Hippocampal asymmetry in the behavioral responses to the 5-HT1A receptor agonist 8-OH-DPAT

The present study examined the behavioral responses of rats to unilateral and bilateral injections of the selective serotonin 1A (5-HT1A)-receptor agonist 8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT) 1 μg into the hippocampal CA1 area of male Wistar rats. 8-OH-DPAT increased locomotor activity, which was most pronounced with injections into the left hippocampus. The agonist impaired learning and memory (shuttle-☐), especially when injected into the right hippocampus. The elevated plus-maze experiments showed that neither left nor right nor bilateral hippocampal injections of 8-OH-DPAT produced any anxiogenic effect. However, with Vogel's conflict test, right injections of 8-OH-DPAT produced anxiety. The present study has revealed hippocampal asymmetry in the behavioral responses to the 5-HT1A-receptor agonist 8-OH-DPAT.     

Medial amygdaloid suppression of predatory attack behavior in the cat: I. Role of a substance P pathway from the medial amygdala to the medial hypothalamus

The medial amygdala is known to powerfully suppress predatory attack behavior in the cat, but the mechanisms underlying such modulation remain unknown. The present study tested the hypothesis that medial amygdaloid suppression of predatory attack is mediated, in part, by a pathway from the medial amygdala to the medial hypothalamus which utilizes substance P as a neurotransmitter. Stimulating electrodes were implanted into the medial amygdala and cannula electrodes were implanted into both the medial and lateral hypothalamus. Predatory attack behavior was elicited by electrical stimulation of the lateral hypothalamus. In the first phase of the study, paired trials compared attack latencies of single stimulation of the lateral hypothalamus with those following dual stimulation of the lateral hypothalamus and medial amygdala. Attack latencies were significantly elevated following dual stimulation of the medial amygdala and lateral hypothalamus. In the second phase of the study, dose and time dependent decreases in response suppression were noted following the infusion of the substance P (NK₁) receptor antagonist, CP96,345 (in doses of 0.05, 0.5 and 2.5 nmol) into the medial hypothalamus. In third phase of the study, the effects of microinjections of the substance P receptor agonist, [Sar⁹,Met(O₂)¹¹]-substance P (in doses of 0.5, 1.0 and 2.0 nmol), directly into the medial hypothalamus upon lateral hypothalamically elicited predatory attack behavior were determined. Microinfusion of this drug elevated attack response latencies in a dose- and time-dependent manner. In addition, pretreatment with CP96,345 into the medial hypothalamus blocked the suppressive effects of subsequent delivery of [Sar⁹,Met(O₂)¹¹]-substance P into the same medial hypothalamic site. Other parts of the study demonstrated the presence of: (1) high densities of substance P receptors in the ventromedial hypothalamus, and (2) neurons that are positively labeled for substance P that project from the medial amygdala to the ventromedial hypothalamus as demonstrated by retrograde labeling with Fluoro-Gold. These findings provide support for the hypothesis that medial amygdaloid suppression of lateral hypothalamically elicited predatory attack behavior includes a substance P pathway from the medial amygdala to the medial hypothalamus. The findings further suggest that stimulation of the medial amygdala activates substance P receptors in the medial hypothalamus, thus triggering an inhibitory mechanism from the medial to the lateral hypothalamus, resulting in suppression of predatory attack behavior.     

The 5-HT1A receptor antagonist (S)-UH-301 blocks the (R)-8-OH-DPAT-induced inhibition of serotonergic dorsal raphe cell firing in the rat

Summary (S)-UH-301 [(S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin, 0.5–4.0 mg/kg i.V.] did not significantly alter the firing rate of 5-hydroxytryptamine (5-HT) containing neurons in the dorsal raphe nucleus (DRN) as a group, although some individual cells were activated whereas others were depressed. However, (S)-UH-301 (2.0mg/kg i.v.) consistently reversed the inhibition of DRN-5-HT cells produced by the selective 5-HT_1A receptor agonist (R)-8-OH-DPAT (0.5 g/kg i.v.) and the dose-response curve for this effect of (R)-8-OH-DPAT was markedly shifted to the right by pretreatment with (S)-UH-301 (1.0mg/kg i.v.). These results support the notion that (S)-UH-301 acts as an antagonist at central 5-HT_1A receptors.     

