Peripherally administered amylin inhibits stress-like behaviors and enhances cognitive performance.

Amylin, a 37 amino acid peptide pancreatic hormone co-secreted with insulin, normalizes the altered eating patterns induced by chronic stress in the rat. Because these stress-induced changes are driven, in part, by brain corticotropin-releasing factor and corticosterone, and because alterations in the activity of these molecules and the stress system are commonly associated with neuropsychiatric diseases like anxiety, depression, and schizophrenia, we hypothesized that amylin might mitigate behavioral states associated with stress. Therefore, we tested the effects of rat amylin in rodent-based behavioral assays sensitive to neuropsychiatric drugs, including anxiolytic, antidepressant, antipsychotic, and cognitive enhancing drugs: stress-induced hyperthermia (SIH); marble burying; elevated plus maze (EPM)), forced swim test (FST), pre-pulse inhibition, and phencyclidine-induced locomotion. To assess the neural underpinnings of amylin's anxiolytic-like effects, we examined the effect of amylin on SIH after lesioning the area postrema (AP), which mediates amylin's metabolic effects. Amylin injection (IP, 0.1, 1.0, & 10 mg/kg) significantly (P < 0.05) decreased SIH (97% below vehicle) and AP lesions inhibited this effect. Amylin also reduced marble burying (72% below vehicle), but had no effect in the EPM. Together, these effects suggest anxiolytic-like activity or potential. Amylin injection also enhanced cognitive performance in the novel object recognition test. When administered continuously by implanted osmotic pumps, amylin (300 mg/kg/d) blocked SIH when tested at 1 and 4 weeks. Compared to vehicle, amylin infusion (1 and 3 mg/kg/d) reduced the time immobile in the FST (P < 0.05; 30% below vehicle), suggesting antidepressant-like potential. Although further testing is needed, our findings support a potential for peripherally administered amylin to access and benefit pathways that regulate memory, emotion, and mood.

Beta adrenergic receptor blockade of feline myocardium. Cardiac mechanics, energetics, and beta adrenoceptor regulation.

Myocardial oxygen consumption is regulated by interrelated mechanical and inotropic conditions; there is a parallel increase in the aerobic metabolism and inotropic state during beta-adrenergic stimulation under fixed mechanical conditions. In contrast, there is some evidence that beta-blockade may reduce oxygen consumption through effects independent of its influence on mechanical conditions and contractile state, and that prolonged beta-blockade may sensitize the myocardium to beta-adrenergic stimulation. To clarify these two points, the present study examined the relationship of myocardial energetics to mechanics and inotropism during acute beta-blockade and after the withdrawal of long-term beta-blockade, whereupon the basis for any effect observed was sought by characterizing the number, affinity, and affinity states of the beta-receptors as well as the coupling of activated beta-receptors to cyclic AMP generation. Studies of right ventricular papillary muscles from control and chronically beta-blocked cats demonstrated contractile and energetic properties as well as dose-response behavior and inotropic specificity suggestive of an increase in myocardial sensitivity to beta-adrenoceptor stimulation in the latter group. Assays of cardiac beta-adrenoceptors from further groups of control and pretreated cats, both in cardiac tissue and in isolated cardiac muscle cells, failed to define a difference between the two groups either in terms of receptor number and affinity or in terms of the proportion of receptors in the high-affinity state. However, coupling of the activated beta-adrenoceptors to cyclic AMP generation was enhanced in cardiac muscle cells from chronically beta-blocked cats. These data demonstrate that beta-adrenoceptor blockade (a) produces parallel effects on inotropic state and oxygen consumption without an independent effect on either and (b) increases myocardial sensitivity to beta-adrenergic stimulation after beta-blockade withdrawal, not by "up-regulation" of the cardiac beta-adrenoceptors, but instead by more effective coupling of these receptors when activated to cyclic AMP generation.

A store-operated calcium channel inhibitor attenuates collagen-induced arthritis.

