Aversive Brain Stimulation Research Articles

Animal models and the embodiment of emotions

This review draws some parallels between the results of experiments, none very recent, of rewarding and aversive brain stimulation in brain stem sectioned cats and the blunting of negative emotions which occurs in the human locked-in syndrome. Within the framework of theories of embodied emotions, it is suggested that a participation of bodily inputs to cerebral mechanisms of emotion is required for negative but not positive emotions.

Accumbens dopamine-acetylcholine balance in approach and avoidance

Understanding systems for approach and avoidance is basic for behavioral neuroscience. Research on the neural organization and functions of the dorsal striatum in movement disorders, such as Huntington's and Parkinson's Disease, can inform the study of the nucleus accumbens (NAc) in motivational disorders, such as addiction and depression. We propose opposing roles for dopamine (DA) and acetylcholine (ACh) in the NAc in the control of GABA output systems for approach and avoidance. Contrary to DA, which fosters approach, ACh release is a correlate or cause of meal satiation, conditioned taste aversion and aversive brain stimulation. ACh may also counteract excessive DA-mediated approach behavior as revealed during withdrawal from drugs of abuse or sugar when the animal enters an ACh-mediated state of anxiety and behavioral depression. This review summarizes evidence that ACh is important in the inhibition of behavior when extracellular DA is high and the generation of an anxious or depressed state when DA is relatively low.

Immobility and flight associated with antinociception produced by activation of the ventral and lateral/dorsal regions of the rat periaqueductal gray

It has long been known that the periaqueductal gray (PAG) plays an important role in the modulation of nociception. Given that activation of the lateral PAG also produces wild running and tachycardia, it has been suggested that PAG mediated antinociception is part of an integrated defensive reaction. However, an alternative hypothesis is that these effects are merely a secondary response to aversive brain stimulation. If antinociception and flight reactions are caused by aversive brain stimulation, then these effects should always occur together. The objective of the present study was to determine whether antinociception and locomotion could be dissociated by microinjecting morphine and kainic acid into various subdivisions of the caudal PAG. Non-selective activation of lateral and dorsal regions of the PAG by microinjection of kainic acid produced wild running, while injections into the ventrolateral PAG produced immobility. Microinjection of morphine evoked similar locomotor effects, although the onset to effect was slower with morphine (approximately 5 min vs. 1 min for kainic acid), and the antinociceptive efficacy of microinjecting 0.2 μl of morphine was less than with kainic acid injections. In fact, microinjection of morphine evoked locomotor effects in the absence of antinociception on 39% of the tests. Increasing the injection volume to 0.4 μl (dose remained at 5 μg) greatly enhanced the likelihood that antinociception and locomotor effects (e.g. running, freezing, circling) occurred simultaneously (79%). These findings indicate that, although distinct locomotor effects are associated with antinociception from the ventral and more dorsal regions of the PAG, antinociceptive and locomotor effects can occur independently. This finding is consistent with the hypothesis that ventral and dorsal regions of the PAG integrate defensive freezing and flight reactions, respectively.

Behavioral effects of 5-HT receptor ligands in the aversive brain stimulation, elevated plus-maze and learned helplessness tests

In order to illustrate the use of animal models in the study of the anxiolytic and antidepressant properties of drugs acting on 5-HT receptors, a series of experiments is described. With electrical stimulation of the midbrain central gray (CG), an aversive area of the brain, the 5-HT-1 receptor antagonist propranolol raised the aversive threshold in a dose-dependent way, following its microinjection into the CG. This antiaversive effect of propranolol, which is similar to that of benzodiazepine anxiolytics, was prevented by microinjection into the same brain site of the 5-HT-2 receptor blocker ritanserin. Ritanserin itself and the 5-HT-1A receptor ligand ipsapirone caused either little or no effect. In another animal model of anxiety, the elevated plus-maze, intra-CG propranolol also caused an anxiolytic-like effect, antagonized by ritanserin, indicating a 5-HT mediation. However, systemically injected isamoltane, a congener of propranolol, was ineffective in the elevated plus-maze, whereas ipsapirone caused an anxiolytic effect. Ritanserin was again inactive. Finally, both ipsapirone as well as another 5-HT-1A receptor ligand BAY R 1531, given IP, reversed the learning deficit resulting from exposure to uncontrollable foot-shocks, an effect characteristic of antidepressant drugs.

