Effect of recurrent yohimbine on immediate and post-hoc behaviors, stress hormones, and energy homeostatic parameters.

Evidence from experimental models has suggested that acute activation of brain stress and anxiety pathways impacts subsequent behaviors that are mediated or modulated by limbic circuitry. There have been limited investigations of prior or chronic activation of these pathways on subsequent limbic-mediated behaviors. In this study, we tested whether recurrent administration of the anxiogenic compound yohimbine (YOH) could have post-injection effects on brain activation, stress hormones, and performance in sucrose self-administration and startle response paradigms. Rats received six injections across two weeks of either 2mg/kg YOH or saline. Behavioral evaluation confirmed the continued efficacy of the YOH regimen, and increased adrenal corticosterone (CORT) was observed. Several days following YOH or SAL administration, cFos, CORT and adrenocorticotropin hormone (ACTH), and behavioral performance were measured. cFos was elevated post-YOH in the hippocampus; ventral tegmental area/zona inserta; and central and medial nuclei of the amygdala. This activation is consistent with a sustained effect of YOH to activate fear and anxiety circuitries in the CNS. CORT but not ACTH was elevated in the YOH-rats following startle testing. Self-administration and startle tests suggested an increase of non-specific activity in the post-YOH rats; there was no increase in sucrose self-administration or startle response per se. Our findings suggest that recurrent YOH administration may prove a useful and reliable model for simulating recurrent stress/anxiety, and that enhancements to the paradigm such as higher or more frequent dosing of YOH could yield stronger or more extensive behavioral effects.

Rats selectively-bred for behavior related to affective disorders: proclivity for intake of alcohol and drugs of abuse, and measures of brain monoamines.

Several lines of rats potentially useful for studying affective disorders have been developed in our laboratory though selective breeding for behavioral characteristics. The propensity of these lines to consume alcohol and other drugs of abuse (amphetamine and cocaine) was examined. Also, measurement of the concentration of brain monoamines - norepinephrine, dopamine, and serotonin - as well as estimation of their metabolism by measurement of the major extracellular metabolites of these monoamines was carried out to examine possible relationships of brain chemistry to the behavioral characteristics shown by these lines, as well as to their propensity for drug usage. The lines of rats are: Swim Low-active (SwLo) and Swim High-active (SwHi), which show either very low (SwLo) or very high (SwHi) amounts of motor activity in a swim test; Swim-test Susceptible (Susceptible or SUS) and Swim-test Resistant (Resistant or RES), which are highly susceptible (SUS) or highly resistant (RES) to having their swim-test activity depressed by being exposed to a stressful condition prior to the swim test; and Hyperactive (HYPER), which show spontaneous nocturnal hyperactivity compared to non-selectively bred (i.e., normal) rats as well as both extreme hyperactivity and behavioral depression after being exposed to a stressful condition. Regarding alcohol and drug usage, SUS rats readily consume alcohol while all other lines including non-selected, normal rats do not, and SwLo rats show a strong tendency to consume amphetamine and cocaine. Marked differences in brain monoamines were found between the various lines and normal rats, with salient differences seen in norepinephrine, particularly in the hippocampus, and in dopamine in forebrain regions (striatum and nucleus accumbens).

The management of immediate post-traumatic seizures in children following minor head injury--time for a multicentre study?

BACKGROUND: Children have a much lower threshold for seizure activity than adults. Consequently, an immediate post-traumatic seizure in a child following a minor head injury does not have the same potentially serious implications as one in an adult. METHODS: The records of children admitted with a post-traumatic fit occurring within 24 h of a minor head injury and with a normal CT scan of the brain on admission were critically reviewed. Those with previous neurological disorders, especially fits (excepting febrile convulsions), or systemic injuries requiring admission to an intensive care unit were excluded. RESULTS: There were 13 children who were not intubated and ventilated, forming the control group, and 13 children who were intubated and ventilated and formed the study group. All the children in both these groups made a good recovery, and none of them had any neurological deficit either at discharge or at follow-up. CONCLUSION: The clinical data suggest that children with immediate post-traumatic seizures following a minor head injury whose CT scan shows no major intracranial abnormalities and who have no prior history of neurological disease are at low risk of developing recurrent seizures or neurological complications and can be safely managed without recourse to intubation and ventilation.

