Chronic clozapine versus chronic haloperidol treatment: differential effects on electrically evoked dopamine efflux in the rat caudate putamen, but not in the nucleus accumbens.

Fast cyclic voltammetry at carbon-fibre micro-electrodes was used to investigate the effects of chronic clozapine or haloperidol administration on electrically evoked dopamine efflux in the nucleus accumbens and caudate putamen of the anaesthetized rat. Stimulation trains were delivered to the median forebrain bundle (60 pulses, 350 microns duration) every 5 min, and the evoked dopamine efflux measured as a function of a) the applied stimulus intensity (range 0.2 mA-1.0 mA), and b) the applied stimulus frequency (range 10 Hz-250 Hz). Chronic administration of either clozapine (20 mg/kg x 21 days, p.o.) or haloperidol (1 mg/kg x 21 days, p.o.) significantly reduced electrically evoked dopamine efflux in the nucleus accumbens over the range of stimulus intensities and frequencies tested. The reduction in evoked dopamine efflux observed in the nucleus accumbens of clozapine- and haloperidol-treated rats showed no statistically significant difference. In contrast, only chronic haloperidol treatment significantly reduced evoked dopamine efflux in the caudate putamen. These findings demonstrate that chronic treatment with either the atypical neuroleptic, clozapine, or the typical neuroleptic, haloperidol, produce long-term changes in mesolimbic dopamine function; actions which may underlie their antipsychotic efficacy. They also provide further evidence that the sparing action of clozapine on nigrostriatal dopamine activity may underlie the lower incidence of extrapyramidal side effects associated with its long-term administration.

Dopamine autoreceptor sensitivity is unchanged in rat nucleus accumbens after chronic haloperidol treatment: an in vivo and in vitro voltammetric study.

Fast cyclic voltammetry was used to assess the effects of chronic oral haloperidol treatment (0.7 mg/kg/day for 21 days) on the sensitivity of dopamine autoreceptors in the rat nucleus accumbens both in vivo and in vitro. Evoked dopamine overflow was significantly reduced after chronic haloperidol treatment, but the sensitivity of dopamine overflow to sulpiride, an antagonist at release-inhibiting dopamine autoreceptors, and quinpirole, an agonist at these receptors, was unchanged. The estimated EC50 values for quinpirole and sulpiride (52 and 60 nM respectively) obtained in vitro and the receptor distribution profiles published in the literature suggest that the autoreceptors involved in this modulation are mainly of the D3 subtype. The finding that the reduced dopamine overflow in the nucleus accumbens observed after chronic treatment with a classical neuroleptic is not due to dopamine autoreceptor supersensitivity may therefore be the first functional evidence for unchanged autoreceptor activity in the nucleus accumbens, supporting biochemical findings of a lack of D3 autoreceptor up-regulation after chronic haloperidol treatment. It lends further support to the assumption that the long-term changes occurring during chronic neuroleptic treatment may not lie at the level of presynaptic dopamine receptor regulation.

Stimulus-evoked dopamine overflow in the rat nucleus accumbens is decreased following chronic haloperidol administration: an in vivo voltammetric study.

Fast cyclic voltammetry was used to investigate the effects of chronic haloperidol (HAL) treatment on electrically evoked dopamine (DA) overflow in the nucleus accumbens of the anaesthetized rat in vivo. Evoked DA efflux was significantly reduced in rats treated with 1.0 mg/kg per day HAL for 21 days. In rats treated with 0.5 mg/kg per day, evoked DA overflow was reduced, but did not differ significantly from control values. In untreated animals, injection of a single dose of HAL resulted in a significant increase in the DA overflow evoked by subsequent stimulus trains. In contrast, this HAL challenge did not produce a significant enhancement in evoked DA overflow in any of the HAL-treated groups. These results are consistent with the previous reports that basal DA release is reduced after chronic HAL treatment, and show for the first time that chronic HAL administration decreases stimulus-evoked DA overflow in the rat nucleus accumbens in vivo.

The NMDA receptor antagonist CPP suppresses long-term potentiation in the rat hippocampal-accumbens pathway in vivo.

Excitation of afferent fibres originating in the ventral subiculum of the hippocampus through stimulation of the fimbria elicits field potentials in the nucleus accumbens. When recorded in the dorsomedial aspect of the nucleus accumbens, the evoked field responses consisted of an early, negative-going component (N1) with a peak latency of 8-10 ms, followed by a second negative-going peak (N2) with a latency of 22-24 ms. The N1 response reflects monosynaptic activation of nucleus accumbens neurons; the N2 component appears to be polysynaptic in origin. In control rats, high-frequency stimulation of the fimbria (three trains at 250 Hz, 250 ms, delivered at 50 min intervals) resulted in a long-lasting potentiation of both the N1 and N2 components. The magnitude of potentiation exhibited by the polysynaptic N2 response was typically greater than that of the monosynaptically evoked N1 response. Following delivery of the first train, the amplitude of the N1 and N2 components was increased by approximately 20 and 50% respectively. Administration of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist 3-[(+-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP, 10 mg/kg i.p.) had no significant effects on the evoked nucleus accumbens responses. High-frequency stimulation failed to produce a significant increase in the amplitude of either the N1 or the N2 response when delivered 45-60 min after CPP administration. To test whether the suppressant effects of CPP were time-dependent, two further high-frequency trains were applied 90 and 180 min after administration of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effects of dentate kindling on working and reference spatial memory in the rat.

An 8-arm radial maze was used to examine the effects of dentate kindling on the performance of a task which requires both working (short-term) and reference (long-term) memory. During the 4-week post-operative training period, control and experimental rats performed both components of the task equally well. Performance of the reference memory component, but not the working memory component of the task was significantly impaired during kindling stimulation. The impairment in reference memory appeared to be primarily due to the elicitation of afterdischarges, since the disruption in maze performance was evident in the pre-convulsive stages of kindling. Following the cessation of kindling stimulation, a gradual recovery in reference memory performance was observed. Dentate kindling may provide a useful model for the study of long-term memory deficits associated with temporal lobe epilepsy.

Lesions of the medial septum which produce deficits in working/spatial memory do not impair long-term potentiation in the CA3 region of the rat hippocampus in vivo.

The effects of removing the septohippocampal pathway on the ability to induce long-term potentiation (LTP) in the CA3 region of the hippocampus was examined in vivo in rats. The septal input to the hippocampus was destroyed by electrolytic lesioning of the medial septum (MS). Prior to electrophysiological investigation, working/spatial memory of lesioned and control rats was tested using an 8-arm radial maze task. Maze performance was significantly impaired in animals with MS lesions. LTP inducibility was examined in the commissural fimbrial fibre- and mossy fibre (mf)-CA3 pathways in MS-lesioned and control rats. The pre-tetanus values in MS-lesioned rats tended to be smaller than those in controls, in both pathways. High-frequency stimulation of the commissural fibres resulted in a sustained increase in the orthodromic population spike and EPSP amplitude in both control and MS-lesioned rats. The magnitude of potentiation was similar in both groups. In control rats, high-frequency stimulation of the mf potentiated the amplitude of both the population spike and EPSP; in MS-lesioned rats, the EPSP amplitude alone was significantly increased by mf high-frequency stimulation. Hippocampal acetylcholinesterase (AChE) content was severely reduced bilaterally in MS-lesioned rats with working/spatial memory impairments, indicating that the lesions were effective in destroying the cholinergic septohippocampal input. These findings suggest that, in contrast to working/spatial memory processes, LTP at CA3 synapses is not dependent upon the integrity of the septohippocampal pathway.