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The effects of perfusion with two selective dopamine receptor agonists SKF38393 and pergolide into the medial prefrontal cortex (mPfc) on local and ventral tegmental area (VTA) glutamate and gamma-aminobutyric acid (GABA) release were investigated using dual probe microdialysis in the awake rat. Intracortical SKF38393 (10, 100, 500 microM, 60 min) decreased glutamate and increased GABA release in the mPfc but had no effect on either amino acid neurotransmitter in the VTA. Intracortical perfusion with the selective GABA(A) receptor antagonist bicuculline (0.1 microM, 140 min) reversed the SKF38393 (100 microM, 60 min)-induced decrease in local glutamate release, while the selective GABA(B) receptor antagonist CGP35348 (100 microM, 140 min) was without effect. Intracortical pergolide (1 microM, 60 min) was associated with a prolonged reversible decrease in local and VTA glutamate release that was also associated with a decrease in VTA GABA release, which was reversed in the presence of intracortical raclopride (10 microM, 140 min). Taken together, the present findings indicate a differential regulation of glutamate and GABA release in the mPfc and VTA by dopamine D(1) and D(2) receptors in the mPfc whereby (a) activation of the dopamine D(1) receptor in the mPfc decreases local glutamate release possibly via a feed-forward activation of the local GABA interneurons; (b) activation of the dopamine D(2) receptor in the mPfc inhibits both local glutamate release and the excitatory glutamate drive on the VTA.

There is growing pharmacological evidence from several animal models of seizure disorder that adenosine possesses endogenous anticonvulsant activity. In order to further evaluate the role of adenosine in seizure activity, we monitored adenosine and its major biochemical metabolites inosine, xanthine, and hypoxanthine in the dorsal hippocampus by in vivo microdialysis before and during the induction of generalized seizures. Seizures were induced pharmacologically in groups of urethane-anesthetized rats by the administration of bicuculline (0.5 mg/kg, i.v.), kainic acid (12.0 mg/kg, i.v.) or pentylenetetrazol (100-250 mg/kg, i.p). Seizure activity was monitored electrophysiologically from the dorsal hippocampus. Dialysate hippocampal purine levels increased during all three seizure types. The largest increases were for the adenosine metabolites hypoxanthine and inosine, with smaller increases observed for adenosine and xanthine. Intra-hippocampal perfusion with the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl-adenine, (EHNA, 300 microM), only slightly increased basal hippocampal adenosine. Guanosine levels in the hippocampus, a purine not directly related to adenosine metabolism, were unaffected by all treatments. These findings demonstrate that an increase in hippocampal adenosine release and metabolism is associated with seizure activity and support the hypothesis that the increased adenosine levels may attenuate hippocampal seizure activity, possibly by terminating ongoing seizures and altering the pattern of subsequent seizures.

Most of the previous experimental studies on the antinociceptive effects of electrical spinal cord stimulation (SCS) have focused on short-lasting effects mainly depending on spinal mechanisms. However, patients treated with SCS for chronic pain often report pain relief exceeding the period of stimulation for several hours. The long lasting effect of SCS might not only involve spinal, but also supraspinal mechanisms. A supraspinal region of major importance for the coordination of descending pain inhibition is the periaqueductal grey matter (PAG). The aim of the present microdialysis study, performed in awake freely moving rats, was to investigate if repeated SCS (two 30 min periods separated by a 90 min resting period) alters the extracellular neurotransmitter concentrations in the ventrolateral PAG. In a first series of experiments significantly decreased (-30%; P < 0.05; n = 7) gamma-aminobutyric acid (GABA) levels were detected immediately after the second SCS session. Neither the concentration of serotonin nor that of substance P-like immunoreactivity (SP-LI) was affected by SCS. The decrease of GABA after two SCS sessions was confirmed in a second series of experiments (-30%; P < 0.05; n = 7). No spontaneous decline of GABA was observed in sham-stimulated animals (n = 6). The glutamate concentration was also determined in this latter series of experiments and a significant decrease (-23%; P < 0.05; n = 5) was observed after the second SCS session. As GABA-neurons in the PAG exert a tonic depressive effect on the activity in descending pain inhibitory pathways, a decreased extracellular GABA level in this region, as detected following repeated SCS, might indicate an increased pain inhibition.

