prove a reliable species independent biomarker of neuronal degeneration regardless of source of injury.

Methamphetamine enhances the cleavage of the cytoskeletal protein tau in the rat brain.

The view that methamphetamine is neurotoxic to dopaminergic and serotonergic axon terminals has been based largely on biochemical and histological studies. In the present study, methamphetamine-induced structural damage to axons was quantified using a sensitive sandwich enzyme-linked immunosorbent assay developed for the detection of the cleaved form of the cytoskeletal protein tau. The administration of a monoamine-depleting regimen of methamphetamine (4 x 10 mg/kg, i.p. every 2 hours for a total of four injections) produced a time-dependent increase in the concentration of cleaved tau in the striatum. Maximal concentrations of cleaved tau were detected 3 days following methamphetamine administration. Cleaved tau concentrations also were significantly elevated in the dorsal hippocampus and, to a lesser extent, in the prefrontal cortex of methamphetamine-treated rats. Maintenance of rats in a cold (4 degrees C) environment not only prevented the methamphetamine-induced depletion of striatal dopamine and serotonin but also prevented the methamphetamine-induced increase in striatal cleaved tau concentrations. The novel findings from this study are supportive of the view that methamphetamine produces acute structural damage to neurons that may lead to the long-term neurotoxic effects of repeated, high-dose administration of the drug and that cleaved tau reliably quantifies the time-dependent neurotoxic effects of methamphetamine.

Comparative effects of limbitrol and amitriptyline on sleep efficiency and architecture.

Chlordiazepoxide-amitriptyline (Limbitrol) has been shown to be more rapidly effective than amitriptyline alone for treating depression. A double-blind, randomized study was designed to compare the effects of Limbitrol and amitriptyline on insomnia, anxiety, and depression. The rate of improvement of symptoms was faster with Limbitrol. No differences were noted between groups in the degree or rate of improvement of the sleep laboratory parameters nor in sleep Stages 1 to 4. Percentages of rapid eye movement (REM) sleep and REM latency were similarly affected by the drugs, but REM density showed a significantly greater decrease with Limbitrol. Phasic REM factors may be crucial in the role of REM sleep and depression.

A controlled double-blind study of high-dose dihydroergotoxine mesylate (Hydergine) in mild dementia.

In a double-blind study of 41 outpatients aged 55 to 80 years with mild memory impairment, the efficacy of dihydroergotoxine mesylate (DEM, Hydergine) at 6 mg per day, administered orally, was tested during a twelve-week period. Specific etiologies for the amnesic syndrome were ruled out by history, physical examination, and laboratory tests. Subjects with a Hamilton Depression Scale rating above 18, ie, possible pseudodementia, were excluded. Physician rating of memory, employing the Inventory of Psychic and Somatic Complaints in the Elderly (IPSC-E), indicated statistically significant improvement of memory function in DEM treated subjects (N = 22) v those on placebo (N = 19), (F = 3.34; df = 1,39; P less than .04). In contrast, structured testing of recent memory using digit symbol substitution and Zahlenverbindungs test (ZVT) showed improvement in both groups (P less than .001) with no significant intergroup differences (P less than .10). Out results indicate that in cases of mild, though subjectively distressing impairment, DEM at higher dosages may help to enhance short-term memory function.

Differential effects of substance P on serotonin-modulated spinal nociceptive reflexes.

Recent immunohistochemical studies indicate the presence of a bulbospinal substance P (SP) system, as well as a bulbospinal serotonin (5-HT) system, involved in spinal pain transmission. Although electrophysiological studies indicate that SP may modulate the effects of 5-HT on postsynaptic spinal nociceptive neurons, the functional relationship between SP and 5-HT on "pain behavior" remains obscure. To bridge this gap between mechanism and behavior, the purpose of the present study was to determine specific postsynaptic behavioral effects of SP and 5-HT on local spinal nociceptive reflexes in spinally transected animals. Administration of the 5-HT agonists 5-methoxydimethyltryptamine (5-MeODMT) (0, 0.5, 1.5, 2.0 mg/kg) and quipazine (0, 5, 10, 20 mg/kg) 2 days after transection significantly expanded the receptive field (RF) areas of three spinal reflexes, as previously reported. Intrathecal administration of SP alone (0, 0.25, 2.5, 7.5 ng) also resulted in hyperalgesia, indicated by a significant expansion of the RF areas of all three nociceptive reflexes. However, administration of SP, in animals pretreated with 5-HT agonists, decreased the 5-HT-induced expansion of RF size. Therefore, SP had opposite effects on spinal nociceptive reflexes depending on whether or not the animal was pretreated with 5-HT agonists, i.e., hyperalgesia in the absence of 5-HT agonists, and analgesia in the presence of 5-HT agonists. The two effects of SP on local spinal reflexes may be related to the anatomical organization of the two spinal SP systems: 1) SP released from primary afferents facilitates nociceptive reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of spinal serotonin1 receptor subtypes in thermally and mechanically elicited nociceptive reflexes.

