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Behavioral performance effects of antihypertensive drugs: human and animal studies.

Antihypertensive drug treatments have been reported in clinical investigations to produce adverse effects to a degree that causes hypertensive patients to discontinue medication. Many of the debilitating effects reported by patients appear to be of central nervous system origin, such as sedation, fatigue, memory loss and sensorimotor disturbances. Human and animal laboratory studies in the past two decades have been characterizing the psychotropic effects of antihypertensive medications with use of a wide range of behavioral techniques. Antihypertensive drug classes covered in this review are beta-adrenergic blocking agents, alpha-adrenergic agonists, diuretics, angiotensin-converting enzyme inhibitors and calcium channel blockers. While findings in animal studies show generally greater behavioral impairments after administration of alpha-adrenergic agonists in comparison with other drug classes, the few laboratory studies conducted with hypertensive subjects present a confusing picture. A need for further laboratory research with hypertensive subjects and, study of antihypertensive drug combinations is discussed.

Animals↗

Neural correlates for the suppression of habitual behavior: a functional MRI study.

It has been suggested that inhibitory executive control of behavior is directed by the frontal lobes. We used functional magnetic resonance imaging to explore the brain regions that are involved in the inhibition of habitual manual responses. Fifteen right-handed subjects performed the rock-scissors-paper game against computer-simulated pictures of hands during the scanning procedure. The subjects were required to win, lose, or draw against the presented picture in a separate block. We considered that the situation in which subjects intentionally lost the game required the suppression of habitual behavior, because it is natural behavior for people to attempt to win the game. Compared with the WIN and DRAW conditions, the left premotor and sensorimotor areas were activated for both hand sessions with a positive correlation with error rates. Importantly, the LOSE condition in the case of the right hand yielded brain activation exclusively in the anterior part of the left inferior frontal gyrus, the activity which showed a negative correlation with error rates. Overall brain activations were predominant in the left hemisphere, irrespective of the hand used for the response. The results suggest that the anterior part of the left inferior frontal gyrus plays a critical role in the inhibition of habitual manual behavior, and that the left hemisphere is dominant for the selection of well-learned manual behavior.

Adult↗

Median nerve neurotization by peripheral nerve grafts directly implanted into the spinal cord: anatomical, behavioural and electrophysiological evidences of sensorimotor recovery.

Over the years, peripheral nerve grafts, a favorable environment to support axonal elongation, have given rise to increasing interest as a possible solution for promoting spinal cord repair. In the experiments described here, following an avulsion injury of the rat brachial plexus, the median nerve was repaired by a peripheral nerve graft (PN) inserted directly into the dorsal side of the spinal cord. Eight months later the animals were submitted to behavioral tests, electrophysiological and histological studies. Regrowth of axons from both motoneurons and ganglionic neurons was demonstrated following a single superficial dorsal implantation of a PN. Sensorimotor peripheral reinnervation allowed most of the studied animals to recover enough flexor activity for grasping. Reinnervation was achieved even without prior root avulsion suggesting that the presence of a PN is sufficient to induce sprouting in the spinal cord from axotomized and non-axotomized neurons.

Animals↗

[The effect of stimulation of the medial hypothalamus on the interaction of rabbit neocortical neurons].

By means of histograms of cross- and autocorrelation plotting the interaction of visual and sensorimotor neocortex neurons was studied before and after stimulation of some medial hypothalamic nucleus. The stimulation was provided by packages of bipolar impulses with frequency of 100 Hz and current value of 50-200 mcA from the bipolar electrodes and resulted in appearance of avoidance reactions to stimulation place at rabbits' free behavior. After stimulation as compared with calm wakefulness the number of pairs of neurons with correlated activity was increased by 45%, the discharges of sensorimotor neurons forestalled the discharges of the visual ones for up to 120 ms, the frequency of periodicity of correlated discharges was basically in the theta-range. By means of comparison the interaction of neurons after stimulation of medial hypothalamus and midbrain reticular formation and in intersignal interval during defensive conditioning the conclusion was made about manifestation of defensive motivation in definite indices of cortical neurons interaction during tonic conditioned reflex.

Animals↗

Inbred strain differences in prepulse inhibition of the mouse startle response.

Prepulse inhibition is the phenomenon in which a weak prepulse stimulus suppresses the response to a startling stimulus. Patients with schizophrenia have impaired prepulse inhibition which is thought to reflect dysfunctional sensorimotor gating mechanisms. To investigate the potential genetic basis for differences in sensorimotor gating, the responses of 13 inbred strains of mice were evaluated using the prepulse inhibition paradigm. Ten male mice from A/J, AKR/J, BALB/cByJ, BUB/BnJ, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, FVB/NJ, ST/bJ, 129/J, 129/SvJ, 129/SvEvTac inbred strains were tested for acoustic prepulse inhibition of acoustic and tactile startle responses. There was a wide range of responses among the inbred strains of mice. Exact strain distributions were determined for each combination of prepulse sound level and startle stimulus. In general, mice from the 129/SvEvTac, AKR/J, 129/J, and 129/SvJ strains displayed high levels of prepulse inhibition of both the acoustic and tactile startle responses. C57BL/6J, C57BL/10J and BUB/BnJ mice showed low levels of prepulse inhibition. There was also a wide range in the amplitude of the acoustic and tactile startle responses. C57BL/10J and FVB/NJ mice displayed the greatest startle responses and DBA/2J, 129/J and 129/SvJ had the poorest startle responses. There was no correlation between the level of prepulse inhibition and the amplitude of the startle response. These findings indicate that inbred strains of mice may be a useful tool to study the genetic basis of sensorimotor gating.