BACKGROUND AND PURPOSE: Store-operated calcium (SOC) channels are thought to play a critical role in immune responses, inflammatory diseases and chronic pain. The aim of this study was to explore the potential role and mechanisms of SOC channels in collagen-induced arthritis (CIA). EXPERIMENTAL APPROACH: The CIA mouse model was used to examine the effects of the SOC channel inhibitor YM-58483 on CIA and arthritic pain. Hargreaves' and von Frey hair tests were conducted to measure thermal and mechanical sensitivities of hind paws. elisa was performed to measure cytokine production, and haematoxylin and eosin staining was used to assess knee histological changes. Western blot analysis was performed to examine protein levels. KEY RESULTS: Pretreatment with 5 or 10 mg · kg(-1) of YM-58483 reduced the incidence of CIA, prevented the development of inflammation and pain hypersensitivity and other signs and features of arthritis disease. Similarly, treatment with YM-58483 after the onset of CIA: (i) reversed the clinical scores; (ii) reduced paw oedema; (iii) attenuated mechanical and thermal hypersensitivity; (iv) improved spontaneous motor activity; (v) decreased periphery production of IL-1ß, IL-6 and TNF-α; and (vi) reduced spinal activation of ERK and calmodulin-dependent PKII (CaMKIIα). CONCLUSIONS AND IMPLICATIONS: This study provides the first evidence that inhibition of SOC entry prevents and relieves rheumatoid arthritis (RA) and arthritic pain. These effects are probably mediated by a reduction in cytokine levels in the periphery and activation of ERK and CaMKIIα in the spinal cord. These results suggest that SOC channels are potential drug targets for the treatment of RA.

Characterization of binding sites for 3H-spiroperidol in human retina.

Binding sites for the D-2-selective antagonist (3H)-spiroperidol were characterized in human retina. Nonspecific binding, measured in the presence of 2 microM (+)-butaclamol, made up 20% of total binding. Scatchard analysis of the binding of (3H)-spiroperidol resulted in linear plots and yielded a Kd value of 87 pM and a Bmax value of 1500 fmol/mg protein. In studies of the inhibition of the binding of (3H)-spiroperidol, (+)-butaclamol was approximately 1000-fold more potent than the (-)-stereoisomer. The inhibition curve for dopamine was shifted to the right and the Hill coefficient was increased by the addition of 300 microM GTP. This effect was agonist-specific and suggests that some of the receptors are coupled to stimulation or inhibition of the enzyme adenylate cyclase. The inhibition curves for most of the antagonists had Hill coefficients between 0.6 and 0.8. Hill coefficients were also consistently less than 1.0 for agonists even in the presence of GTP. Nonlinear regression analysis of untransformed data revealed that these shallow inhibition curves were best explained by the presence of two populations of binding sites, 40% of the sites having a high affinity for dopamine in the presence of GTP and domperidone and the remaining 60% having a lower affinity for these ligands. The larger population of sites had a higher affinity for sulpiride, fluphenazine, and N-propylnorapomorphine in the presence of GTP. The possibility that either of these classes of sites consisted of serotonin receptors was ruled out by the finding that the 5-HT2 antagonist ketanserin had a low affinity for both classes of sites.

Time-course of recovery of 5-HT1A receptors and changes in 5-HT1A receptor mRNA after irreversible inactivation with EEDQ.

In this study, the relationship between the expression of 5-HT1A receptors and level of receptor mRNA in discrete regions of rat brain was examined by inactivation of 5-HT1A receptors with the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; i.p., 10 mg/kg) and measurement of the time-course of receptor recovery and changes in receptor mRNA levels. Inactivation of 5-HT1A receptors ranged from 84% in the dorsal raphe to 97% in the cortex 12 h after administration of EEDQ. Receptor levels returned to 62-100% of control levels by day 7 and the rate of recovery was uniform across all regions examined. The rate of recovery of 5-HT1A receptors labeled by the agonist [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) and by the putative antagonist [125I]4-(2'-methoxy)phenyl-1-[2'-(N-2"-pyridinyl)-p-iodobenzamido] ethylpiperazine ([125I]p-MPPI) did not differ across regions, suggesting that the ratio of high versus low affinity states of the 5-HT1A receptor remains relatively constant during receptor recovery. However, there did appear to be a short lag in the recovery of sites labeled with the agonist. Significant increases in 5-HT1A receptor mRNA levels were observed as early as 12 h after treatment in all regions but the magnitude of these increases varied. The time-courses of recovery of 5-HT1A receptors and changes in mRNA levels were not parallel in individual regions. Moreover, inactivation of low (8-26%) to moderate (29-57%) levels of 5-HT1A receptors produced no change in mRNA levels, whereas inactivation of greater than 90% elicited a robust increase in mRNA levels. Thus, changes in 5-HT1A receptor expression are not mediated exclusively by changes in mRNA levels and extensive receptor inactivation is required to trigger transcriptional regulation.

