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The GABAergic and dopaminergic pathways in the central nervous system (CNS) play a pivotal role in the control of emotions and in the adaptive responses to stressful stimuli. The present study was aimed at characterizing a range of biochemical markers of GABA- and dopamine-mediated neurotransmission in the CNS of Roman high-avoidance (RHA/Verh) and Roman low-avoidance (RLA/Verh) rats, two psychogenetically selected lines that differ in their level of emotionality. The stimulatory effect of GABA on 36Cl- uptake was less pronounced in the cerebral cortex of RLA/Verh rats as compared to RHA/Verh rats, whereas no line-related changes were detected in [3H]GABA and [3H]flunitrazepam binding. On the other hand, the density of D1 dopamine receptors labeled with [3H]SCH 23390 was lower in the nucleus accumbens of RLA/Verh rats as compared to their RHA/Verh counterparts, whilst no line-dependent changes were observed in the binding parameters of D1 dopamine receptors in the striatum, amygdala, and prefrontal cortex. These biochemical differences may contribute to the distinct emotionality and responsiveness to the effects of psychoactive drugs of RHA/Verh and RLA/Verh rats.

We investigated connections between the rostral ventrolateral medulla (rVLM) and the two main inspiration-related medullary areas, i.e., the dorsal respiratory group (DRG) and the rostral ventral respiratory group (rVRG) in the cat. Non respiration-related tonically firing units encountered in the rVLM displayed either antidromic or orthodromic responses to DRG or rVRG microstimulation. Some units responded to the stimulation of both regions. We suggest that at least part of rVLM neurons are components of medullary loops operating in the control of breathing.

The functional role of Bötzinger complex (Böt. c.) projections to the expiration-related (ER) area of the caudal ventral respiratory group (cVRG) was investigated in anesthetized, vagotomized, paralyzed and artificially ventilated cats. ER neurons in both the ipsi- and the contralateral cVRG displayed excitatory responses to Böt. c. electrical microstimulation. They were also activated by microinjections of D,L-homocysteic acid into the Böt. c. region. We propose that at least part of the Böt. c. projections to the cVRG have an excitatory function.

Rats habituated to handling preceding sacrifice have higher [3H]GABA receptor binding in different brain areas (cerebellum, frontal cortex, caudate nucleus) than naive animals. The increase in GABA binding in handling-habituated rats is due to an increase in the number of receptors (Bmax) with no changes in the affinity of GABA binding for its ligand (Kd). Foot shock causes a sudden fall in GABA binding in handling-habituated rats but does not, or only slightly, in naive ones. The results indicate that stress causes a rapid decrease in GABA receptor binding in the central system and that the GABA binding values which are usually considered as normal are, in fact, values decreased by the handling manoeuvers preceding sacrifice.

The influences of vagal and laryngeal afferent inputs on expiration-related neurons of Bötzinger complex were studied in anesthetized, paralyzed and artificially ventilated cats. Unilateral electrical stimulation (single shocks or short trains of stimuli at 200 Hz) applied to the cervical vagus nerve or to the superior laryngeal nerve induced inhibitory effects on the activity of these neurons. During apnoea due to hyperventilatory hypocapnia, expiration-related units displayed a low level of tonic activity which was rhythmically inhibited by pump-induced lung inflations. The functional significance of these findings is briefly discussed.

The cerebral cortices of rats habituated to the handling manipulation that precedes sacrifice by guillotine (unstressed rats) have a higher number of low affinity GABA receptors than naive rats (stressed rats). Foot shock stress delivered to handling-habituated rats 5 min before sacrifice decreased the number of low affinity GABA receptors to the level found in naive animals, while leaving almost unchanged the [3H]GABA binding in the latter group. Since benzodiazepine (BZ) recognition sites are the target through which benzodiazepines modulate the emotional states of the animals, we investigated whether these receptors were involved in the action of foot shock stress on GABA binding. The in vitro addition of diazepam (5 X 10(-6) M) to cortical membranes from foot-shocked handling-habituated rats brought back the number of low affinity GABA receptors to the level found in cortical membranes from handling habituated rats. Moreover, the effect of foot shock on low affinity GABA receptors was completely antagonized in vivo by pretreatment with the specific benzodiazepine antagonist Ro15-1788 (30 mg/kg per os). Since the effect of foot shock on [3H]GABA binding is mimicked by the in vitro addition of beta-carbolines to cortical membranes from handling habituated rats, our working hypothesis is that an endogenous ligand for BZ recognition sites, possessing beta-carboline-like properties, is released during foot shock stress.