Rats selectively bred for high and low swim-test activity show differential responses to dopaminergic drugs.

RATIONALE: Selective breeding of Sprague-Dawley rats has been used to generate a line of animals with very low swim-test activity (SwLo) in an attempt to model certain characteristics of depression. For comparison with the SwLo animals, a line bred for high swim-test activity (SwHi) and a non-selectively bred line (SwNS) have been generated. Previous studies using these lines suggested an inverse relationship between dopamine (DA) function in the brain and inactivity in the swim test. OBJECTIVES: The current experiments investigated the possibility that SwLo and SwHi rats show differences in central DA processes, as suggested by responsiveness to DA agonists. RESULTS: The increase in ambulation produced by d-amphetamine (0.25-1.0 mg/kg) was largest in SwHi rats and smallest in SwLo rats, with SwNS rats showing an intermediate response. Amphetamine levels in plasma and brain tissue were similar in SwHi and SwLo rats, indicating that pharmacokinetic differences were not responsible for the behavioral differences. Repeated amphetamine administration produced enhancement in the ambulation-increasing effects of this drug (i.e., sensitization), with significant enhancement seen in all three lines. Apomorphine in doses that stimulate postsynaptic receptors (0.25-4.0 mg/kg) produced mainly increased sniffing behaviors in SwHi and SwNS rats and oral behaviors in SwLo rats, suggesting that the lines differ in proportions of D1, D2, and D3 postsynaptic receptors. CONCLUSIONS: The findings suggest that DA function differs in lines of rats selectively bred for differences in swim behavior, a feature that may make these lines useful for studying certain depressive symptoms that might be related to DA function.

Motor activation by amphetamine infusion into nucleus accumbens core and shell subregions of rats differentially sensitive to dopaminergic drugs.

Selective breeding based on activity in a swim test has been used to produce lines of rats that show a high level of activity in the swim test (Swim High-active (SwHi) rats) and a low level of activity in the swim test (Swim Low-active (SwLo) rats). Previous studies have indicated that dopamine (DA) function is enhanced in SwHi rats and reduced in SwLo rats; a principal finding was that SwLo rats showed much smaller increases in ambulatory activity after systemic administration of amphetamine than did SwHi or non-selected rats. In light of the importance of the nucleus accumbens (NAC) in amphetamine-induced activity, the present study investigated whether DA function in NAC differs in SwHi and SwLo rats. Amphetamine was infused bilaterally into either the core or shell subregion of NAC, and ambulation or swim test activity was then measured. In SwLo rats, infusion of amphetamine (0.2-2.0 microg) into either NAC core or shell produced moderate increases in ambulation. In SwHi rats, infusion of amphetamine into NAC shell produced similar moderate increases in ambulation, but infusion into the core produced markedly larger dose-related increases in ambulation. In the swim test, infusion of amphetamine (1.0 microg) increased activity by affecting the dominant behavior of each line; i.e. struggling increased in SwHi rats and floating decreased in SwLo rats, with large effects seen in both lines with infusion into either NAC core or shell. These results support the idea that the distinct behavioral characteristics of SwHi and SwLo rats are mediated in part by differences in NAC-DA function.

Selective breeding of rats for high and low motor activity in a swim test: toward a new animal model of depression.

Because low motor activity ina swim test has been found to represent "depression-like" behavior in the rat, Sprague-Dawley (SD) albino rats were selectively bred for low motor activity (low struggling time/high floating time) in a swim test, while others were bred for high motor activity (high struggling time/low floating time). Eighty-four male and 42 female SD rats were initially purchased from Charles-River Breeding Laboratories in 1987, their behavior assessed in a 15-min swim test, and selective breeding carried out by mating those male and female rats that showed either low or high levels of motor activity in the test; results from behavioral testing of the first 18 generations produced by this selective breeding process are reported here. Two rat lines have been obtained, Swim Low-Active (SwLo) and Swim High-Active (SwHi) rats, which differ dramatically in swim-test behavior--SwLo rats show little struggling and much floating, while SwHi rats show the reverse. Activity scores of individual SwLo and SwHi rats now show no overlap. Selective breeding has produced bidirectional changes; that is, SwLo rats are considerably less active than randomly bred Sprague-Dawley albino rats, while SwHi rats are considerably more active than randomly bred rats. Measuring activity of SwLo and SwHi rats in other situations--ambulation in the home cage, open-field activity, exploratory activity in a novel, home cage-like situation, and immobility in the Porsolt swim test--revealed that differences are most pronounced when animals respond to acute challenges; under these conditions, SwHi rats show active, assertive behavior, whereas SwLo rats show a distinct absence of this type of response. When SwLo rats from the 8th to the 11th generations were given antidepressant medication [desipramine, (DMI), a tricyclic, or phenelzine, an MAO inhibitor], chronic but not acute administration of both drugs increased swim-test activity of SwLo rats. Buspirone, an anxiolytic, did not increase activity of SwLo rats. Use of animals selectively bred for high and low activity in the swim test may represent a new tool for studying physiological processes relevant to affective disorders and for testing antidepressant drugs/treatments.