Regional variability in changes in 5-HT2A receptor mRNA levels in rat brain following irreversible inactivation with EEDQ.

In this study, the relationship between the expression of 5-HT2A receptors and level of 5-HT2A receptor mRNA in discrete regions of rat brain was examined by inactivating 5-HT2A receptors with the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 10 mg/kg, i.p.) and measuring the time course of receptor recovery and changes in mRNA levels. In untreated controls, the distribution and levels of 5-HT2A receptors labeled with [3H]ketanserin and receptor mRNA labeled with a 230-base 33P-labeled riboprobe were found to be highly correlated in most sub-regions of the cortex, the caudate-putamen and the claustrum but not in the piriform cortex or the hippocampus. Administration of EEDQ produced 90-99% inactivation of 5-HT2A receptors and the rate of receptor recovery was uniform in most regions studied. 5-HT2A receptors in most regions reached control levels by day 14, the lone exception being the caudate-putamen where receptors reached only 56% of control by day 14. Following inactivation of receptors with EEDQ there was a transient increase in levels of 5-HT2A receptor mRNA in several regions. Although rates of receptor recovery were uniform, four distinct patterns of mRNA response were observed: (1) early elevation followed by late elevation, (2) early elevation only, (3) late elevation only, and (4) no detectable change. The absence of a direct relationship between changes in 5-HT2A receptor mRNA and 5-HT2A receptor recovery in this model system suggests that transcriptional regulation is not the mechanism controlling the recovery of these receptors after irreversible inactivation. This study also lends support to the idea that alternative mechanisms may play a role in 5-HT2A receptor regulation after other pharmacological and physiological manipulations. The regional variability in 5-HT2A mRNA regulation reported here highlights the importance of using techniques with a high level of anatomical resolution to study changes in 5-HT2A receptor mRNA levels.

Anatomical differentiation within the nucleus accumbens of the locomotor stimulatory actions of selective dopamine agonists and d-amphetamine.

The effects of local injections of dopamine receptor agonists into various areas within the nucleus accumbens or the medial caudate-putamen on the generation of locomotor activity were examined. Combinations of 0.32 microgram/side of the dopamine receptor agonists SKF 38393 (D1) and quinpirole (D2) produced increases in locomotor activity that varied according to the rostral-caudal placement of the cannulae within the nucleus accumbens. The greatest levels of locomotion were generated by injections into a region in the caudal-central nucleus accumbens, with lower levels of activity elicited by injections into more rostral or caudal regions. A similar pattern of responses was produced by administration of the indirect dopamine agonist d-amphetamine. These results indicate that there is marked heterogeneity in the response of discrete sub-regions of the nucleus accumbens to dopamine receptor stimulation and that this heterogeneity is functionally expressed in the mediation of the locomotor effects of dopaminergic agonists.

A comprehensive method for the quantitative determination of dopamine receptor subtypes.

We have demonstrated that three subtypes of dopamine receptors can be characterized using several radioligand binding techniques. Indirect binding assays in which several competing ligands were used to inhibit the binding of the nonselective radioligand spiroperidol resulted in shallow displacement curves with Hill coefficients less than 1. Nonlinear regression analysis of these curves also indicated that there were two subtypes of the D-2 receptor present in a ratio of approximately 3 to 1. Direct binding assays with [3H]alpha-flupenthixol showed that this radioligand nonselectively labeled D-2A, D-2B, and D-1 receptors. Inhibition of the binding of [3H]alpha-flupenthixol by spiroperidol revealed that spiroperidol had a much higher affinity for D-2A and D-2B receptors than for D-1 receptors. Masking D-2 receptors with nanomolar concentrations of spiroperidol permitted characterization of D-1 receptors with the radioligand [3H]alpha-flupenthixol. Indirect binding assays of D-1 receptors with numerous competing ligands resulted in steep displacement curves with Hill coefficients of 1. This is consistent with the existence of a single, homogeneous population of D-1 receptors.