Facilitating antidepressant-like actions of estrogens are mediated by 5-HT1A and estrogen receptors in the rat forced swimming test

Previous studies have shown that 17beta-estradiol (E2) induces antidepressant-like actions per se and potentiates those produced by fluoxetine (FLX) in the forced swimming test (FST). The aim of the present work was to explore the participation of serotonin 1A receptors (5-HT1A) and estrogen receptors (ERs) in the antidepressant-like actions of E2, FLX or their combination in the FST. Although all antidepressants reduce behavioral immobility, antidepressants that modulate serotonergic neurotransmission increase swimming behavior whereas those that modulate the catecholaminergic neurotransmission increase climbing behavior. Thus, using this animal model, it is possible to infer which neurotransmitter system is modulating the action of an antidepressant compound. Ovariectomized female Wistar rats were used in all experiments. In the first experiment, an effective dose of E2 (10 microg/rat, -48 h) was combined with several doses (0.5, 1.0 and 2 mg/kg) of RU 58668 (a pure ER antagonist) 48 h previous to the FST. The second experiment evaluated the action of (1 mg/kg, -48 h or -23, -5 and -1 h) WAY 100635 (5-HT1A receptor antagonist) on the antidepressant-like action of FLX (10 mg/kg, -23, -5 and -1 h). In the third experiment, the effect of RU 58668 (2 mg/kg, -48) or WAY 100635 (1 mg/kg, -48 h) on the antidepressant-like action of the combination of a sub-optimal dose of E2 (2.5 microg/rat, -48 h) plus a non-effective dose of FLX (2.5 mg/kg, -23,-5 and -1 h) was evaluated. The results showed that RU 58668, the antagonist to the ER, canceled the antidepressant-like action of E2 in a dose-dependent manner. The antagonist to the 5-HT1A receptor blocked the antidepressant action of FLX only when administered simultaneously with FLX, i.e. -23, -5 and -1 h before the FST. Finally, the administration of both RU 58668, and WAY100635 canceled the antidepressant-like action of the combination of E2/FLX. These results imply that both 5-HT1A receptors and ERs participate in the facilitating actions of E2 on the antidepressant-like action of FLX in the FST.     

Partial 5-HT(1A) receptor agonist activity by the 5-HT(2C) receptor antagonist SB 206,553 is revealed in rats spinalized as neonates

Modification of spinal serotonergic receptors caudal to spinal injury occurs in rats that received spinal cord transections as neonates. Evaluation of the serotonin syndrome, a group of motor stereotypies elicited by serotonergic (5-HT) agents in 5-HT-depleted animals, and open field locomotor behavior were used to assess behavioral consequences of injury and treatment. We extend these findings to show that a partial 5-HT(1A) agonist activity is revealed by the 5-HT(2C) receptor antagonist (SB 206,553) in this animal model, as measured by evaluation of serotonin syndrome behavior. Treadmill stimulation enhances this motor response, caudal to the injury, in the hindlimbs and tail. These results imply a broader modification of serotonergic receptors than previously thought and suggest a potential strategy by which serotonergic agents may enhance functional recovery following neonatal injury.     

5-HT1A agonists and dopamine: the effects of 8-OH-DPAT and buspirone on brain-stimulation reward