The injection of kainic acid into the substantia nigra causes, 3 weeks after treatment, a 40% decrease in the total number of binding sites for [3H]diazepam with an increase in the dissociation constant. This decrease was restored to approximately normal by the subsequent injection of kainic acid into the striatum, homolateral to the lesioned substantia nigra. The injection of kainic acid into the striatum of intact animals failed to modify the number of [3H]diazepam binding sites but increased the KD. The results indicate that benzodiazepine binding sites in the substantia nigra are partly located on kainic acid sensitive elements (probably interneurons) and, partly, on kainic acid resistant ones. These binding sites become supersensitive after degeneration of striato-nigral pathways. The possible role of GABAergic denervation of the substantia nigra in the development of benzodiazepine binding sites supersensitivity is discussed.

Chronic treatment with the beta-carboline derivative FG 7142 (15 mg/kg i.p. twice a day for 10 consecutive days) produced a long-lasting enhancement of shock-induced suppression of drinking in rats, without affecting unpunished behaviour. This proconflict effect was observed up to 15 days after withdrawal from FG 7142. A significant sensitization to seizures induced by isoniazid, a drug known to inhibit GABAergic transmission, was also found to occur after long-term (25 days) withdrawal. Moreover, the density of low-affinity GABA receptors was decreased by 30% in the cerebral cortex of rats repeatedly injected with FG 7142 at 5 and 15 days after withdrawal. The capacity of high-affinity GABA receptors, as well as the apparent dissociation constants for both high- and low-affinity GABA receptors were unchanged. Similar modifications in [3H]GABA binding were also observed in the cerebellum. The enhancement of punishment suppressed behaviour, the sensitization to isoniazid-induced convulsions and the decrease in the density of low-affinity GABA receptors suggest that chronic administration of FG 7142 induces a persistent down-regulation of GABAergic transmission in the central nervous system.

Intraocular injection of kainic acid caused a marked decrease in GABA content in the rat retina and the almost complete loss of GAD activity in this tissue, within 3 days. Moreover, kainic acid produced a decrease of approximately 65% in the number of both [3H]diazepam and [3H]GABA binding sites without changing the apparent dissociation constants for their ligands. In contrast to that in brain areas, cyclic GMP content in the retina is neither influenced by kainic acid nor by the systemic administration of diazepam and muscimol.

Cerebral cortex membranes from rats habituated to manipulations preceding decapitation (habituated rats) had 40% higher GABA binding than membranes from naive animals. Diazepam (5 X 10(-6) M), added to membranes from naive rats, increased GABA binding to the level of habituated rats, but failed to induce any further increase in membranes from the latter animals. Vice versa, beta-carbolines (FG 7142, beta-CCE, DMCM) added to membranes from habituated rats lowered GABA binding to the level of naive animals, but caused no further decrease in the membranes from this last group. Diazepam removed the effect of beta-carbolines in membranes from habituated rats. It is suggested that handling represents a stressful stimulus for naive animals and that stress lowers GABA binding by releasing an endogenous ligand for benzodiazepine receptors possessing similar properties to beta-carbolines. Finally, the results indicate that the emotional status of animals from which brain tissue is obtained should be considered when connections between GABA and benzodiazepine receptors are studied.

Three days after the acute oral administration of methyl mercury (MeHg), a 27-60% increase in the total number of binding sites for [3H]diazepam was seen in the retina and different areas of the rat brain, with no change, except in the retina, in the apparent dissociation constant for its ligand. In contrast, MeHg failed to change [3H]spiroperidol and [3H]GABA binding in the same areas. Moreover, MeHg decreased cyclic GMP content in the cerebellar cortex. The various possible mechanisms involved in the action of MeHg on benzodiazepine binding are discussed.