Specific neurotoxin lesions of median raphe serotonergic neurons disrupt maternal behavior in the lactating rat.

Impairments in lactation after electrolytic lesions of the median raphe (MR) nucleus have been corrected by treatment with PRL. Specific serotonin neurotoxin lesions were used in the present study to determine whether decrements in litter growth after electrolytic lesions could be attributed to serotonergic neuron damage at the MR locus, and whether MR lesions (MRL) disrupted suckling-induced PRL release. Intracerebral microinjection of 5,7-dihydroxytryptamine (5,7-DHT) into the MR nucleus produced dose-related decrements in litter growth after either 4 micrograms (sham, 1.35 +/- 0.05; MRL, 1.04 +/- 0.05 g/pup X day; P less than 0.001) or 8 micrograms 5,7-DHT (sham, 1.35 +/- 0.06; MRL, 0.87 +/- 0.11 g/pup X day; P less than 0.001). Despite hypothalamic serotonin depletions of 15% and 55%, respectively, for the two doses of 5,7-DHT, there was no difference between sham and MRL animals in either basal or suckling-induced PRL release. When lesions were placed on day 1 of lactation (L) so that killing on day 7-L corresponded to the early maximal neurotoxin effect, MRL mothers still showed litter growth decrements (0.37 +/- 0.07; sham, 0.98 +/- 0.08 g/pup X day; P less than 0.001) and normal PRL values. When maternal behavior was examined, MRL animals exhibited a higher incidence of abnormal behaviors (failure to retrieve pups, cannibalism, and failure to initiate suckling during a 1-h test period; Fisher's exact P, Sham vs. MRL, less than 0.01, less than 0.05, and 0.15, respectively) than sham animals or animals with 5,7-DHT lesions in the dorsal raphe nucleus or superior colliculus. In addition, suckling behavior scores, determined from daily suckling behavior observations, were lowest in the MRL group and correlated with litter growth only in this group (r = 0.789; P less than 0.01). These data suggest that serotonergic elements in the MR nucleus play an obligatory role in maintaining normal maternal behavior during lactation, but they are not involved in suckling induced PRL release.

Age-related reduction in pituitary corticotropin-releasing hormone receptors in two rat strains.

Open field behavior and age-related changes in anterior pituitary corticotropin-releasing hormone (CRH) receptors, as well as plasma ACTH levels, were measured in two inbred rat strains. The strains utilized were Wistar Kyoto (WKY) and Brown-Norway (BN), the former characterized by shorter life-span and hyper-reactivity to stressors as compared to the latter. Behaviorally, WKY rats showed hyper-responsivity to a novel environment as indicated by their delay in entering the open field, increased grooming, reduced rearing, and reduced locomotion. These strain-dependent behavioral differences were not affected by aging. The binding capacity of CRH receptors was similar in both strains and Bmax values were decreased (25-27%) with aging, with no changes in Kd values. In contrast, plasma ACTH levels were 67% higher in WKY than in BN rats but did not change with aging. Thus, despite pituitary CRH receptor down regulation, plasma ACTH levels following decapitation were sustained during aging. This suggests the presence of some compensatory factors in the hypothalamic-pituitary axis regulation which sustain ACTH response during aging. Furthermore, the findings indicate that higher plasma ACTH levels and hyper-reactivity to a novel environment are inversely correlated with longevity in the rat.

Nicotine blocks quinpirole-induced behavior in rats: psychiatric implications.

RATIONALE AND OBJECTIVES: Because of known and imputed roles of dopaminergic and nicotinic cholinergic systems in a variety of neurological and neuropsychiatric disorders, combined neurochemical and behavioral methods assessments were made to study the intermodulatory roles of these neurochemical systems. METHODS: Rats were treated daily during postnatal ontogeny with the dopamine D2/D) agonist, quinpirole (QNP) HCl (1.0 mg/kg/day), for the first 3 weeks from birth. This priming process replicated previous findings of behavioral sensitization, manifested as hyperlocomotion, increased paw treading with jumping, and increased yawning. RESULTS: All effects were partially or totally blocked by acute treatment with nicotine (0.3 mg/kg, i.p.). The effects of nicotine, in turn, were partially or totally blocked by the nicotinic antagonist, mecamylamine (1.0 mg/kg, i.p.). In concert with these behavioral actions, QNP-primed rats displayed greater binding of [3H]cytisine in midbrain and cerebellum and greater [125I]alpha-bungarotoxin binding in hippocampus and striatum. CONCLUSIONS: Accordingly, these selective ligands for alpha4beta2 and alpha7 nicotinic receptors, respectively, demonstrate that nicotinic receptors are altered by dopamine D2/D3 agonist treatment of rats with primed dopamine receptors. We propose that nicotinic agonists may have a therapeutic benefit in behavioral disorders brought about by central dopaminergic imbalance.