Summary Two specific 5-HT_1A agonists, 8-OH-DPAT (0–300 g/kg), and buspirone (0–3.0 mg/kg), were tested on variable-interval, threshold-current self-stimulation of rat lateral hypothalamus. Buspirone produced a prolonged monotonic depression of responding, whereas the effects of 8-OH-DPAT were biphasic: 3.0 g/kg produced a sustained enhancement of responding while higher doses (100–300 g/kg) produced a relatively short-lasting depression. This biphasic pattern parallels previously reported effects of 8-OH-DPAT on food intake and on various other behaviours. Threshold-current self-stimulation is highly sensitive to alterations in dopaminergic transmission but relatively insensitive to changes in 5-HT. Thus the facilitatory effect of low-dose 8-OH-DPAT seems most plausibly interpreted in terms of enhanced dopaminergic transmission. This could be brought about by 5HT_1A autoreceptor-mediated inhibition of 5-HT release and consequent disinhibition of dopaminergic transmission. Depression of self-stimulation by higher doses of 8-OH-DPAT may reflect the activity of 8-OH-DPAT at postsynaptic 5-HT receptors, with consequent inhibition of DA transmission. Suppression of responding after buspirone at all doses tested may reflect the action of this compound as a partial agonist at postsynaptic 5-HT receptors, and/or its effects on other systems.     

Antagonism of muscarinic receptors in the rabbit iris-ciliary body by 8-OH-DPAT and other 5-HT1A receptor agonists

Summary Physiological studies have shown that serotonin and 5-HT_1A agonists can influence muscarinic function in the rabbit iris-ciliary body (ICB). The purpose of this study was to examine whether a direct interaction exists between muscarinic and 5-HT_1A receptors in the ICB. At high concentrations, the 5-HT_1A agonist 8-OH-DPAT attenuated the carbachol-induced stimulation of inositol phosphates (InsPs) production, but this was not blocked by the presence of 5-HT_1A antagonists. In contrast, serotonin failed to influence carbachol-induced InsPs formation. Moreover, 8-OH-DPAT but not serotonin displayed affinity for [³H]QNB binding sites in the ICB. The combined data suggest that activation of 5-HT_1A receptors in the ICB does not cause a modulation of muscarinic receptor-stimulated phosphoinositide turnover. The data instead suggest that, at high concentrations, 8-OH-DPAT acts as an antagonist at muscarinic receptors and in this way influences muscarinic receptor function. The mechanism of 5-HT-induced modulation of muscarinic function in the ICB therefore remains to be elucidated.     

Chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT differentially desensitizes 5-HT1A autoreceptors of the dorsal and median raphe nuclei

The present study investigated alterations of the regulation of serotonin (5-hydroxytryptamine; 5-HT) release by 5-HT_1A autoreceptors following single and repeated treatment with the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT). Rats were pretreated with 8-OH-DPAT (1.0 mg/kg, s.c.) for 1, 7, or 14 days. The ability of an acute challenge administration of 8-OH-DPAT (1.0 mg/kg, i.p.) to decrease 5-HT release in the ventral striatum and the ventral hippocampus of rats maintained under chloral hydrate anesthesia was examined 24 h after the last pretreatment injection using in vivo microdialysis. The decrease of 5-HT release in the striatum produced by the challenge dose of the 5-HT_1A receptor agonist was diminished following 7 and 14 days of pretreatment, but not after 1 day of pretreatment, with 8-OH-DPAT. In contrast, decreases of 5-HT release in the hippocampus by the 8-OH-DPAT challenge were not altered after 1 or 7 days of pretreatment, and only a trend for attenuation appeared after pretreatment for 14 days. The results of the present study indicate that desensitization of 5-HT_1A autoreceptors regulating 5-HT release in different brain regions by repeated treatment with 8-OH-DPAT occurs at different rates. Synapse 25:107–116, 1997. © 1997 Wiley-Liss, Inc.     

The site of the anti-emetic action of tachykinin NK1 receptor antagonists may exist in the medullary area adjacent to the semicompact part of the nucleus ambiguus