Variation in cell loss and mossy fiber reorganization was examined along the longitudinal axis of the dentate gyrus from temporal lobe epileptic (TLE) patients. Previous evidence has indicated that the anterior hippocampus is prone to seizure activity. We compared granule and hilar cell number in addition to Timm stain density of the molecular layer and hilus in more anterior and more posterior specimens of hippocampus obtained from patients surgically treated for intractable epilepsy by the removal of the anterior half of the hippocampus. Granule cells/mm in the more anterior specimen were less than or equal to those in the more posterior specimen locations in 77% of the patients, while there was no significant difference in hilar neuron density between the two blocks. These results demonstrate a significantly greater pathology in the granule cell layer in more anterior specimens and no difference in pathology for hilar neurons. Molecular layer Timm stain density was significantly greater in the more anterior specimen of 71% of the patients. The molecular layer Timm stain density ratio was inversely related to hilar cell density in more anterior specimens, whereas in more posterior specimens there was no significant relationship with hilar cell density. Our observations show that although differences exist among TLE patients for these neuroanatomic measures, pathology was greater in more anterior specimens. The latter result is consistent with the conclusion that seizure activity may originate in the anterior region of the hippocampus in a majority of patients.

The effects of local perfusion with the tridecapeptide neurotensin (NT) on endogenous gamma-aminobutyric acid (GABA), acetylcholine (ACh) and choline release in the dorsal neostriatum were monitored using in vivo microdialysis in the halothane anaesthetized rat. The results show that NT (10 and 1000 nM) differentially regulates striatal GABA release without significantly influencing the release of either striatal ACh or choline. NT increased striatal GABA release both in the absence and presence of the ACh esterase inhibitor neostigmine (neo; 10 microM) in the perfusion medium. However, both basal GABA levels and responsitivity to NT were elevated in the presence of neo. The NT induced increase in striatal GABA release was reversed by the addition of tetrodotoxin (TTX; 1 micron) to the perfusion medium. These data suggest that (1) NT may play a role in modulating GABAergic neurotransmission in the dorsal neostriatum and (2) that the increase in GABA release may occur independently of an increase in the cholinergic component in the dorsal neostriatum, possibly via high affinity NT receptors located on striatal GABAergic neurons.

The effects of injections of gamma-aminobutyric acid (GABA) and dynorphin A into the substantia nigra, pars reticulata on the levels of extracellular dopamine (DA) and GABA in the ipsilateral striatum of halothane-anaesthetized rats were studied using microdialysis. The effects of intranigral injections of substance P and neurokinin A were also studied. Intranigral GABA (300 nmol) or dynorphin A (0.5 nmol) injections produced a simultaneous decrease in DA and increase in GABA levels, while intranigral substance P (0.07 nmol) or neurokinin A (0.09 nmol) injections produced an increase in DA but had no effect on GABA levels. DA agonists, apomorphine (D1/D2), SKF 38393 (D1) and pergolide (D2) were applied locally by perfusing them through the microdialysis probe, each at a concentration of 10(-5) M. All 3 agonists decreased the levels of DA in the striatum. However, while apomorphine and SKF 38393 increased, pergolide decreased the levels of GABA in the striatum. The increase in striatal GABA produced by intranigral injections of GABA (300 nmol) was reversed by local perfusion with pergolide (10(-5) M), but was not reversed by local perfusion with SKF 38393 (10(-5) M). These findings suggest that D1 and D2 receptors differentially regulate striatal GABA release, and are stimulatory and inhibitory, respectively. Furthermore, it is suggested that nigrostriatal DA functions as an inhibitory modulator of striatal GABA neurons, acting via D2 receptors.