Effects of morphine and midazolam on reactivity to peripheral noxious and central aversive stimuli

Electrical stimulation of the mesencephalic tectum elicits behavioral and autonomic responses similar to those following peripheral noxious stimulation. Benzodiazepine and opioid compounds attenuate escape behavior induced by electrical stimulation of the dorsal periaqueductal gray (PAG) and deep layers of the superior colliculus (SC). The present study determines if microinjections of midazolam and morphine applied to these PAG-SC sites affect both responsiveness to peripheral noxious stimulation and to aversive PAG-SC stimulation. Both aversive brain stimulation or foot-shocks applied at threshold intensities caused running or jumps concomitant with increases in mean arterial blood pressure (MBP) and heart rate (HR). Microinjection of both drugs attenuated the behavioral reaction and increases in MBP and HR induced by mesencephalic tectum stimulation, while attenuating only the increase in heart rate induced by peripheral painful stimulation. These results suggest that the neural substrates of the behavioral and autonomic effects of stimulating the mesencephalic tectum and peripheral nociceptors are different although they may partially overlap.

Effects of serotonin receptor antagonists on PAG stimulation induced aversion: different contributions of 5HT1, 5HT2 and 5HT3 receptors

The effects of serotonin receptor antagonists with differential selectivity for the various classes of 5HT receptors (5HT1, 5HT2 and 5HT3) were tested for their effects on the response to aversive brain stimulation. Electrical stimulation was administered to the dorsal part of the periaqueductal gray matter (PAG), one of the main cerebral structures subserving negative reinforcement. Stimulation frequency thresholds for escape responses were recorded before and following administration of the compounds. Ketanserin (0.32-32 mg/kg IP), trazodone (1.0-22 mg/kg), pirenperone (0.032-1.0 mg/kg) and spiperone (0.1-0.2 mg/kg) dose-dependently increased stimulation frequency thresholds necessary to induce escape responses. Opposite effects were observed with mianserin (0.01-32 mg/kg) and metergoline (0.032-10 mg/kg) which decreased threshold for escape. ICS 205-930 (0.01-10 mg/kg), did not affect the stimulation frequency threshold for escape. Prazosin (0.1-22 mg/kg) did not specifically affect aversive brain stimulation. Haloperidol (0.02-1.0 mg/kg) increased the frequency threshold for escape responses but with some motoric side effects. These data show that the various types of 5HT receptors differentially contribute to the control of central aversive systems in rats. It is suggested that blockade of 5HT2 receptors suppresses the central aversive system, whereas blockade of some 5HT1 receptors enhances aversion and overcomes the 5HT2-mediated suppression. Blockade of 5HT3 receptors has no effects. Dopamine receptor blockade further contributes to the suppression of the central aversive system. The relevance of these findings to some pathophysiological mechanisms of anxiety and depressive disorders is discussed.

Opposite control mediated by central 5-HT 1A and non-5-HT 1A (5-HT 1B or 5-HT 1C) receptors on periaqueductal gray aversion

8-OH-DPAT, a selective 5-HT 1A agonist, and mCPP, which has preferential affinity for 5-HT 1B and 5-HT 1C receptors, were studied for their effects on aversive brain stimulation in rats. Opposite effects were found with these two agonists: D, L-8-hydroxy-N,N-dipropyl-2-aminotetralin HBr (8-OH-DPAT; 0.1–1.0 mg/kg i.p.) dose dependently decreased the threshold for neurostimulation-induced escape behaviour while mCPP (0.1–1.0 mg/kg i.p.) dose dependently increased the threshold. The proaversive effect of 8-OH-DPAT and the antiaversive effect of mCPP suggest that 5-HT 1A and non-5-HT 1A (5-HT 1B or 5-HT 1C) receptors play distinct roles in mechanisms of aversion, perhaps at different locations in the CNS.

