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In the rat, neurochemical, behavioral, and anatomical investigations suggest that medial prefrontal cortical input modulates the activity of the basal ganglia. To understand how prefrontal dysfunction might alter striatal-accumbens function, in situ hybridization histochemistry with S35-labeled oligonucleotide probes was used to assess changes in striatal-accumbens gene expression following bilateral excitotoxic ibotenic acid (IA) lesions of the rat medial prefrontal cortex. Quantitative densitometry was used to measure changes in mRNA levels for preproenkephalin A (ENK), D1 dopamine receptor, protachykinin (SubP), glutamic acid decarboxylase (GAD65), and D2 dopamine receptor. No differences were found between sham and lesion groups for ENK, D1, SubP, or GAD65 mRNA levels in the striatum or nucleus accumbens (NAC). D2 receptor mRNA levels were, however, significantly higher in the dorsomedial striatum and in the core area of the NAC of the lesioned rats. Although the functional significance of increased D2 mRNA is unclear, these findings demonstrate that glutamate mPFC projections modulate gene expression in relatively regionally-localized subcortical neuronal populations., (Copyright 1998 Elsevier Science B.V.)

The syndrome of vacuous chewing movements (VCMs) in rats is similar in many respects to tardive dyskinesia (TD) in humans. Both syndromes are characterized by delayed onset of persistent orofacial dyskinesias in a sub-group of subjects chronically treated with neuroleptics. Using the rat model, we examined the role of NMDA receptor-mediated corticostriatal neurotransmission in the expression of VCMs. Rats were treated for 36 weeks with haloperidol decanoate or vehicle and then withdrawn for an additional 28 weeks. Chronic persistent VCMs were induced in one subgroup of treated animals (+VCM), but not in another group (-VCM). Rats from +VCM, -VCM groups and vehicle-treated controls were selected for post mortem studies (n = 12 to 14 per group). NMDA receptor levels were assessed using [3H]-MK-801 binding in sections from the mid-striatum and nucleus accumbens. Chronic haloperidol treatment produced a marked reduction of NMDA receptor binding levels throughout the striatum and nucleus accumbens. Post hoc comparisons demonstrated that -VCM rats had lower NMDA receptor binding levels than +VCM and vehicle-treated controls. Ventromedial striatum and nucleus accumbens core were the most affected areas. These findings suggest that down-regulation of striatal NMDA receptor binding levels may protect against the expression of neuroleptic-induced dyskinesia.

Multiple lines of evidence indicate dopamine is a neurotransmitter or neuromodulator in the cerebellum and hippocampus. In this study, we explored the utility of 3-methoxytyramine as an index of dopamine release in these regions. We found that: (1) cerebellar and hippocampal 3-methoxytyramine levels can be measured by combined gas chromatography-mass fragmentography with negative chemical ionization; (2) basal 3-methoxytyramine accumulation rates following monoamine oxidase inhibition, but not the steady-state tissue levels, are several times lower in these regions than in the frontal cortex; (3) accumulation of 3-methoxytyramine in the hippocampus and cerebellum can be enhanced following electroconvulsive shock, but not acute haloperidol (0.4 mg/kg) treatment. We conclude that 3-methoxytyramine accumulation may be a useful index of dopamine release in the cerebellum and hippocampus, but dopamine release is regulated differently in these regions than in the frontal cortex and striatum.

Rats treated with haloperidol that developed vacuous chewing movements (VCM), a possible animal model of tardive dyskinesia, were studied with quantitative autoradiography for dopamine type-1 (D1) and type-2 (D2) receptors as well as dopamine re-uptake sites. Haloperidol increased striatal D2 receptors, but did not affect D1 receptors or the dopamine re-uptake site. D2 receptor increases occurred in rats with and without VCMs. In so far as VCM is a model for tardive dyskinesia, haloperidol induced increases in striatal D2 receptors do not appear to be etiologic for these abnormal movements.