Acoustic Stimulation↗

Visual processing in the ketamine-anesthetized monkey. Optokinetic and blood oxygenation level-dependent responses.

We used optokinetic responses and functional magnetic resonance imaging (fMRI) to examine visual processing in monkeys whose conscious state was modulated by low doses (1-2 mg/kg) of the dissociative anesthetic ketamine. We found that, despite the animal's dissociated state and despite specific influences of ketamine on the oculomotor system, optokinetic nystagmus (OKN) could be reliably elicited with large, moving visual patterns. Responses were horizontally bidirectional for monocular stimulation, indicating that ketamine did not eliminate cortical processing of the motion stimulus. Also, results from fMRI directly demonstrated that the cortical blood oxygenation level-dependent (BOLD) response to visual patterns was preserved at the same ketamine doses used to elicit OKN. Finally, in the ketamine-anesthetized state, perceptually bistable motion stimuli produced patterns of spontaneously alternating OKN that normally would be tightly coupled to perceptual changes. These results, taken together, demonstrate that after ketamine administration cortical circuits continue to processes visual patterns in a dose-dependent manner despite the animal's behavioral dissociation. While perceptual experience is difficult to evaluate under these conditions, oculomotor patterns revealed that the brain not only registers but also acts upon its sensory input, employing it to drive a sensorimotor loop and even responding to a sensory conflict by engaging in spontaneous perception-related state changes. The ketamine-anesthetized monkey preparation thereby offers a safe and viable paradigm for the behavioral and electrophysiological investigation of issues related to conscious perception and anesthesia, as well as neural mechanisms of basic sensory processing.

Anesthetics, Dissociative↗

A triggered hyperkinesia induced in rats by lesions of the corpus striatum.

The role of the corpus striatum (caudate, putamen, and globus pallidus) in movement control has been suggested to involve the modulation of sensory traffic to downstream motor mechanisms. We report that kainic acid lesions of the posterior corpus striatum, which preferentially spare fibers of passage while destroying striatopallidal neurons, produce a stimulus-sensitive movement pattern in rats that has a highly specific sensory trigger. The triggered choreic movement pattern is not a motor pathology per se, nor a response to diffuse states of arousal or stress, but rather is activated specifically in response to oral sensory stimulation. This sensory-specific hyperkinesia may be relevant to certain human sensorimotor pathologies.

Animals↗

A QTL on rat chromosome 7 modulates prepulse inhibition, a neuro-behavioral trait of ADHD, in a Lewis x SHR intercross.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a complex neuropsychiatric disorder with a substantial genetic component. The Spontaneously Hypertensive Rats (SHR), considered as a good animal model of ADHD, also show less anxiety-like behaviors than Lewis (LEW) rats. The use of these inbred rat strains led us to the mapping of two quantitative trait loci (QTL), named Ofil1 (on chromosome 4) and Ofil2 (on chromosome 7), related to locomotion in the central and aversive area of an open field. Herein, we examined whether LEW and SHR rats differ in the acoustic startle reflex, a test used to study the neurobiology of anxiety, and in the prepulse inhibition of the startle response, which is known to be impaired in ADHD patients. The effect of the two aforementioned loci on these behavioral responses was also studied. METHODS: For this latter purpose, rats deriving from an F2 intercross between the LEW and SHR strains were selected according to their genotype at markers flanking the QTLs and bred to obtain lines of rats homozygous LEW/LEW or SHR/SHR for each of the two loci, thus generating 4 genotypic combinations. RESULTS: The SHR rats displayed decreased startle and prepulse inhibition levels when compared to LEW rats. Ofil2 affected prepulse inhibition in female rats only. CONCLUSION: The results suggest that the LEW and SHR strains are appropriate for studying mechanisms of sensorimotor gating and indicate that the locus Ofil2 on rat chromosome 7 contain genes controlling prepulse inhibition, a neuro-behavioral trait of ADHD.

Journal Article↗

Conscious and subconscious sensorimotor synchronization--prefrontal cortex and the influence of awareness.

One of the most compelling challenges for modern neuroscience is the influence of awareness on behavior. We studied prefrontal correlates of conscious and subconscious motor adjustments to changing auditory rhythms using regional cerebral blood flow measurements. At a subconscious level, movement adjustments were performed employing bilateral ventral mediofrontal cortex. Awareness of change without explicit knowledge of the nature of change led to additional ventral prefrontal and premotor but not dorsolateral prefrontal activations. Only fully conscious motor adaptations to a changing rhythmic pattern showed prominent involvement of anterior cingulate and dorsolateral prefrontal cortex. These results demonstrate that while ventral prefrontal areas may be engaged in motor adaptations performed subconsciously, only fully conscious motor control which includes motor planning will involve dorsolateral prefrontal cortex.

