Injections Of GABA Antagonists Research Articles

Towards a primate model of Gilles de la Tourette syndrome: Anatomo-behavioural correlation of disorders induced by striatal dysfunction

IntroductionGilles de la Tourette syndrome (GTS) is characterized by abnormal movements (tics) often associated with behavioural disorders. Neuropathological data from GTS patients have suggested that aberrant activation of distinct striatal functional territories could produce a large spectrum of GTS symptoms. In a monkey model, injections of GABA-antagonist into the striatum enabled us to produce tic-like movements, hyperactivity and stereotyped behaviours. These effects had similarities with simple motor tics, hyperactivity and compulsive behaviours observed in GTS patients. In this study, we first aimed to identify the neuronal circuits involved in the different behavioural effects using anatomical antero/retrograde tracer in monkeys. We also compared the neuronal circuits thus obtained with the available neuro-anatomical data on GTS patients. MethodsUsing injections of axonal tracer into different functional parts of the striatum of eight monkeys, we identified cortical, thalamic and basal ganglia regions related to the expression of tic-like movements, hyperactivity and stereotyped behaviours induced in response to microinjection of GABA-antagonist. ResultsIn this monkey model, different anatomical circuits involving distinct cortical and thalamic areas and sub-territories of the basal ganglia underpinned movement and behavioural disorders. Thus, tic-like movements were associated with neuronal labelling within the sensorimotor network, mostly in the medial and lateral premotor cortex and sensorimotor parts of the basal ganglia. Neuronal labelling in the prefrontal dorso-lateral cortex and associative territories of the basal ganglia was related to hyperactivity disorder and stereotyped behaviours were linked to the orbitofrontal cortex and limbic part of the basal ganglia. ConclusionsThese results support the hypothesis that different behavioural effects could arise from distinct but inter-digitated neuronal circuits. As these behavioural disorders shared some similarities with simple motor tics, hyperactivity and compulsive behaviours observed in GTS patients, this model could be a good tool for future studies involving the modulation of neuronal circuits, such as deep brain stimulation.

Medioventral medulla-induced locomotion

Previous anatomical studies demonstrated the presence of descending projections from the physiologically identified mesencephalic locomotor region (MLR) to the medioventral medulla (MED) in the cat. The present experiments were designed to determine if a similar low threshold locomotion-inducing area is present in the rat medulla. In addition, the nature of the neurochemical control of this area of the brain was explored using localized injections of neurochemical agents in the decerebrate rat during locomotion on a treadmill. A region virtually identical to that reported in the cat was found to lead to controlled locomotion on a treadmill following stimulation at low amplitude currents (≤60 μA). Injections of cholinergic agonists into the MED of the rat induced locomotion which could be blocked by injections of cholinergic antagonists. In addition, injections of GABA antagonists were found to induce stepping which could be blocked by injections of GABA or GABA agonists. Substance P (SP) also was found to induce walking following injection into the MED of the rat. Injections of an excitatory amino acid agonist (NMDA) also were found to induce locomotion in the rat. These effects were blocked by injections of an excitatory amino acid antagonist (APV). Since these results had not been reported for the cat MED, a short series of experiments revealed that the MED in the cat also responded to NMDA.

Posterior midbrain-induced locomotion

The purpose of this study was to determine the nature of the neurochemical signals which impinge on the mesencephalic locomotor region (MLR) to produce locomotion in the rat. Injections of GABA antagonists into NADPH diaphorase-positive regions (PPN) were found to induce locomotion for short episodes (5–30 sec) which were repeated for several minutes (1–40 min). Such activity was blocked by injections of GABA and the GABA agonist, muscimol. Locomotion was induced by injection of substance P (SP), which also produced short, repeated episodes of locomotion. The more potent excitatory amino acid agonist, n-methyl-d-aspartic acid (NMDA), however, did produce dose-dependent, long-lasting (20 sec–5 min) locomotor episodes which were repeated over prolonged periods at the higher concentrations used (2–24 min). Additional injections of NMDA could drive stepping from a walk to a trot to a gallop. The effects of NMDA were blocked by injections of the excitatory amino acid antagonist, aminophosphonovalerionic acid (APV) (1–10 mM). Preliminary evidence suggests that carbachol (10–50 mM), a cholinergic agonist, inhibits NMDA-induced increases in muscle tone and episodes of stepping. The effect of carbachol was blocked by the cholinergic antagonist, atropine.

Defense reaction elicited by injection of GABA antagonists and synthesis inhibitors into the posterior hypothalamus in rats

Blockade of γ-aminobutyric acid (GABA) in the posterior hypothalamic nucleus elicits cardiorespiratory stimulation in anesthetized rats. The present study was conducted to test the hypothesis that blockade of GABA in this cardiostimulatory area of the posterior hypothalamus in conscious animals would elicit a defense reaction characterised by a “fight or flight” response. Blockade of GABA was achieved by injecting bicuculline methiodide (BMI 1–25 ng) and picrotoxin (4–100 ng), two post-synaptic GABA antagonists and isoniazid (INH 35 and 70 μg), an inhibitor of the synthesis of GABA, bilaterally into the posterior hypothalamus through chronically implanted microinjection cannulae. All three drugs produced dose-dependent increases in locomotor activity, suggesting an “escape” reaction which was quantified as number of crossings and rearings. The effects of bicuculline and picrotoxin appeared immediately after the injection while those of isoniazid appeared much more slowly, attaining peak effects 24 ± 1 min after injection. Injection of either strychnine (38 ng) into the posterior hypothalamus or bicuculline into the lateral hypothalamic area (LHA) or the dorso-medial/ventro-medial hypothalamus (DMH/VMH) did not elicit a significant increase in locomotor behavior. These results suggest that both the physiological and locomotor components of the hypothalamic defense reaction may be under tonic GABAergic inhibition in the region of the posterior hypothalamus.

Dyskinetic effects of intrastriatally injected GABA-transaminase inhibitors

Injection of GABA antagonists into the striatum of rats induces abnormal involuntary movements that are blocked by increasing GABA levels in this area. Attempts to increase GABA by intrastriatal (i.s.) injection of GABA-transaminase (GABA-T) inhibitors surprisingly induced identical dyskinesias. This property was shared by all GABA-T inhibitors tested except ethanolamine-O-sulphate. This dyskinesia is easily blocked by i.s. injection of GABA and muscimol, as well as by intraperitoneal pretreatment with the GABA-T inhibitors themselves. These observations suggest that some GABA-T inhibitors may behave as GABA antagonists when locally applied in the brain at high concentrations.