Alterations of mouse adrenal medullary catecholamines and enzymes in response to attack: effect of pre- and post-treatment with phenobarbital.

Group-housed male C57BR/cdJ mice (victims) were exposed to attack for 10 min daily for up to 14 days by male Swiss-Webster mice, made aggressive by prolonged isolation. Their adrenal glands were analyzed for tyrosine hydroxylase (TH) and phenylethanolamine-N-methyltransferase (PNMT) activities and for norepinephrine (NE) and epinephrine (EPI) concentrations. TH was increased to 41 per cent above control after two exposures and remained elevated through 14 exposures to attack. PNMT was increased to 29 per cent above control after 2 days and increased further to 50 per cent above control after 14 days of attack. Both NE and EPI increased to 88 per cent and 51 per cent above control, respectively, after 7 days. In victim mice recuperating after 1 week of daily stress, EPI levels and PNMT activities were back to normal after 4 days whereas NE levels and TH activities returned to normal only after 1 week. Phenobarbital (40 mg/kg, i.m.) was effective in preventing the biochemical changes when given 2 h prior to each daily attack but was ineffective when given immediately after each daily stress.

Both nicotine and mecamylamine block dizocilpine-induced explosive jumping behavior in mice: psychiatric implications.

Dizocilpine (MK-801) administration to an outbred strain of NIH Swiss mice elicits discrete episodes of explosive jumping behavior designated as "popping." This behavior may serve as a useful preclinical paradigm for the screening of potentially novel antipsychotic medications. Both nicotine and mecamylamine, a nicotinic antagonist, dose-dependently blocked dizocilpine-induced popping. The data suggest that nicotine may be of therapeutic benefit in the treatment of schizophrenia and that some of its effects may be mediated by non-nicotinic receptors.

Antidepressant effects of nicotine in an animal model of depression.

Epidemiological studies indicate a high incidence of cigarette smoking among depressed individuals. Moreover, individuals with a history of depression have a much harder time giving up smoking. It has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. Although some animal and human studies suggest that nicotine may act as an antidepressant, further verification of this hypothesis and involvement of nicotinic cholinergic system in depressive symptoms is required. Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression. These rats, selectively bred for their hyperresponsiveness to cholinergic stimulation, show an exaggerated immobility in the forced swim test compared to their control Flinders Resistant Line (FRL) rats. Acute or chronic (14 days) administration of nicotine (0.4 mg/kg s.c.) significantly improved the performance of the FSL but not the FRL rats in the swim test. The effects of nicotine on swim test were dissociable from its effects on locomotor activity. Moreover, the FSL rats had significantly higher [3H]cytisine binding (selective for the alpha4beta2 nicotinic receptor subtype) but not [125I]alpha-bungarotoxin binding (selective for the alpha7 subtype) in the frontal cortex, striatum, midbrain and colliculi compared to FRL rats. These data strongly implicate the involvement of central nicotinic receptors in the depressive characteristics of the FSL rats, and suggest that nicotinic agonists may have therapeutic benefits in depressive disorders.

Changes in alpha-melanotropin in discrete brain areas of isolated aggressive mice.

Adult male Swiss-Webster (NIH) mice were isolated for 6 weeks. Aggressive behavior was tested on 2 occasions, 24 hours apart. Immediately following the 2nd test period, aggressors and isolated non-aggressors (controls) were decapitated and alpha-MSH concentration was measured in discrete areas of the brain. Only the nucleus accumbens and preoptic lateralis of the aggressors, showed a higher level of alpha-MSH when compared to the controls. The significance of these changes is discussed.

Distribution and origin of bombesin, substance P and somatostatin in cat spinal cord.