NK1 receptor antagonists have been shown to act centrally and to produce a broad-spectrum anti-emetic action. To determine precisely the site of this action, we microinjected GR205171, an NK1 receptor antagonist, into the left medulla oblongata in decerebrate paralyzed dogs. The right medulla was transected 2.5 mm rostral to the obex to eliminate the emetic function of that half. Fictive retching induced by vagal stimulation was still observed after each of 32 injections (0.5-5 microgram in 1-30 microliter) in the area ventrolateral to the solitary complex in six dogs. Retching was also observed for 30 min or more after all but 2 of 30 injections (0.5-1 microgram in 0.5-1 microliter) in the area dorsal to the retrofacial nucleus in 17 dogs. In contrast, retching disappeared within 5-30 min after each of 20 injections (0.5-1 microgram in 1 microliter) in the area adjacent to the semicompact part of the nucleus ambiguus (scAMB) in 15 dogs. The threshold dose for abolition of the retching response was examined in seven dogs and was about 0.1 ng in 1 microliter. The maximum velocity of salivation occurred before the onset of retching and significantly decreased after its abolition. These results suggest that the site of the anti-emetic action of NK1 receptor antagonists may lie in a limited area adjacent to the scAMB, and that neurons in the site induce prodromal signs and retching in a sequential manner.     

Investigating the effect of bilateral amygdala lesions on fear conditioning and social interaction in the male Mongolian gerbil

Immunohistochemical distribution patterns of neuropeptide FF (NPFF) and neuropeptide tyrosine (NPY) were studied in the brain of rats submitted to two different protocols of heroin treatment. In drug-naive rats, acutely injected heroin significantly depleted NPFF-immunoreactive material within the neurons of the nucleus of solitary tract (NTS), significantly decreased the density of NPFF-immunoreactive nerve fibers within the median eminence, pituitary stalk, and neurohypophysis, and markedly increased NPY-immunoreactive neurons and nerve fibers in the thalamic paraventricular nucleus and bed nucleus of stria terminalis. In drug-sensitized rats, heroin significantly increased the number and immunostaining intensity of the NPFF-immunoreactive neurons within the NTS and induced minor changes in the NPFF-immunoreactive nerve fiber network of the median eminence, pituitary stalk, and neurohypophysis and a relatively minor increase in NPY neurons in the thalamic paraventricular nucleus and bed nucleus of stria terminalis. These heroin-induced changes suggest that NPFF is involved in regulating the effects of the heroin injection and in the mechanisms underlying behavioral sensitization. They also add further support to the key role of NPY in any conditions tending to change the animal homeostasis.     

Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder.

BACKGROUND: An early clinical trial suggested that the substance P (neurokinin(1) receptor) antagonist, aprepitant, might provide a unique mechanism of antidepressant activity. Phase III trials were conducted to confirm these findings. METHODS: Five 8-week, randomized, double-blind, parallel-groups, placebo-controlled, multicenter trials in outpatients with Major Depressive Disorder were performed. Aprepitant 160 mg and placebo were included in all trials. Aprepitant 80 mg and paroxetine 20 mg (active comparator) were included in three trials. Approximately 150 patients were enrolled per treatment group in each trial. The primary end point was the mean change-from-baseline of the first 17 items of the Hamilton Rating Scale for Depression (HAM-D(17)) score at 8 weeks. A positron emission tomography (PET) study was also performed in normal subjects to determine the relationship between neurokinin(1) receptor occupancy and aprepitant plasma concentrations in dosing regimens relevant to the trials. RESULTS: No statistically significant differences from placebo on the HAM-D(17) were observed at week 8 for either dose of aprepitant in any of the trials, whereas paroxetine 20 mg was significantly (p 相似文献   

Effect of the adenosine A2A receptor antagonist 8-(3-chlorostyryl)caffeine on L-DOPA biotransformation in rat striatum

In the present study, we investigated effects of the new selective adenosine A2A receptor antagonist 8-(3-chlorostyryl)caffeine (CSC) on L-DOPA-induced dopamine (DA) release in the striatum of intact and reserpine-treated rats. CSC given in a pharmacologically effective dose of 5 mg/kg i.p. significantly increased striatal DA release after joint administration of L-DOPA (100 mg/kg, i.p.) and benserazide (50 mg/kg, i.p.) to intact and reserpine (2.5 mg/kg, s.c.)-injected rats. CSC did not change the elevated level of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in intact rats, but raised it in DA-depleted animals. The availability of exogenous L-DOPA in the extracellular space was similar and equally increased by CSC in both intact and reserpinized rats. Our results suggest that the observed effects may be mediated by striatal adenosine A2A receptors, and are probably related to the CSC action on DA metabolism and the increased transport of exogenous L-DOPA into the brain. These observations might be of relevance, considering the use of selective A2A antagonists as potential supplements to L-DOPA therapy of Parkinson's disease.     