Effects of antidepressant drugs on rats bred for low activity in the swim test.

To determine responsivity to antidepressant medication of Sprague-Dawley rats bred for low activity in the swim test [Swim Low-Active (SwLo) rats], these animals were given different antidepressant drugs via subcutaneously implanted minipumps for 1, 12, or 26 days, and then were tested for activity in the swim test and 2 days later in the open field. Antidepressant drugs given were amitriptyline, imipramine, desipramine (tricyclics), phenelzine (monoamine oxidase inhibitor (MAOI)], fluoxetine [selective serotonin reuptake inhibitor (SSRI)], venlafaxine, and bupropion (atypical). To assess specificity of response, the nonantidepressant drugs amphetamine, caffeine, and haloperidol were also tested. For comparison, several drugs were also tested in rats bred for high activity in the swim test [Swim High-Active (SwHi) rats]. When administered for 14 and/or 28 days (but not for 1 day), imipramine, desipramine, venlafaxine, phenelzine, and bupropion significantly increased struggling behavior of SwLo rats in swim test. No nonantidepressant drug significantly elevated struggling activity. Long-term administration of phenelzine and bupropion also significantly decreased floating behavior in the swim test, although amphetamine also had this effect at all times of administration. No significant effects of antidepressants were seen in SwHi rats. Amitriptyline and fluoxetine were ineffective in altering either struggling or floating in SwLo rats; however, a high dose of an SSRI (sertraline) did reduce floating, but this type of effect is probably not indicative of antidepressant action. Behavior in the open field was not consistently affected by any drug type. It is concluded that, based on pharmacological response profile in the swim test, SwLo rats represent depression that is responsive to potent norepinephrine reuptake-blocking antidepressants and also MAOIs; atypical depression may fit this profile.

Galanin: a significant role in depression?

This paper describes a hypothesis that attempts to account for how changes in noradrenergic systems in the brain can affect depression-related behaviors and symptoms. It is hypothesized that increased activity of the locus coeruleus (LC) neurons, the principal norepinephrine (NE)-containing cells in the brain, causes release of galanin (GAL) in the ventral tegmentum (VTA) from LC axon terminals in which GAL is colocalized with NE. It is proposed that GAL release in VTA inhibits the activity of dopaminergic cell bodies in this region whose axons project to forebrain, thereby resulting in two of the principal symptoms seen in depression, decreased motor activation and decreased appreciation of pleasurable stimuli (anhedonia). The genesis of this hypothesis, which derives from studies using an animal model of depression, is described as well as recent data consistent with the hypothesis. The formulation proposed suggests that GAL antagonists may be of therapeutic benefit in the treatment of depression.

Enhanced responses of nucleus accumbens neurons in male rats to novel odors associated with sexually receptive females.

One group of male rats was trained to associate novel odors with three different environmental conditions: the presence of (i) a sexually receptive female (RF), (ii) an unreceptive female (UF) and (iii) no other rat (NO). A second group of males received no training. Single units in nucleus accumbens (NAC) were then recorded in anesthetized animals and their responsiveness to various odors was tested. Odors that had been associated with receptive females during training evoked significantly more unit responses in NAC than did the same odors in untrained males. There were no differences between trained and untrained males in the numbers of units responsive to odors associated with unreceptive females and with the empty training chamber. In trained animals, both the percentage of responding units and the magnitude of olfactory-evoked responses were significantly larger with RF-associated odors than with either UF or NO odors. Both of these effects were more pronounced in rats that had ejaculated with females during training than in rats that had not. Findings demonstrated that pairing odors with the presentation of sexually receptive females enhanced the responsiveness of NAC neurons to those odors and indicated a role for NAC in associating environmental stimuli with natural reward processes.