Bombesin (BN), substance P-(SP) and somatostatin (SRIF) were measured in individual laminae of the cervical, thoracic and lumbar (L) spinal cord of control cats, and in the L6 segment of cats receiving a spinal hemisection (L2) or deafferentation via dorsal rhizotomy at L6, 7, S1. The interlaminar distribution of BN, SP, and SRIF was remarkably similar. Highest concentrations were found in the superficial dorsal horn, and progressively less was found proceeding ventrally. Some intersegmental variations in peptide concentration within a single lamina were found. Dorsal rhizotomy caused a significant decline in BN, SP and SRIF in lamina I-III, therefore all three peptides appear to be contained in dorsal root ganglion cells. Evidence is presented for the existence of ascending BN and SP projections originating in lamina I-III and VII, for a descending SRIF pathway terminating in lamina VIII, and for an ascending BN path in lamina VIII. Dorsal root afferents to lamina VIII influence levels of BN, SP and SRIF.

Characteristics of 3H-substance P binding sites in rat brain membranes.

Binding characteristics of 3H-Substance P (SP) were studied with rat brain membranes using a method applied to peripheral tissues by Lee and Snyder [15]. This method was well applicable to central nervous system (CNS) tissues. The results in the present study indicate that specific 3H-SP binding reaches a plateau only after 20 minutes of incubation, and the binding sites are saturable at a relatively low concentration of 3H-SP. Scatchard analysis of specific binding data reveals a single class of binding sites with a high affinity (Kd = 0.30 nM) and a low density (Bmax = 27.7 fmol/mg protein) in rat brain membranes. A Hill plot of the displacement curve of 3H-SP with unlabelled SP showed no indication for cooperativity (nH = 0.83). The relative potencies of binding of various SP fragments at 3H-SP binding sites were fairly parallel to the length of the C-terminal fragments. Neurotransmitters not structurally related to SP produced no effect on 3H-SP binding even when used at micromolar concentrations.

Effect of chronic reserpine and desmethylimipramine treatment on CRF-like immunoreactivity of discrete brain areas of rat.

The corticotropin releasing factor-like immunoreactivity (CRF-LI) of discrete areas of rat brain were measured following reserpine (2 mg/kg i.p. for 3 days) or chronic desmethylimipramine (DMI) (20 mg/kg i.p. for 14 days) treatment. Reserpine caused a 40% and 36% reduction in the (CRF-LI) of the median eminence (ME) and posterior pituitary respectively, while DMI caused a 61% rise in CRF-LI of the posterior pituitary only. The results support the role of monoaminergic regulation of CRF release from the ME and further suggest an interaction between monoaminergic and CRF neurons in the posterior pituitary.

Age-dependent loss and compensatory changes of septohippocampal cholinergic neurons in two rat strains differing in longevity and response to stress.

Inbred Wistar-Kyoto rats which are behaviorally more reactive to stress have a shorter life span than Brown-Norway rats. This is paralleled by higher basal activity and more pronounced changes in the septohippocampal cholinergic system of Wistar-Kyotos after stress. Age- and strain-dependent differences were therefore characterized in the septohippocampal system of 3- and 24-month-old (aged) Wistar-Kyotos and Brown-Norways, and in 30-month-old Brown-Norways. High affinity [3H]choline uptake and newly synthesized [3H]acetylcholine release served as markers for cholinergic terminals in the hippocampus. [3H]Quinuclidinylbenzilate binding served as a marker of muscarinic receptors in the hippocampus. Choline acetyltransferase activity served as a marker for cholinergic neurons and their terminals in the septum and hippocampus respectively. Acetylcholinesterase histochemical staining served to localize cholinergic neurons and their terminals in the septum and hippocampus respectively. In the hippocampus of aged Wistar-Kyotos choline uptake and acetylcholine release were reduced by approximately 50% compared to their young counterparts, but remained unchanged in aged Brown-Norways. Hippocampal choline acetyltransferase activity, acetylcholinesterase staining and muscarinic binding were unchanged in aged rats of both strains. Pyramidal cell loss (observed in Cresyl violet stained sections) was detected in hippocampus of 24-month-old Wistar-Kyotos and 30-month-old, but not younger Brown-Norways. Numbers of acetylcholinesterase-stained cells in the septum were reduced by 45 and 25% in 24-month-old Wistar-Kyotos and Brown-Norways respectively, and by 50% in 30-month-old Brown-Norways. Mean diameter of these cells was increased only in aged Wistar-Kyotos (approximately 46%) and in 30-month-old Brown-Norways (40%). The results indicate: (1) there is an ongoing age-dependent degeneration of septohippocampal cholinergic neurons which is associated with two principal compensatory changes in remaining cholinergic neurons: (a) hypertrophy of perikarya and (b) relative increase in activity of presynaptic markers in terminals with unchanged regional distribution, suggesting possible collateral sprouting; (2) age-dependent loss of septal cholinergic neurons precedes loss of hippocampal pyramidal neurons and (3) loss of pyramidal neurons in the hippocampus is associated with a compensatory increased muscarinic binding by remaining target hippocampal neurons. The results imply that higher basal and stress-induced activity of septohippocampal cholinergic neurons may be correlated with an accelerated and more pronounced age-dependent degeneration of this cholinergic system.(ABSTRACT TRUNCATED AT 400 WORDS)