Sleep effects following intrathecal administration of the 5-HT1A agonist 8-OH-DPAT and the NMDA antagonist AP-5 in rats

The modulating effect of an intrathecally (i.t.) administered 5-HT_1A agonist and an NMDA antagonist on sleep, waking and EEG power spectra was investigated in rats. The 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (38 nmol) increased total slow wave sleep (TSWS) and decreased waking over the 8 h recording period. The TSWS increase was mostly due to an increase in SWS1. Sleep latency to SWS1 was also reduced. The NMDA antagonist dl-2-amino 5-phosphonovaleric acid (AP-5) (31.5 nmol) reduced waking. SWS1 was increased, but TSWS was not changed. An increase in REM sleep was seen during the last part of the recording. Combined treatment with 8-OH-DPAT and AP-5 reduced waking and increasd TSWSS. No change in REM sleep was seen. There were no systematic changes in either waking, TSWS or REM fronto-frontal or fronto-parietal EEG power spectrum after any of the treatments. The results suggest that in the spinal cord stimulation of 5-HT_1A receptors have a dampening effect on transmission of sensory information, leading to deactivation and thereby increased possibilities for sleep induction. Blockade of the NMDA receptors may also lead to a small dampening of sensory transmission with similar consequences.     

The 5-HT1A agonist 8-OH-DPAT increases the number of spike-wave discharges in a genetic rat model of absence epilepsy

The effects of the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) on the epileptiform activity has been investigated in adult WAG/RIJ rats. Either intraperitoneal (0.1–0.5 mg/kg) or intracerebroventricular (2–20 μg/rat) administration of 8-OH-DPAT caused marked, dose-dependent increases in the number and mean cumulative duration of spike-wave discharges. These effects were attenuated by NAN-190, a 5-HT_1A receptor antagonist. These data indicate that serotonergic system regulates the epileptiform activity in this genetic model of human absence epilepsy.     

Functional effects of chronic electroconvulsive shock on serotonergic 5-HT(1A) and 5-HT(1B) receptor activity in rat hippocampus and hypothalamus

The aims of this work were to determine the influence of chronic electroconvulsive shock (ECS) on presynaptic 5-HT(1A) receptor function, postsynaptic 5-HT(1A) receptor function in hippocampus and hypothalamus, and presynaptic 5-HT(1B) receptor function in hippocampus and hypothalamus. This represents part of an on-going study of the effects of ECS on serotonergic receptor activity in selected brain areas which may be relevant to the effects of electroconvulsive therapy (ECT) in humans. Chronic ECS reduced the ability of the 5-HT(1A) receptor agonist 8-hydroxy-2(di-n-propylamino)tetraline (8-OH-DPAT) (0.2 mg/kg s.c.) to decrease 5-HT levels in hypothalamus as shown by in vivo microdialysis, indicative of a reduction in sensitivity of presynaptic 5-HT(1A) autoreceptors. The ability of the 5-HT(1B) receptor antagonist GR 127935 (5 mg/kg s.c.) to increase 5-HT levels in both hippocampus and hypothalamus was unaffected by chronic ECS. 8-OH-DPAT (0.2 mg/kg s.c.) increased cyclic AMP levels in hippocampus measured by in vivo microdialysis approximately 2-fold. The degree of stimulation of cyclic AMP formation was not altered by chronic ECS. However the cyclic AMP response to forskolin (50 micro M) administered via the microdialysis probe, which was approximately 4-fold of basal in sham-treated rats, was almost completely abolished in ECS-treated rats. Since this indicates that either adenylate cyclase catalytic unit activity or Gs protein activity is reduced in the hippocampus after chronic ECS, the lack of change in 8-OH-DPAT-induced cyclic AMP formation may be taken as possible evidence of an increase in sensitivity of postsynaptic 5-HT(1A) receptors in the hippocampus by chronic ECS. Chronic ECS increased basal plasma levels of corticosterone, ACTH and oxytocin. The ACTH response to s.c. injections of 0.2 mg/kg or 0.5 mg/kg 8-OH-DPAT was reduced by chronic ECS. Postsynaptic 5-HT(1A) receptor activity in the hypothalamus, in contrast to the hippocampus, thus appears to be desensitized after chronic ECS. We conclude that chronic ECS has regionally specific effects on both pre- and post-synaptic 5-HT(1A) receptors, but, in contrast to some antidepressant drugs, does not affect presynaptic 5-HT(1B) receptor activity.     

