Dopaminergic denervation of the globus pallidus produces short-memory impairment in rats.

Rats with low-level globus pallidus (GP) dopaminergic denervation can develop anxiety without any motor alterations. The aim of this study was to evaluate the effect of low-level 6-OHDA-induced unilateral and bilateral GP lesions in male Wistar rats (n = 8/group) on recognition memory, motor activity, and the number of TH+ neurons in the SNc. For unilateral- and bilateral-lesioned animals, there was a significant decrease in the number of TH+ neurons (27% and 42%, respectively) and in the object, location, and temporal order discrimination indexes of recognition memory tests. Motor activity was unaffected. Thus, GP dopamine denervation was detrimental to short-memory.

Dopamine-dependent modulation of rat globus pallidus excitation by nicotine acetylcholine receptors.

The globus pallidus (GP) coordinates information processing in the basal ganglia nuclei. The contribution of nicotinic cholinergic receptors (nAChRs) to the spiking activity of GP neurons is largely unknown. Several studies have reported that the effect of nAChRs in other nuclei depends on dopaminergic input. Via in vivo single unit extracellular recordings and intranuclear drug infusions, we analyzed the effects of local activation and blockade of nAChRs in neurons of both sham and 6-hydroxydopamine (6-OHDA)-lesioned rats. In sham rats, the local application of nicotine and edrophonium (an acetylcholinesterase inhibitor) increases GP neurons spiking rate. Local application of mecamylamine, a neuronal nicotinic cholinergic antagonist, diminishes pallidal neurons spiking rate, an effect not produced by d-tubocurarine, a peripheral nicotinic cholinergic antagonist. Moreover, mecamylamine blocks the excitatory effect evoked by nicotine and edrophonium. In 6-OHDA-lesioned rats, local infusion of nicotine does not change pallidal neurons firing rate. Our results show that there is a tonic cholinergic input to the GP that increases their spiking rate through the activation of nAChRs and that this effect depends on functional dopaminergic pathways.

6-Hydroxydopamine lesion in thalamic reticular nucleus reduces anxiety behaviour in the rat.

We have studied the effect of the lesion of the dopaminergic innervation of the thalamic reticular nucleus (TRn) on anxiety and motor behaviour. The lesion of the dopamine innervation was produced by the injection of 6-hydroxydopamine into the dorsal part of the thalamic reticular nucleus. The lesion decreased the number of TH (+) cells of the pars compacta of substantia nigra by 33%, without modifying the number of TH (+) cells in ventral tegmental area. The lesion increased the time spent by the rats on the open arms of the elevated plus maze and decreased the duration of burying in the shock-probe test. Both results suggest reduced anxiety. The loss of the dopamine innervation to the TRn decreased the number of rearings but did not significantly affect total motor activity, gait or motor coordination, as evidenced by rotarod performance. These findings suggest that dopamine in the TRn plays a role in fear-related behaviour.

6-OHDA-induced hemiparkinsonism and chronic L-DOPA treatment increase dopamine D1-stimulated [(3)H]-GABA release and [(3)H]-cAMP production in substantia nigra pars reticulata of the rat.

It has been proposed that striatonigral GABAergic transmission in the substantia nigra reticulata (SNr) is enhanced during Parkinson's disease and subsequent L-DOPA treatment. To evaluate this proposal we determined the effects of activating dopamine D1 receptors on depolarization induced [(3)H]-GABA release and on [(3)H]-cAMP accumulation in slices of SNr of rats with unilateral 6-OHDA lesions with and without l-DOPA treatment. Denervation increased depolarization induced D1-stimulated [(3)H]-GABA release, while repeated L-DOPA treatment further enhanced this response. Both also enhanced the effects of forskolin on [(3)H]-cAMP production and [(3)H]-GABA release, while neither modified the stimulating effects of 8-Br-cAMP on the release. These results shown that, after 6-OHDA lesions and l-DOPA treatment, cAMP signaling is enhanced. Furthermore, the results suggest that activation of sites in the signaling cascade downstream of cAMP synthesis is not required to increase release.

Intranigral injection of the H3 agonist immepip and systemic apomorphine elicit ipsilateral turning behaviour in naive rats, but reduce contralateral turning in hemiparkinsonian rats.

There is evidence that histamine H3 receptors co-localise with dopamine D1 receptors on the terminals of striato-nigral neurones. In this work we studied the effect of the local activation of H3 receptors present in substantia nigra pars reticulata (SNr) on turning behaviour following apomorphine administration to either naive or hemiparkinsonian rats. In naive rats the intranigral (SNr) injection of the H3 receptor agonist immepip (3.2 or 32 ng/1 microl) resulted in ipsilateral turning following systemic apomorphine (0.5 mg/kg, subcutaneous). The effect of immepip was related to the dose and prevented by the H3 antagonist thioperamide (5 mg/kg, intraperitoneal). Conversely, in rats with 6-hydroxydopamine (6-OHDA) lesions to either substantia nigra pars compacta or the medial forebrain bundle (mfb), apomorphine-induced contralateral turning was reduced by intranigral immepip, an effect prevented by systemic thioperamide. Our data show that H3 receptors present in SNr regulate the synaptic output of the basal ganglia, most likely by reducing GABA release from striato-nigral terminals. These results may be relevant for the understanding of the role of histamine and H3 receptors in the control of motor behaviour both in normal and pathophysiological conditions, such as Parkinson's disease in which histaminergic innervation and histamine levels in substantia nigra have been shown to increase.