Region-selective stress-induced increase of glutamate uptake and release in rat forebrain.

The study describes stress-induced changes in high-affinity uptake and release of glutamate by synaptosomal preparations from several regions of rat brain. The results demonstrate that restraint stress can lead to increased glutamate uptake and release in limbic forebrain regions (frontal cortex, hippocampus and septum) but not in the striatum. The increase in glutamate uptake was evident after 30 min of stress. A plateau (140-150% of unhandled controls) was reached after 1 h and was maintained after 4 h of continuous stress. The stress-induced increase in glutamate uptake was observed with glutamate concentrations of up to 10 microM, but not with 500 microM. the results indicate that forebrain glutamatergic terminals are activated by stressful stimuli in a regionally selective manner, and suggest that enhanced high-affinity uptake is important in clearing increased levels of released glutamate.

Deafferentation causes a loss of presynaptic bombesin receptors and supersensitivity of substance P receptors in the dorsal horn of the cat spinal cord.

Bombesin (BN)- and substance P (SP)-containing neurons are found in the dorsal root ganglia, and project to the dorsal horn of the spinal cord. The present study was undertaken to determine if chronic deafferentation of the cat spinal cord would affect BN or SP receptors in the spinal cord. Ten and 30 days after a unilateral lumbosacral dorsal rhizotomy, BN and SP receptor binding was evaluated autoradiographically using iodinated ligands to bind to these receptors in vitro. The normal distribution of BN receptors detected by this method was restricted to the head of the dorsal horn. Deafferentation caused a 38% and 22% decline in BN receptor binding in laminae I-IV at 10 or 30 days postoperatively, respectively. These data suggest that 'presynaptic' BN receptors are found on the central nervous system terminals of primary sensory afferents. Normal SP receptor distribution was most dense in lamina X, not in the superficial laminae of the dorsal horn. Deafferentation caused an initial decline in SP receptor binding in laminae I-II, followed by a 14% increase at 30 days in comparison to the unoperated side of the spinal cord. This delayed supersensitivity of SP receptors was confirmed in a separate experiment using a homogenate binding assay. These data are discussed with respect to the potential roles of receptor supersensitivity or subsensitivity in the development of deafferentation-induced changes in reactivity of dorsal horn neurons to nociceptive and non-nociceptive stimuli.

Evidence for a frontocortical-septal glutamatergic pathway and compensatory changes in septal glutamate uptake after cortical and fornix lesions in the rat.

To determine the source of glutamatergic input to the septum and to the nucleus accumbens septi, glutamate uptake was assessed after transections of the frontal cortex and/or fornix. Uptake in the septum and accumbens was reduced by 25 and 30% respectively, 6 days after bilateral frontal cortex transections. Both indices returned to control levels 30 days postoperatively. In contrast, while unilateral fornix transection did not affect uptake in the accumbens at either day 6 or 30, uptake in the septum was significantly reduced (25-35%) at both times. When a unilateral transection of the fornix was performed in rats with a pre-existing bilateral ablation of the frontal cortex, a further reduction in uptake was observed in the septum (50-60% at both 6 and 30 days after the fornix transection). The data implicate glutamate as a neurotransmitter in frontocortico-septal projections and suggest that the contribution of the hippocampo-septal system to total glutamate uptake in the septum is increased following ablation of the frontocortico-septal system.

Aging and stress-induced changes in choline and glutamate uptake in hippocampus and septum of two rat strains differing in longevity and reactivity to stressors.