Hippocampal 5-hydroxytryptamine synthesis is greater in female rats than in males and more decreased by the 5-HT1A agonist 8-OH-DPAT

Summary Brain regional 5-hydroxytryptamine (5-HT) and/or 5-hydroxyindoleacetic acid (5-HIAA) concentrations tended to be slightly higher in female rats than in males but differences were substantial only in the hippocampus where female values were 34% and 36% higher respectively. These findings were consistent with the synthesis rates of 5-HT as this was 53% greater in the female than in the male hippocampi. Other regions did not show significant sex differences. The 5-HT[n1A] agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 1 mg/kg sc) caused comparable decreases of 5-HT synthesis rate in both sexes and in all regions studied except the hippocampus where the percentage decrease was twice as large in the females (–64%) as in the males (–32%) so that the sex difference in 5-HT synthesis in this region largely disappeared. The results are discussed in relation to sex differences in behaviour and hippocampal function.     

5-HT(1B) receptor knockout mice show no adaptive changes in 5-HT(1A) receptor function as measured telemetrically on body temperature and heart rate responses

Two presynaptic receptors play an important role in the regulation of serotonergic neurotransmission, i.e., the 5-HT(1A) and 5-HT(1B) receptor. The present study focuses on putative adaptive changes in the 5-HT(1A) receptor system in mice that lack 5-HT(1B) receptors (5-HT(1B) KO). 5-HT(1A) receptor sensitivity was assessed in vivo in two models of presynaptic 5-HT(1A) receptor activity: agonist-induced hypothermia and prevention of stress-induced hyperthermia. The effects of 5-HT(1A) receptor activation by flesinoxan (0.1-3.0 mg/kg s.c.) were determined telemetrically on body temperature and heart rate in 5-HT(1B) KO and wild-type (WT) mice. Flesinoxan induced hypothermia dose-dependently without affecting heart rate and prevented stress-induced hyperthermia and tachycardia equipotently in both genotypes. Specificity of these responses was confirmed by blockade with the selective 5-HT(1A) receptor antagonist WAY100635 (1.0 mg/kg s.c.). The importance of continuous sampling in freely moving subjects to improve appropriate characterization of mutants is discussed. 5-HT(1B) KO mice showed no shift in 5-HT(1A) receptor sensitivity compared to WT mice. This study found no indications for adaptive changes in presynaptic 5-HT(1A) receptor function in 5-HT(1B) KO mice as measured telemetrically on body temperature and heart rate responses.     

Anxiolytic effect of the 5-HT1A compounds 8-hydroxy-2-(di-n-propylamino) tetralin and ipsapirone in the social interaction paradigm: Evidence of a presynaptic action

This study analyses at which site, pre- or postsynaptic, the 5-HT_1A ligands—8-hydroxy-2(dl-n-propyilamino)tetralin (8-OH-DPAT) and ipsapirone—induce their amdoytic action. The experimental anxiety was assessed in the social interaction test. An anxioyfic action was observed after the systemic administration of 8-OH-DPAT (025 and 0.5 mg/kg and ipsapirone (5 but not 10 mg/kg). In 5,7-dihydroxytrpytamine (5,7-DHT, 150 μg/10 μl) lesioned rats the arodoytie effect of 8-OH-DPAT and ipsapirone was not observed, suggesting a presynaptic action of these drugs.dnVs. When directly injected into the dorsal raphe nucleus 8-OH-DPAT (0.1 μgμl) and ipsapirone (0.2 μg/μl), both compounds produce an)dolytic effects. At same doses, these drugs lacked an effect after their intrahippocampal infusion. All data strongly suggest that both drugs act presynaptically to reduce the anxiety levels in the social interaction paradigm.     