Animal Models for Anxiety and Response to Serotonergic Drugs

In examining anxiety and the response of animal models to serotonergic drugs, four aspects should be taken into account: (1) the serotonin receptor is subdivided into at least six receptor subtypes; (2) benzodiazepines have acute anxiety-relieving effects, whereas antidepressants, serotonin-uptake inhibitors, buspirone, and serotonin antagonists have antianxiety effects only after prolonged administration; (3) diagnostic criteria differentiate several distinguishable anxiety disorders that have different responsiveness to serotonin-related drugs, and (4) various types of animal models exist, each responding differently to serotonin-related drugs. Perhaps particular animal models are relevant only for the study of one particular type of anxiety disorder. This differentiated view will be used when discussing the role of 5-hydroxytryptamine (5-HT) receptor subtypes in anxiety disorders and anxiety models. The 5-HT1A receptor is implicated in anxiety by the compounds buspirone and 8-hydroxy-2-(di-n-propyl-aminotetraline) (OHDPAT). The 5-HT1B or the 5-HT1D receptors play a role in the 'defensive burying' anxiety model and probably mediate antidepressant and antianxiety effects of serotonin-uptake inhibitors. The 5-HT1C receptor plays a role in the aversive brain stimulation anxiety model and could play a role in antianxiety effects of mianserin. The 5-HT2 receptor is selectively blocked by ritanserin. In animal 'conflict models' for anxiety, 5-HT-2-receptor antagonists are active, although they are weaker than the benzodiazepines. The 5-HT3-receptor antagonists are reported to be active in social interaction models for anxiety; however, clinical experience in anxiety using these compounds is not yet available.

The anti-aversive action of minor tranquillizers

Minor tranquillizers attenuate behavioural responses induced by aversive brain stimulation in several experimental conditions. This effect of anti-anxiety drugs probably results from the enhancement of GABA-ergic neurotransmission in the midbrain periaqueductal grey matter, medial hypothalamus and amygdala. The anti-aversive action of minor tranquillizers is likely to mediate, at least in part, their clinical anti-anxiety effect.

Neuroeffector mechanisms of the defense reaction in the rat

Electrical stimulation of the dorsal periaqueductal gray matter (DPAG) eliciting flight behavior in awake rats caused an increase in arterial blood pressure (BP), heart rate (HR) and respiration in rats anesthetized with urethane. The hypertension was markedly reduced by 5 mg/kg of intravenously injected hexamethonium or bretylium, virtually abolished by 5 mg/kg of phentolamine and partially antagonized by 0.1 mg/kg of the α 1-adrenoceptor blocker, prazosin. The tachycardia induced by DPAG stimulation was partially antagonized by hexamethonium or bretylium and abolished by propranolol (5 mg/kg, IV) or practolol (5 mg/kg, IV), but not affected by N-butylscopolamine (10 mg/kg, IV). Phentolamine increased basal HR and abolished the tachycardic response caused by either brain stimulation or intravenous noradrenaline. Prazosin moderately decreased the response to noradrenaline, but did not affect basal HR or the tachycardia induced by brain stimulation. The increase in respiratory amplitude occurring during brain stimulation was abolished by phentolamine as well as by prazosin, while the increase in respiratory rate was moderately reduced by phentolamine and propranolol. These results demonstrate that the cardiovascular component of the defense reaction of the rat is almost entirely due to a sharp increase in sympathetic tone. They also suggest that the hyperventilation induced by aversive brain stimulation is modulated by central and peripheral adrenergic mechanisms.