Stress induced changes in neurochemical indices of neurotransmission are more pronounced in the septohippocampal cholinergic system of Wistar Kyoto rats, which are behaviorally more reactive to stressors and have a shorter life span, than in Brown Norway rats. Moreover, pronounced degeneration of septohippocampal cholinergic neurons occurs earlier in life in Wistar Kyoto rats. In the present study the high affinity synaptosomal uptakes of choline and glutamate were used as indices for cholinergic and glutamatergic systems respectively. Following 2 hr of mild restrain stress increases in both uptake systems were observed in all regions examined (hippocampus, septum and frontal cortex). The stress-induced increases were generally similar in young (3 months) and aged (20 months) rats of both strains. The noted exception was that choline uptake levels, which were reduced in the hippocampus of unhandled aged WKY rats, remained unchanged after stress. The results confirm the involvement of the septohippocampal cholinergic system in the response to acute stress and extend the findings to include the hippocamposeptal glutamatergic system activation as well. It is suggested that in spite of neuronal degeneration during aging, these responses to stress can be maintained by compensatory efforts of neurons that remain intact.

Evaluation of the effect of p-chloroamphetamine on individual catecholaminergic nuclei in the rat brain.

Short and long term effects of p-chloroamphetamine (PCA) on levels of catecholamines (CA) in discrete CA cell body and axon terminal areas were investigated. The levels were unaffected, except for a transient fall in dopamine in the arcuate nucleus. These results do not support the suggestion that PCA is neurotoxic to CA cells.

Effects of chronic stressors or corticosterone treatment on the septohippocampal cholinergic system of the rat.

The effects of prolonged (2 months) corticosterone (CORT) treatment on several cholinergic markers of various brain areas were compared to the effects of prolonged intermittent exposure to stress. CORT, but not stress, caused a significant reduction in the number of acetylcholinesterase-stained neurons in the medial septal area. Neither treatment resulted in any hippocampal pyramidal cell loss. It is concluded that a time-dependent degeneration of the septohippocampal cholinergic system follows 2 months of CORT administration but not chronic intermittent stress of this duration.

Nicotine attenuates DOI-induced head-twitch response in mice: implications for Tourette syndrome.

Tourette syndrome (TS), a chronic neuropsychiatric disorder, is characterized by motor and vocal tics. Preliminary clinical studies indicate possible therapeutic benefits of nicotine in the treatment of Tourette's syndrome (TS). It has been proposed that twitches of the head in mice or twitches of head and shoulders in rats following administration of the selective 5HT(2A/C) agonist DOI (1-)2,5-dimethoxy-4-iodophenyl-2-aminopropane, can serve as an animal model of tics in TS. In this study, the effects of acute and chronic administration of nicotine on DOI-induced head twitch response (HTR) in male albino ICR mice were evaluated. Both acute and chronic nicotine (daily injections for 10 days) reduced the DOI-induced HTR. Moreover, chronic administration of DOI (1 mg/kg/day for 10 days) resulted in 65% increase in [125I]alpha-bungarotoxin binding in cerebellum and 41% increase in striatal [3H]cytisine binding. However, the acute inhibitory effects of nicotine were not blocked by pretreatment with the nicotinic antagonist, mecamylamine. Indeed, at higher doses, mecamylamine also reduced the DOI-induced HTR. The data suggest that both nicotine and mecamylamine may be of therapeutic potential in the treatment of some symptoms of TS.

Isolation induced aggression and catecholamine variations in discrete brain areas of the mouse.

Norepinephrine (NE) and dopamine (DA) levels and turnover were measured in 17 discrete brain regions of Swiss-Webster (NIH) mice made aggressive by prolonged isolation. The NE steady state level was significantly lower in olfactory tubercle and substantia nigra and significantly higher in the septal area of the aggressive mice when compared to the isolated non-fighter controls. NE turnover was only higher in the A-10 region of the aggressors. DA steady state level and turnover was lower in olfactory tubercle and higher in caudate putamen of the aggressors. The significance of these changes in isolation-induced aggression is discussed.

Identification and distribution of alpha-melanotropin in discrete regions of the cat brain.

The distribution of alpha-melantropin-like material (alpha-MSH) was demonstrated in rat brain using a microdissection technique combined with radioimmunoassay. Highest concentrations of alpha-MSH were noted in the hypothalamus and preoptic area. Particularly high concentrations were observed in the arcuate nucleus, median eminence, suprachiasmatic nucleus, periventricular nucleus and the medial preoptic nucleus. The thalamic paraventricular nucleus also contained high alpha-MSH concentrations. Moderate to low concentrations were noted in other thalamic, septal, amygdaloid and midbrain nuclei. Low concentrations were observed in cortical and striatal regions.