Substance P injections into the ventral tegmentum affect unit activity in mesolimbic terminal regions.

Microinjections of substance P (SP) into the ventral tegmental area (VTA) increase locomotor activity in rats, and this effect is thought to be produced by activation of the mesolimbic dopamine system. In the present study, firing rates of neurons in areas receiving projections from the mesolimbic dopamine system were recorded during injections of SP (3 microgram in 0.5 microliters saline) into the VTA of rats anesthetized with chloral hydrate. Significant changes in firing rates were observed in 84% of the units recorded in nucleus accumbens and olfactory tubercle. There were mostly decreases in nucleus accumbens (NAC, 21 of 25 units affected by SP) and mostly increases in olfactory tubercle (OT, 13 of 18 units affected by SP). In contrast, neither saline injections into VTA nor SP injections 2 mm dorsal to VTA had any effect on NAC or OT neurons. Haloperidol (0.5 mg/kg IV) blocked the effects of SP, suggesting that effects were mediated, at least in part, by the mesolimbic dopamine system. Results indicated that activation of dopaminergic neurons by SP injections into VTA can produce changes in the activity of neurons in NAC and OT, areas which receive mesolimbic dopaminergic projections.

Responses of units in the mesolimbic system to olfactory and somatosensory stimuli: modulation of sensory input by ventral tegmental stimulation.

It is well known that neurons of the nigrostriatal dopamine (DA) system respond to sensory stimuli, and our primary objective here was to ascertain if neurons in the terminal regions of the mesolimbic DA system respond to sensory input also. In addition, the effects of electrical stimulation of the ventral tegmentum, which contains the DA cells of origin of the mesolimbic system, on sensory-evoked responses in mesolimbic neurons was studied. In rats anesthetized with chloral hydrate, responses of single units to olfactory and somatosensory stimuli were recorded in 6 forebrain regions including nucleus accumbens and olfactory tubercle. Both increases and decreases in spontaneous firing rates were evoked in 225 of 336 units by one or more of the 8 types of sensory stimuli employed (5 olfactory, 3 somatosensory). Excitatory responses occurred twice as frequently as inhibitory responses, but a few units responded with excitatory responses to some stimuli and inhibitory responses to others. The proportions of units responsive to olfactory and/or somatosensory stimuli were different in different regions. After electrical stimulation of the ventral tegmentum, sensory-evoked responses were changed in 30 of the 49 units tested (61%). There were increases, decreases or combinations of a decrease followed by an increase in sensory-evoked responses, which persisted for 1-10 min after the application of a single electrical stimulus train. Haloperidol (0.3 mg/kg, i.p.) either blocked the effect of tegmental stimulation or decreased all responses. The present results demonstrated that units in the terminal regions of the mesolimbic DA system are responsive to sensory input and that these responses can be affected by prior electrical stimulation of the ventral tegmentum.

Amphetamine affects the extinction of self-stimulation differently in prefrontal cortex and posterior hypothalamus of rats.

The effects of amphetamine on the extinction of intracranial self-stimulation (ICSS) and on postextinction ICSS performance were examined in rats implanted with electrodes either in medial prefrontal cortex (mPFC) or in the posterior hypothalamus-ventral tegmental area (PH-VTA). Lever-pressing for ICSS was allowed to stabilize in daily 15-minute sessions before each animal was exposed to 5 minutes of extinction (responding without reward). Animals were administered either 0.25 mg/kg d-amphetamine or saline before baseline, extinction and postextinction sessions. After amphetamine treatment, the number of lever presses during extinction was higher in mPFC animals and lower in PH-VTA animals compared with saline-treated controls. Rates did not change immediately after extinction but, one day later, rates had increased in all saline-treated animals (both PH-VTA and mPFC animals) and had decreased in all amphetamine-treated animals. These findings demonstrated that the effects of amphetamine on the extinction of ICSS were different in cortical and hypothalamic sites, possibly because of regional differences in stimulus-evoked reinforcement and inhibitory processes.

Assessment of the neural substrate for intracranial self-stimulation by the postreinforcement pause technique.