Polyamines modulate the neurotoxic effects of NMDA in vivo.

The ability of polyamines to alter NMDA-induced neurotoxicity in neonatal rats was examined to determine whether polyamines modulate NMDA receptor activity in vivo. Unilateral injections of NMDA and/or polyamines were made into the striatum of 7-day-old rats. After 5 days, the brains were removed and 20 microns thick coronal sections were cut and stained with Cresyl violet. A computer-based image analysis system was used to densitometrically measure the cross-sectional area of intact tissue in the control and injected hemispheres. Administration of NMDA (5-40 nmol) produced a dose-dependent tissue damage that ranged from 7 to 52% of the area of the uninjected hemisphere. The polyamine agonist spermine (10-500 nmol) dose-dependently exacerbated the toxicity of a 15 nmol dose of NMDA, increasing the size of the lesion by up to 50%. Administration of spermine alone produced dose-dependent tissue damage that ranged from 9 to 52%. The damage produced by both NMDA and spermine could be completely inhibited by co-administration of the NMDA antagonist MK-801. The polyamine inverse agonist 1,10-diaminodecane (DA-10, 50-400 nmol) inhibited the damage produced by NMDA in a dose-dependent manner, with a maximal inhibition of 50%. Administration of DA-10 alone produced limited damage at doses above 100 nmol. The weak partial agonist diethylenetriamine had no effect by itself or on NMDA-induced toxicity at the doses tested. These results indicate that polyamines can modulate the activity of NMDA receptors in vivo and suggest that polyamines or related compounds may have important therapeutic potential as neuroprotective agents.

Effects of chronic treatment with selective agonists on the subtypes of dopamine receptors.

The effects of chronic administration of selective dopaminergic agonists on D1 and D2 receptor density, affinity and function were measured in Sprague-Dawley rats. Animals received daily injections (i.p.) of the D1-selective agonist SKF-38393 (10 mg/kg), the D2-selective agonist quinpirole (1 mg/kg), SKF-38393 plus quinpirole, or saline for 14 days. Quantitative autoradiographic analysis revealed that the density of D2 receptors was decreased following chronic treatment with quinpirole alone or in combination with SKF-38393 whereas SKF-38393 by itself had no effect on this receptor. In contrast, the density of D1 receptors was increased following treatment with SKF-38393. Although quinpirole by itself had no effect on D1 receptors, co-administration with SKF-38393 attenuated the up-regulation of D1 receptors produced by SKF-38393 in the caudate-putamen and nucleus accumbens but not in the substantia nigra. The up-regulation of D1 receptors in response to chronic SKF-38393 may be attributed to the partial agonist properties of SKF-38393 which may not provide sufficient D1 receptor stimulation to down-regulate the receptor. Quinpirole-induced hypothermia and SKF-38393-induced hyperthermia were measured before and after chronic agonist treatments to examine the effects of these treatments on thermoregulatory functions mediated by each receptor subtype. Treatment with quinpirole or quinpirole plus SKF-38393 resulted in desensitization of quinpirole-induced hypothermia, whereas treatment with SKF-38393 alone had no effect. All of the chronic treatments produced sensitization of SKF-38393-induced hyperthermia. Since not all treatments result in an increase in the density of D1 receptors, up-regulation of D1 receptors is not the sole mechanism for this sensitization.

Neurochemical changes associated with the persistence of spontaneous oral dyskinesia in rats following chronic reserpine treatment.