Evidence that substance P is utilized in medial amygdaloid facilitation of defensive rage behavior in the cat

The present study was designed to test the hypothesis that a major excitatory mechanism for the expression of feline defensive rage behavior involves the medial nucleus of the amygdala which utilizes substance P as a neurotransmitter in a direct output pathway that supplies the medial hypothalamus. In phase I of the experiment, stimulating electrodes were implanted into the medial amygdala and cannula electrodes were implanted into the medial and lateral hypothalamus from which defensive rage and predatory attack behavior could be elecited by electrical stimulation, respectively. Response latencies for defensive rage were significantly lowered after dual stimulation of the medial amygdala and medial hypothalamus relative to single stimulation of the medial hypothalamus alone. In phase II, dose- and time-dependent decreases in medial amygdaloid-induced facilitation of defensive rage were observed after the i.p. administration of the NK₁ antagonist, CP-96,345 (0.05, 2 and 4 mg/kg). In phase III of the study, the effects of microinjections of CP-96,345 placed directly into defensive rage sites within the medial hypothalamus (0.05, 0.5 and 2.5 nmol) upon medial amygdaloid modulation of this response were assessed. Again, intracerebral administration of this antagonist blocked the facilitatory effects of medial amygdaloid-induced facilitation of defensive rage in a manner parallel to that observed with peripheral administration of the NK₁ antagonist. The results suggest that the medial amygdala facilitates defensive rage by acting through a substance P mechanism at the level of the medial hypothalamus. Other experiments revealed that peripheral administration of the NK₁ antagonist: (1) had little effect upon the latency or threshold for elicitation of defensive rage, suggesting that the medial amygdaloid-substance P facilitatory mechanism acts in a phasic rather than tonic manner; and (2) also blocks the suppressive effects of medial amygdaloid stimulation upon predatory attack behavior elicited from the lateral hypothalamus. The latter finding suggests that similar neurochemical mechanisms regulate medial amygdaloid modulation of both forms of hypothalamically elicited aggression. The final aspect of this study utilized the combination of retrograde-tracing of amygdaloid neurons into the medial hypothalamus after microinjections of Fluoro-Gold into defensive rage sites, and the immunocytochemical analysis of substance P neurons within the amygdala. The data indicated that large numbers of retrogradely and immunocytochemically positive labeled cells were identified in the medial nucleus, including many that were double-labeled. The overall findings of this study support the hypothesis that the medial amygdala provides a powerful excitatory monosynaptic input to the medial hypothalamus for the expression of defensive rage behavior and that this mechanism is mediated, at least in part, via a substance P mechanism.     

R(+)-8-OH-DPAT, a selective 5-HT1A receptor agonist, attenuated amphetamine-induced dopamine synthesis in rat striatum, but not nucleus accumbens or medial prefrontal cortex

R(+)-8-OH-DPAT (0.05, but not 0.025, 0.1, 1 mg/kg), a 5-HT_1A receptor agonist, decreased l-3,4-dihydroxyphenylalanine (DOPA) accumulation in rat striatum following NSD-1015, an l-aromatic amino acid decarboxylase inhibitor. Amphetamine (1 mg/kg) increased striatal DOPA accumulation, an effect attenuated by R(+)-8-OH-DPAT (0.05 mg/kg). However, both amphetamine (1 mg/kg) and R(+)-8-OH-DPAT (0.05 mg/kg) decreased cortical DOPA accumulation; there were no additional decreases from their combination. Neither amphetamine (1 mg/kg), R(+)-8-OH-DPAT (0.05 mg/kg), or the combination, significantly affected DOPA accumulation in the nucleus accumbens. The significance of and possible mechanisms for these findings are discussed.