The poststimulation excitability of neurons mediating intracranial self-stimulation (ICSS) was evaluated by the paired-pulse method. Stimulus effectiveness was assessed by the postreinforcement pause (PRP) and by frequency threshold (FT) determinations in 7 rats performing ICSS in the medial forebrain bundle (MFB) and in the ventral tegmental area (VTA). Stimulus effectiveness values were minimal at conditioning-test (C-T) pulse intervals of 0.6 and 0.8 ms for MFB and VTA animals, respectively, because of neuronal refractoriness. Local potential summation could account for the increase in effectiveness at very short C-T intervals, and an additional peak of enhanced effectiveness at a C-T interval of 2.0 ms, perhaps reflecting synaptic events, was observed only in VTA animals with the PRP method. Important advantages of the PRP method were that the C-T interval was the only stimulus parameter that was varied, and the behavioral output of the animal remained relatively constant.

Mild stress influences sex differences in exploratory and amphetamine-enhanced activity in rats.

The locomotor activity of experimentally naive male and female rats was monitored in a novel environment during two sessions one week apart. Half of the animals were handled for 5 days before testing, and all animals were injected before each activity session either with saline or with D-amphetamine (0.25 mg/kg). Overall, there were no sex differences in activity. However, activity was increased both by prior handling and by amphetamine treatment, and these effects were larger in females than in males. The finding that the activity-increasing effects of handling were greater in females than in males suggested that sex differences in behavior may be influenced by previous experience and that this should be considered in the design of behavioral experiments involving naive animals.

Self-training for brain stimulation in the medial forebrain bundle of rats: a comparison of saline with amphetamine.

Rats were implanted with stimulating electrodes in the medial forebrain bundle-lateral hypothalamus (MFB-LH). Following recovery from surgery, they were placed in 3 groups prior to brain self-stimulation training. This consisted of one 15-min session on each of 5 consecutive days. Animals in the first group (controls) were placed in a conventional, single lever operant chamber without any additional manipulation. There were no priming stimuli, there was no experimenter intervention of any kind, and no exteroceptive cues in the chamber to indicate the availability or otherwise of the reinforcement. Animals in the second group (saline-injected) were treated similarly to the first group except that they were weighed and injected subcutaneously with saline (1 ml/kg) immediately before being placed in the chamber. Animals in a third group (D-amphetamine-injected) were weighed and administered D-amphetamine (0.5 mg/kg in saline) immediately before being placed in the chamber. The number of lever-presses made per 15-min session was recorded. In addition, the time taken to achieve a lever-pressing rate of 10 presses per min was recorded. There were no significant differences between groups in the number of presses per 15-min session. Animals administered D-amphetamine reached the rate of 10 presses per min significantly more rapidly than animals administered saline, but the latter did so significantly more rapidly than controls. These results demonstrated that the simple manipulation, and perhaps the mild stress, associated with a saline injection strongly affected the acquisition of a brain self-stimulation task.

Handling facilitates the acquisition of lever-pressing for brain self-stimulation in the posterior hypothalamus of rats.

Adult male rats implanted with stimulating electrodes in the posterior hypothalamus-ventral tegmental area (PH-VTA) were allowed to learn to lever press for intracranial self-stimulation (ICSS) without any priming by the experimenter or use of external cues. Animals that had been handled for seven days prior to testing acquired the lever-pressing task more rapidly than non-handled animals. Prior handling had no effect on the amount of locomotor activity in a novel environment nor on the number of non-reinforced lever presses. This suggested that the effect of handling on ICSS acquisition was not due to a change in locomotor activity or exploratory behavior. Implanted rats that were injected before each session with d-amphetamine (0.25 mg/kg) or saline did not differ in their rates of acquisition of ICSS in PH-VTA. However, injected animals acquired ICSS more slowly than the non-injected (handled and non-handled) animals. These results suggest that mild stressors applied before acquisition testing can alter the rate of learning of an operant task for ICSS in the posterior hypothalamic region and that small routine manipulations of animals can affect learning in operant training situations.

Measurement of intracranial self-stimulation thresholds using the post-reinforcement pause.