Rats treated chronically with reserpine develop spontaneous oral dyskinesia. The present study examined the development of the oral dyskinesia during the course of reserpine treatment, and its persistence after termination of treatment. Rats were injected with either reserpine (1 mg/kg, s.c.) or vehicle once daily for 4 days and then every other day for 6 weeks. Oral dyskinesia developed rapidly, reaching a maximal level after 3 days. It persisted at a maximal level for up to 20 days after termination of reserpine treatment, and continued to persist above control level for at least 60 days. The reserpine-treated rats also exhibited stereotypy in response to acute injection of the D1-selective agonist SKF-38393 (10 mg/kg), which was not observed in control rats. In contrast to the oral dyskinesia, this altered sensitivity to SKF-38393 returned to normal within 20 days after terminating the reserpine treatment, suggesting that these two behavioral responses involve different neural mechanisms. Quantitative autoradiographic measurement of dopamine receptor subtypes revealed that both D1 and D2 receptors were increased in the caudate-putamen (Cpu) and nucleus accumbens. Only the increase in D2 receptor density in the CPu correlated with the persistence of the oral dyskinesia; both changes persisted following termination of the reserpine treatment, and their magnitude was less at 60 days than at 1 and 20 days post-treatment. These results may have important implications for tardive dyskinesia.

Destruction of the nucleus raphe obscurus and potentiation of serotonin-mediated behaviors following administration of the neurotoxin 3-acetylpyridine.

Systemic administration of the neurotoxin 3-acetylpyridine (3-AP) to rats produced spontaneous episodes of spasmodic movement involving the trunk and limbs including torticollis, contortions of the trunk and rigid extension of the limbs. Because the neurotransmitter serotonin (5-HT) has been implicated in various human involuntary movement disorders, the functional and anatomical integrity of the 5-HT system in rats treated with 3-AP were examined. 5-HT-containing neurons in the brain stem were studied using immunohistochemical labeling with antiserum to 5-HT. Cells in the nucleus raphe obscurus were found to be altered following 3-AP treatment as shown by a decrease in 5-HT immunoreactivity as compared to control rats. No changes in 5-HT immunoreactivity were observed in any other region containing 5-HT cell bodies. Behaviorally, rats treated with 3-AP were 2.5-fold more sensitive to the ability of the 5-HT1A agonist 8-OH-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.33-3.3 mg/kg) to produce the 5-HT syndrome. Similarly, 3-AP-treated rats were 2-fold more sensitive to the selective 5-HT2 agonist 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB; 0-1.0 mg/kg) at producing the head shake response. Although these behaviors associated with brain stem 5-HT receptors were potentiated by 3-AP, the hypothermic effect of 8-OH-DPAT which involves ascending mesencephalic 5-HT neurons was unchanged following 3-AP treatment. Treatment with 3-AP did not produce significant alterations of 5-HT or 5-hydroxyindoleacetic acid (5-HIAA) content in any brain region studied. Quantitative autoradiographic analysis of the density of 5-HT1A receptors labeled with [3H]8-OH-DPAT revealed that these sites were unchanged in regions of the brain (frontal cortex, hippocampus and brain stem) and in the spinal cord. Similarly, few changes in the density of 5-HT2 receptors measured with [3H]ketanserin were observed in various brain regions. These results suggest that neurons from the nucleus raphe obscurus are involved in the elicitation of 5-HT-mediated behavioral responses by 5-HT1A and 5-HT2 receptor agonists that are though to be mediated through brain stem and spinal cord mechanisms. In addition, because of the close neuroanatomical relationship of the nucleus raphe obscurus with various brain regions known to be involved in motor control, the destruction of this region by 3-AP may contribute to the spasmodic motor behaviors observed following 3-AP treatment.

Longitudinal variation in cell density and mossy fiber reorganization in the dentate gyrus from temporal lobe epileptic patients.

Variation in cell loss and mossy fiber reorganization was examined along the longitudinal axis of the dentate gyrus from temporal lobe epileptic (TLE) patients. Previous evidence has indicated that the anterior hippocampus is prone to seizure activity. We compared granule and hilar cell number in addition to Timm stain density of the molecular layer and hilus in more anterior and more posterior specimens of hippocampus obtained from patients surgically treated for intractable epilepsy by the removal of the anterior half of the hippocampus. Granule cells/mm in the more anterior specimen were less than or equal to those in the more posterior specimen locations in 77% of the patients, while there was no significant difference in hilar neuron density between the two blocks. These results demonstrate a significantly greater pathology in the granule cell layer in more anterior specimens and no difference in pathology for hilar neurons. Molecular layer Timm stain density was significantly greater in the more anterior specimen of 71% of the patients. The molecular layer Timm stain density ratio was inversely related to hilar cell density in more anterior specimens, whereas in more posterior specimens there was no significant relationship with hilar cell density. Our observations show that although differences exist among TLE patients for these neuroanatomic measures, pathology was greater in more anterior specimens. The latter result is consistent with the conclusion that seizure activity may originate in the anterior region of the hippocampus in a majority of patients.