GABA modulation of the defense reaction induced by brain electrical stimulation

Earlier behavioral results led to the suggestion that GABA exerts a tonic inhibitory influence in the dorsal periaqueductal gray (DPAG) matter of the rat integrating defensive behavior. In the present experiments, the role of GABAergic mechanisms in the modulation of the autonomic component of the defense reaction was studied. Thus, the effects of intravenous (IV) injections of chlordiazepoxide as well as of intracerebral (IC) injections of midazolam in the dorsal midbrain, on the blood pressure (BP), heart rate (HR) and respiratory increases induced by electrical stimulation of the DPAG were measured in rats anesthetized with urethane. Chlordiazepoxide (10 mg/kg, IV) as well as midazolam (40 and 160 nmol, IC) attenuated the centrally-induced hypertension, without affecting basal BP. The tachycardia induced by aversive brain stimulation was similarly decreased by the benzodiazepines. In addition, the HR baseline was significantly raised by chlordiazepoxide and by the highest dose of midazolam. The tachypnea induced by brain electrical stimulation was also reduced by both benzodiazepines. Basal respiratory rate was slightly, but significantly decreased by chlordiazepoxide as well as by the two doses of midazolam used and to a lesser extent by the vehicle alone. Chlordiazepoxide attenuated the increase in respiratory depth caused by brain stimulation, while basal respiratory amplitude was not affected. The effects of midazolam on this parameter were unclear. Microinjection of bicuculline (5 and 10 nmol) or picrotoxin (0.3 and 1 nmol) into the DPAG increased the BP, HR and respiration, like the electrical stimulation. The latency and duration of bucuculline effects were shorter than those of picrotoxin. Since the benzodiazepines enhance, whereas bicuculline and picrotoxin antagonize GABA neural actions, these results indicate that the DPAG contains neurons integrating the defense reaction which are tonically inhibited by GABAergic nerve fibers.

Discriminative properties of aversive brain stimulation

This study investigates the rat's ability to discriminate between the effects of electrical stimulation applied to two brain sites located in periventricular structures (medial hypothalamus: MH, and mesencephalic central gray: CG). Wistar rats were trained in a T maze to interrupt aversive effects induced by the stimulation applied to one brain site by pressing a lever located in one arm of the maze, and those induced at another site by pressing a second lever in the other arm. All animals were found able to discriminate between stimulations randomly applied to the two brain sites, not only when these two sites were located one in MH and the other in CG, but also when both were in one or the other of these two brain structures and when the sites were ipsi- or contralateral to each other. The rat discriminated between the effects induced at the two sites even when the escape latencies induced by stimulating either site were similar (Experiment 1). Variation of stimulation intensity or frequency resulted in variation of the escape latencies; however, such variation did not exert any appreciable effect on the rat's ability to discriminate between the two stimulations with only a few exceptions (Experiments 2 and 3). Generalization experiments were then conducted to determine which lever the rat would press in order to stop aversive stimulations in other periventricular sites. It appeared that generalization depended on both the type of discrimination that had been established in Experiment 1 and on some characteristics of the site being stimulated. The results demonstrate that aversive brain stimulation has discriminative stimulus properties. The precise nature of the cues that allowed the rat to discriminate is discussed.

Additive effects of simultaneous midbrain and bulbar opiate microinjections on orofacial nociception and aversive brain stimulation in main sensory trigeminal nucleus

Additive effects of simultaneous midbrain and bulbar opiate microinjections on orofacial nociception and aversive brain stimulation in main sensory trigeminal nucleus

Habituation of the orienting response: Experimental evidence in favor of a “dual-process” theory

In chronic cats, it was found that the magnitude of the intracerebrally elicited orienting response (OR) increased as a direct function of the baseline arousal level immediately preceding the stimulus. Statistically significant positive correlations were found both for fast habituating ORs and ORs resistant to habituation, with the possible exception of resistant ORs elicited by aversive brain stimulation. The results are discussed with reference to the “dual-process” theory of habituation, and seem to give support to this theory.

Adaptation of aversive brain stimulation. III. Excitability characteristics of behaviorally relevant neural substrates : S.G. Dennis, J.S. Yeomans and J.A. Deutsch, Behav. Biol., 18 (1976) 531–544

The excitability characteristics of the neural substrates that mediate escape from and behavioral adaptation to aversive brain stimulation were measured using double-pulse methods in rats. The stimulation was applied through electrodes implanted in or near the midbrain medial lemiscus. When methods were used which did not permit adaptation, the stimulated neurons that mediate escape in nonadapting rats were found to have shorter refractory periods (0.4–0.8 msec) than the neurons that mediate escape in adapting rats (0.6–1.0 msec). This is taken to be evidence of at least two functionally aversive axonal populations in the medial lemniscus. Double-pulse analysis of adaptation produced slowly rising double-pulse curves over a broad range of pulse-pair spacings in excess of 2msec. Several interpretations for this result are presented, and possible mechanisms for the adaptation process are discussed.