A method for measuring the current threshold for intracranial self-stimulation (ICSS) using the post-reinforcement pause (PRP) is described. Rats trained to lever press on a fixed ratio schedule for ICSS in prefrontal cortex, medial forebrain bundle, ventral tegmental area or periaqueductal gray received stimuli of opposite polarity in an alternating fashion. Stimuli of one polarity were sufficient to maintain ICSS responding by themselves (maintaining stimuli). Stimuli of the other polarity were systematically varied in 5-10 microA steps (experimental stimuli). PRPs following both maintaining (Pm) and experimental (Pe) stimuli were measured, and the ratio Pm/Pe was calculated. The PRP threshold was defined as the lowest experimental stimulus current producing PRP ratios significantly less than the ratios produced by all lower current steps. After the PRP threshold for one polarity was determined in 5 daily sessions, the experimental and maintaining stimuli were reversed, and the PRP threshold was measured for the alternate polarity. Rates of ICSS on a continuous reinforcement schedule were subsequently measured at currents around the PRP threshold. Rates increased sharply at PRP threshold, suggesting a correlation between PRP threshold and reinforcement threshold. Similar results were obtained from all four ICSS sites indicating the broad applicability of the PRP threshold method.

Time-dependent modulation by estrogen of amphetamine-induced hyperactivity in male rats.

The effect of estradiol benzoate on the increase in activity induced by d-amphetamine (0.25 mg/kg) was studied in male rats. Both short latency and long latency effects were observed. Amphetamine-induced hyperactivity was increased 45 minutes after estradiol (50 micrograms/kg) administration, decreased one day later and again increased during the period 8-16 days after injection. At doses of 12.5 and 25 micrograms/kg, effects were smaller and not statistically significant, although they had a similar temporal pattern to the 50 micrograms/kg dose. The short-latency, presumably non-genomic, effect of EB was studied in more detail at 15, 30, 45 and 60 minutes after the administration of 50 micrograms/kg EB. An enhancement of the amphetamine-induced increase in locomotor activity reached its maximum 30 minutes after injection. The time factor was critical for the effects observed, and the results supported the view that estrogen may alter behavior mediated by dopaminergic pathways.

Acquisition of intracranial self-stimulation in medial prefrontal cortex of rats facilitated by amphetamine.

Two groups of rats were trained to lever press for intracranial self-stimulation (ICSS) in the medial prefrontal cortex (mPFC) using a uniform amount of stimulation for all animals. One group acquired the lever pressing task very gradually during saline pretreatment but dramatically improved its rate of acquisition during the third week of training when pretreated with d-amphetamine (0.5 mg/kg). Administration of amphetamine to the other group of rats before each of the first five training sessions greatly facilitated acquisition of the ICSS task, and a significant improvement in performance over the saline control group appeared on the third day of training. After ICSS performance had stabilized, testing the animals revealed a significant amphetamine-induced increase in rate over the dose range of 0.25 to 1.0 mg/kg. These effects of amphetamine suggest that ICSS in mPFC is sensitive to changes in catecholamine neurotransmission during both the acquisition and maintenance of this behavior.

Effects of stimulation of the mediodorsal nucleus and its projection cortex on heart rate in the rabbit.

Electrical stimulation of prefrontal cortex in anesthetized rabbits evoked small (less than 10%) changes in heart rate. In contrast, stimulation of the thalamic mediodorsal nucleus (MD) elicited decreases in heart rate proportional to the stimulating current. The maximal peak reductions in heart rate evoked by higher current intensities were 85% from prestimulus levels. The bradycardiac response had a short latency after stimulus onset (less than 1 s, peak within 5 s), and the heart rate usually returned to baseline within 30 s after stimulation. Vagal cholinergic innervation of the heart was suggested as the final effector pathway since bilateral vagotomy or administration of atropine (sulfate or methyl nitrate, 0.15-0.4 mg/kg, i.v.) virtually abolished the rapid bradycardiac responses. Administration of a beta-adrenergic receptor blocker (propranolol, 3 mg/kg, i.v.) was without effect on the heart rate response. The effective medial thalamic area for evoking a response was localized to MD, the thalamic midline nuclei between both MDs and a region continuous with, but posterior to MD (e.g. parafascicular nucleus). A descending effector pathway from the thalamus was implicated since complete bilateral ablation of prefrontal cortex did not reduce the stimulus-produced bradycardia evoked from MD. Similar large bradycardiac responses were obtained in an unanesthetized preparation to both MD stimulation and to sensory stimuli, suggesting a possible physiological correlate for these intracranially-evoked heart rate changes.