Ontogeny of dopamine D3 receptors in the nucleus accumbens of the rat.

The expression of dopamine D2 and D3 receptors in the developing rat nucleus accumbens and striatum was examined using quantitative receptor autoradiography. Male Sprague-Dawley rats were sacrificed on postnatal day 3, 7, 10, 14, 21, or 60. Sections were labeled with [125I]NCQ 298, which binds to both D2 and D3 receptor subtypes. Binding to D2/D3 receptors in the caudate-putamen appeared as early as P3 (approximately 20% of adult) and approached adult levels (75% of adult) by P21. D2/D3 receptors in the nucleus accumbens and olfactory tubercle developed with a similar time course. [125I]R(+)trans-7-hydroxy-2-(N-n-propyl-N-3'-iodo-2'-propenyl)aminotetra lin ([125I]7-OH-PIPAT) was used to selectively label D3 receptors in adjacent sections. [125I]7-OH-PIPAT binding was absent at P3 and just detectable at P7 and P10 (approximately 5% of adult). Appreciable D3 labeling appeared in the islands of Calleja at P14 and in the nucleus accumbens at P21. [125I]7-OH-PIPAT also detected a very low density of D3 receptors in the caudate-putamen which developed with a profile very similar to that of D3 receptors in the nucleus accumbens. Expression of the D2 receptor subtype therefore appears to precede expression of the D3 receptor subtype. Additionally, D2 receptors in different regions are expressed with a similar developmental profile, but there appears to be more heterogeneity in the ontogeny of forebrain D3 receptor expression.

Variations in the behavioral responses to apomorphine in different strains of rats.

The present experiments compared patterns of locomotor activity during repeated acclimation sessions and determinations of locomotion and stereotypy elicited by administration of the direct dopamine receptor agonist apomorphine in five inbred strains of rats: the results suggest that each strain can be differentiated phenotypically according to these behavioral responses. Brown Norway rats demonstrated the greatest locomotion during acclimation sessions. Low doses of apomorphine (0.1 and 0.32mg/kg) produced a flat body posture in Lewis animals. A higher dose of apomorphine (1.0mg/kg) markedly increased locomotion in Fisher rats. Buffalo animals showed licking during control sessions and the greatest increase in gnawing at higher doses of apomorphine. DA rats were less responsive than the other strains of apomorphine. Between-strains autoradiographic determination of dopamine receptor densities revealed several differences in D1 receptors labeled by (3)H-SCH 23390 and D2/D3 receptors labeled by (125)I-NCQ 298 in the caudate-putamen and nucleus accumbens. However, the heterogeneity of dopamine receptor densities was not sufficient to explain the strain-specific behavioral responses. These experiments demonstrate variations in behavioral and neurochemical characteristics of inbred strains of rats which could be used to model genetically determined differences in dopamine-mediated behavioral responses.

Mossy fiber reorganization and its possible physiological consequences in the dentate gyrus of epileptic humans.

It is unlikely that MF reorganization is the cause of epilepsy, but it may affect the progression of the disease, i.e., the frequency or severity of seizures. We propose that early events, yet undiscovered, lead to an increased likelihood of excitability. This hyperexcitability, which initially may not be manifested in overt seizures, may erode vulnerable hilar neurons that serve an important inhibitory function, as illustrated in Fig. 6-15. As inhibition is lost, hyperexcitability reaches the level of clinically manifested seizures that are severe enough to lead to substantial loss of hilar neurons. When the loss of these cells is sufficiently high, MF reorganization occurs, first to neighboring hilar neurons and later to dendrites of granule cells (Fig. 6-15). Thus, the functional consequence of MF reorganization may provide a compensatory form of inhibition, as well as a circuit for feedback excitation. Although definitive evidence indicating that MF reorganization contributes to the acceleration or progression of epilepsy is missing, the findings to date are consistent with this hypothesis. In the event that reorganization contributes to the epileptic condition, treatments that reduce indicators of neuropathology may lead to a reduction of seizure frequency and severity. Evidence suggests that reorganization in the dentate gyrus may follow the pathways of neuronal processes of hilar neurons that have died. Thus, further study of the events that guide MF reorganization may hold important clues for developing methods for targeting regenerating axons following central nervous system injury.