The ability of 5-HT1A and 5-HT1B agonists to alter a spinal animal's nociceptive threshold was examined using two analgesiometric tests. In the spinal withdrawal reflex test, administration of the selective 5-HT1A agonists ipsapirone, gepirone and PAPP resulted in significant dose-dependent increases in receptive field (RF) area for withdrawal reflexes when compared to predrug baseline values, indicating an increase in nociceptive sensitivity. The average overall percent maximal increase in RF area following administration of 5-HT1A selective compounds was: 80 +/- 16% for the ventroflexion reflex, 90 +/- 6% for the dorsiflexion reflex and 87 +/- 8% for the lateral flexion reflex. Similar to the effects noted with 5-HT1A agonists, administration of 5-HT1B agonists RU24969, mCPP and TFMPP resulted in a hyperalgesic response with an overall percent maximal increase of 43 +/- 6% for the ventroflexion reflex, 51 +/- 6% for the dorsiflexion reflex and 38 +/- 9% for the lateral flexion reflex. In the tail-flick analgesiometric test, administration of the 5-HT1A agonists 8-OH-DPAT and ipsapirone and the 5-HT1B agonists RU24969 and mCPP resulted in a significant dose-dependent increase in tail-flick latencies when compared to predrug baseline values, indicating a decrease in nociceptive sensitivity to noxious thermal stimuli. No differences in magnitude of the effect of the two receptor subtypes were found, indicating that stimulation of either 5-HT1A or 5-HT1B receptors was equipotent in producing the antinociceptive tail-flick response.(ABSTRACT TRUNCATED AT 250 WORDS)

Fluphenazine activity and antipsychotic response.

Plasma fluphenazine levels and plasma total neuroleptic activity (as quantitated by the neuroleptic receptor binding assay) were related to therapeutic response in 15 DSM-III schizophrenic patients who received a predetermined, fixed dose of fluphenazine for 14 days. Mean neuroleptic activity of the plasma was 84% greater than can be accounted for by the parent fluphenazine alone, and varied widely between patients. A sigmoidal relationship between total neuroleptic activity of plasma and response was found, with a continued plateau of response at higher total neuroleptic levels. Furthermore, the RBA data suggested (P less than 0.002) that two populations of drug-responsive schizophrenics exist which may be discriminated by the total D2 binding activity of plasma required for response.

BMY 7378: Partial agonist at spinal cord 5-HT(1A) receptors.

Recent data indicate that BMY 7378 demonstrates high affinity, selectivity and low intrinsic activity at hippocampal 5-HT(1A) receptors, suggesting that BMY 7378 may represent the first selective 5-HT(1A) functional antagonist. The present study examined the agonist and antagonist properties of BMY 7378 at spinal cord 5-HT(1A) receptors. In electrophysiological studies, iontophoretic administration of either the 5-HT(1A) agonist 8-OH-DPAT (43.8 +/- 5.4 nA) or BMY 7378 (46.3 +/- 5.2 nA) significantly inhibited the firing rate of wide-dynamic-range dorsal horn units indicating that BMY 7378 demonstrates significant intrinsic activity at spinal cord 5-HT(1A) receptors. Concomitant BMY 7378 and 8-OH-DPAT administration identified no BMY 7378 ejection current (20-100 nA) which antagonized the 8-OH-DPAT induced inhibition of dorsal horn unit activity. In behavioral studies in the spinal rat, 8-OH-DPAT increased the animals' sensitivity to noxious levels of mechanical stimulation (ED(50) = 269 +/- 24 nmol/kg) as did BMY 7378 (ED(50) = 295 +/- 70 nmol/kg) with no statistically significant difference in the maximal response (Y(max)) observed. Concomitant BMY 7378 and 8-OH-DPAT administration identified no BMY 7378 dose (10-1100 nmol/kg) which blocked the hyperalgesic effect of 8-OH-DPAT, rather, each drug produced similar effects which were additive. Further, the 5-HT(1A) agonist effects of BMY 7378 were blocked by the 5-HT(1A) antagonist, spiperone. Therefore, both the electrophysiologic and reflex data indicate that BMY 7378 possesses significant intrinsic activity at spinal cord 5-HT(1A) receptors, and like 8-OH-DPAT is a partial agonist at these receptors. Differences in BMY 7378 intrinsic activity at spinal cord as opposed to hippocampal 5-HT(1A) receptors are discussed in terms of regional differences in G-proteins coupled to 5-HT(1A) receptors in these two CNS regions.