Tonic reticular activating system: Relationship to aversive brain stimulation effects

Acute and chronic experiments were performed on albino rats using high-frequency electrical brain stimulation of the dorsal mesencephalon. It was found that: (i) Certain areas of rat mesencephalon generate intense, tonic electrocorticogram activation as well as tonic depression of photic, cortical evoked potential amplitudes. (ii) Often this tonic activation appears suddenly; that is, there is a threshold for activation. (iii) Invariably, if such a threshold is seen, the rat manifests the first escape response coincident with onset of activation. (iv) In some rats no threshold is seen; duration of electrocorticogram activation is monotonic with current intensity. But at some point of moderate intensity (< 80 μA) an escape reaction is elicited. (v) Neither threshold properties nor monotonic relations characterize behaviorally neutral electrical brain stimulation or its application to perirubral reticular formation. From these and other data a hypothetical neural circuit is postulated as being responsible for tonic reticular activation and the production of escape responses.

Adaptation of aversive brain stimulation III. Excitability characteristics of behaviorally relevant neural substrates

The excitability characteristics of the neural substrates that mediate escape from and behavioral adaptation to aversive brain stimulation were measured using double-pulse methods in rats. The stimulation was applied through electrodes implanted in or near the midbrain medial lemiscus. When methods were used which did not permit adaptation, the stimulated neurons that mediate escape in nonadapting rats were found to have shorter refractory periods (0.4–0.8 msec) than the neurons that mediate escape in adapting rats (0.6–1.0 msec). This is taken to be evidence of at least two functionally aversive axonal populations in the medial lemniscus. Double-pulse analysis of adaptation produced slowly rising double-pulse curves over a broad range of pulse-pair spacings in excess of 2msec. Several interpretations for this result are presented, and possible mechanisms for the adaptation process are discussed.

Adaptation of aversive brain stimulation II. Effects of current level and pulse frequency

Behavioral adaptation to aversive stimulation applied through electrodes implanted in or near the midbrain medial lemniscus was studied in rats. Using operant behavior as the dependent variable, adaptation was found to be a direct function of input pulse frequency, but an inverse function of current level. The occurrence of adaptation renders the rat insensitive to transient increases in pulse frequency, although sensitivity to transient increases in current is maintained. The results suggest that there are at least two aversive axonal systems in the region, only one of which possesses the capability for mediating adaptation. Two simple neural mechanisms for the behavioral adaptation effect are presented.

Acceleration and pacing of copulatory performance of male rats by repeated, aversive brain stimulation

Repetitive electric shocks applied to the dorsal midbrain (DM) paced the copulatory behavior of sexually experienced male rats. DM stimulation also accelerated the rate of copulation, the achievement of ejaculation and the resumption of copulation after ejaculation and increased the number of ejaculations in an hour test.

Monoaminergic mechanisms in aversive brain stimulation

In these experiments we have examined the role of brain monoamines in the fearlike aversive responses produced by the electrical stimulation of the dorsal midbrain tegmentum (DMT). Chronic bipolar stimulating electrodes were bilaterally implanted into the DMT of 77 rats. Electrical stimulation via 34 of these electrodes produced fearlike, escape seeking responses. These animals were then trained for stable stimulus escape using a decremental bar pressing paradigm. In this paradigm, each bar press reduced the stimulation current by a predetermined fraction (5 percent) of the initial current level. Perceived aversive strength of the initial stimulus current was thereby represented by an increasing function of the number of bar presses to escape. Administration of the catecholamine depleting drug alpha-methyl-para-tyrosine yielded no change in bar pressing relative to saline-injected controls. However, the serotonin depleting drug para-chlorophenylalanine produced a marked increase in decremental bar pressing compared to saline-injected controls. These results suggest that fearlike responses to DMT stimulation may be dependent upon brain serotonin levels and relatively insensitive to levels of brain catecholamines.