Physiological and anatomical correlates of the human dentate gyrus: consequences or causes of epilepsy.

The presence of paroxysmal discharges in the epileptic human dentate gyrus provides a physiologic basis for hyperexcitability that may initiate seizure discharges during the development of epilepsy. Although these responses can occur with single orthodromic stimulation, data obtained under conditions that weaken synaptic inhibition (e.g., 1 Hz stimulation or bicuculline disinhibition) suggest that paroxysmal discharges may be a more common feature of tissue from temporal lobe epileptic patients than has been reported previously. Hilar cell loss and weakened synaptic inhibition may provide conditions favorable for the activation of N-methyl-D-aspartate acid (NMDA) receptors that would allow triggering of paroxysmal discharges that normally never are evoked in dentate granule cells in nonepileptic humans. As the dentate gyrus in normal animal tissue is not susceptible to intrinsic bursting behavior and is characterized by a relatively short duration excitatory postsynaptic potential even under pharmacologic disinhibition, paroxysmal discharges in the epileptic human dentate gyrus may provide an important clue to understanding the prerequisite conditions for seizure discharge.

Changes in behavioral sensitivity to SKF-38393 and quinpirole following withdrawal from continuous cocaine administration in rats.

The effects of withdrawal from continuous administration of cocaine on spontaneous locomotor activity and behavioral sensitivity to SKF-38393 and quinpirole were examined in rats. Subdermal minipumps that delivered either saline or 20 mg/kg/day cocaine hydrochloride were implanted for 14 days. Spontaneous locomotor activity, SKF-38393-induced (10 mg/kg, SC) grooming and tongue protrusions, and quinpirole-induced locomotor activity and stereotypy (0.32 and 1.0 mg/kg, SC) were examined either 4-5 h or 7 days after removal of the minipumps. Animals withdrawn from cocaine for 4 h exhibited a decrease in spontaneous locomotor activity relative to saline-pretreated controls, whereas animals withdrawn for 7 days did not differ from controls. Animals withdrawn from cocaine for 4 h did not differ from controls in their sensitivity to SKF-38393, whereas animals withdrawn from cocaine for 7 days exhibited an increase in SKF-38393-induced tongue protrusions relative to controls. In contrast, animals withdrawn from cocaine for 4 h exhibited a decrease in quinpirole-induced locomotion, whereas animals withdrawn for 7 days did not differ from controls. There were no differences in sensitivity to quinpirole-induced stereotypy relative to controls at either withdrawal period. These findings suggest that an increased sensitivity of D1-like receptors emerges within 7 days during the course of withdrawal from continuous cocaine administration, whereas a change in sensitivity of D2-like receptors may occur early during withdrawal but normalizes within 7 days.

Thyroid and thyroxine effects on adrenoreceptors in relation to circadian activity.

Experiments were conducted to ascertain if changes in central adrenergic receptors could be associated with altered circadian activity patterns induced by thyroparathyroidectomy (TPX) and thyroxine. An initial experiment used TPX and sham-operated rats that had been exposed to dim red light for 7 months. The alpha and beta receptor densities were compared in the suprachiasmatic nuclei (SCN), preoptic (PO), septum, and caudate-putamen. TPX animals showed significant reductions in beta 1 and beta 2 receptor densities in SCN and PO, and alpha 1 densities in SCN, but no other changes. A second experiment, lasting 4 months, examined the effects of thyroxine, which has been shown to reverse the period-shortening effects of TPX surgery. Thyroxine significantly increased beta 1 receptors in both the SCN and ventromedial hypothalamus (VMH), the only regions that displayed significant reductions in TPXs during the second experiment. Increases of sevenfold and threefold were observed in the SCNs of TPXs and shams, respectively, but thyroxine's action in the VMH was limited to TPX animals, an effect that mimics thyroxine's action on circadian activity rhythms.