Acoustic Stimulation↗

Adrenal medullary transplants attenuate sensorimotor dysfunction in rats with peripheral neuropathy.

Previous work in our laboratory has demonstrated that adrenal medullary transplants into the spinal subarachnoid space can alleviate neuropathic pain behaviors. The purpose of this study was to test the possibility that motor, as well as, sensory dysfunction is reduced by adrenal medullary transplants. Peripheral neuropathy was induced by a chronic constriction injury (CCI) of the sciatic nerve of rats. In addition to exaggerated responses to noxious and innocuous stimuli characteristic of peripheral nerve injury, severe impairment of hindpaw placing and grasping reflexes following CCI was observed. Two weeks following CCI, either adrenal medullary or control striated muscle tissue was implanted into the spinal subarachnoid space. Adrenal medullary, but not control transplants, produced significant restoration of hindlimb reflex function in animals with peripheral nerve injury. This was reversed by pretreatment with the alpha-adrenergic antagonist phentolamine, but not the opiate antagonist naloxone, suggesting a role for catecholamines secreted by the implanted cells in reflex recovery. Adrenal medullary transplants also attenuated hyperalgesia and allodynia resulting from nerve injury. These results indicate that adrenal medullary transplants can alleviate sensorimotor dysfunction consequent to peripheral nerve injury.

Adrenal Medulla↗

Functional aspects of dopamine metabolism in the putative prefrontal cortex analogue and striatum of pigeons (Columba livia).

Dopamine (DA) in mammalian associative structures, such as the prefrontal cortex (PFC), plays a prominent role in learning and memory processes, and its homeostasis differs from that of DA in the striatum, a sensorimotor region. The neostriatum caudolaterale (NCL) of birds resembles the mammalian PFC according to connectional, electrophysiological, and behavioral data. In the present study, DA regulation in the associative NCL and the striatal lobus parolfactorius (LPO) of pigeons was compared to uncover possible differences corresponding to those between mammalian PFC and striatum. Extracellular levels of DA and its metabolites (homovanillic acid [HVA], dihydroxyphenylacetic acid [DOPAC]) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were investigated by in vivo microdialysis of urethane-anesthetized pigeons under basal conditions and after systemic administration of D-amphetamine. DA was reliably determined only in LPO dialysates, and DA metabolite levels were significantly higher in LPO than in NCL. The HVA/DOPAC ratio, indicating extracellular lifetime of DA, was more than twice as high in NCL than in LPO dialysates. After amphetamine, DA increased in LPO while still being undetectable in NCL, and DA metabolites decreased in both regions. 5-HIAA slightly decreased in NCL dialysates. Amphetamine effects were delayed in NCL compared with the striatum. In conclusion, effects of amphetamine on the pigeon's ascending monoamine systems resemble those found in mammals, suggesting similar regulatory properties. The neurochemical differences between NCL and LPO parallel those between associative regions, such as PFC and dorsal striatum in mammals. They may reflect weaker regulation of extracellular DA, favoring DAergic volume transmission, in associative than striatal forebrain regions.

3,4-Dihydroxyphenylacetic Acid↗

Prepulse inhibition during withdrawal from an escalating dosage schedule of amphetamine.

RATIONALE: Psychomotor stimulants can induce psychotic states in humans that closely resemble those observed in patients with idiopathic schizophrenia. Attentional and sensorimotor gating impairments are observed in schizophrenic patients using the latent inhibition (LI) and prepulse inhibition (PPI) behavioral assays, respectively. Our previous studies demonstrated that after 4 days of withdrawal from a period of amphetamine (AMPH) administration, animals exhibited disrupted LI but normal PPI. OBJECTIVE: The aim of the present study was to test PPI in AMPH-withdrawn rats under experimental conditions similar to those used to best demonstrate locomotor sensitization following AMPH withdrawal. METHODS: We examined the effects on PPI of (1) pairing drug injections with PPI test-associated cues, (2) administration of a low-dose dopamine agonist challenge and (3) testing following longer withdrawal periods (23, 30, 60 days). RESULTS: Although none of these conditions revealed a disruption of PPI in AMPH-withdrawn rats, we did observe that the acoustic startle response was reduced during a restricted time period following AMPH withdrawal. Similar to our previous findings, AMPH-withdrawn animals showed disrupted LI on day 16 of withdrawal and locomotor sensitization to a challenge injection of AMPH after 62 days of withdrawal. CONCLUSION: We conclude that the effects of repeated AMPH on PPI are not modulated by the same experimental parameters known to be important for eliciting locomotor sensitization and that withdrawal from the schedule of AMPH administration used in this study models only specific cognitive dysfunctions linked to schizophrenic symptoms, since LI was disrupted but PPI was not affected.

Acoustic Stimulation↗