Role for the M1 Muscarinic Acetylcholine Receptor in Top-Down Cognitive Processing Using a Touchscreen Visual Discrimination Task in Mice.

The M1 muscarinic acetylcholine receptor (mAChR) subtype has been implicated in the underlying mechanisms of learning and memory and represents an important potential pharmacotherapeutic target for the cognitive impairments observed in neuropsychiatric disorders such as schizophrenia. Patients with schizophrenia show impairments in top-down processing involving conflict between sensory-driven and goal-oriented processes that can be modeled in preclinical studies using touchscreen-based cognition tasks. The present studies used a touchscreen visual pairwise discrimination task in which mice discriminated between a less salient and a more salient stimulus to assess the influence of the M1 mAChR on top-down processing. M1 mAChR knockout (M1 KO) mice showed a slower rate of learning, evidenced by slower increases in accuracy over 12 consecutive days, and required more days to acquire (achieve 80% accuracy) this discrimination task compared to wild-type mice. In addition, the M1 positive allosteric modulator BQCA enhanced the rate of learning this discrimination in wild-type, but not in M1 KO, mice when BQCA was administered daily prior to testing over 12 consecutive days. Importantly, in discriminations between stimuli of equal salience, M1 KO mice did not show impaired acquisition and BQCA did not affect the rate of learning or acquisition in wild-type mice. These studies are the first to demonstrate performance deficits in M1 KO mice using touchscreen cognitive assessments and enhanced rate of learning and acquisition in wild-type mice through M1 mAChR potentiation when the touchscreen discrimination task involves top-down processing. Taken together, these findings provide further support for M1 potentiation as a potential treatment for the cognitive symptoms associated with schizophrenia.

Metabotropic glutamate receptors for new treatments in schizophrenia.

Metabotropic glutamate receptors (mGluRs) represent exciting targets for the development of novel therapeutic agents for schizophrenia. Recent studies indicate that selective activation of specific mGluR subtypes may provide potential benefits for not only the positive symptoms, but also the negative symptoms and cognitive impairments observed in individuals with schizophrenia. Although optimization of traditional orthosteric agonists may still offer a feasible approach for the activation of mGluRs, important progress has been made in the discovery of novel subtype-selective allosteric ligands, including positive allosteric modulators (PAMs) of mGluR2 and mGluR5. These allosteric mGluR ligands have improved properties for clinical development and have served as key preclinical tools for a more in-depth understanding of the potential roles of these different mGluR subtypes for the treatment of schizophrenia.

Neurotransmitter concentrations and binding at dopamine receptors in rats after maternal exposure to 3,4,3',4'-tetrachlorobiphenyl: the role of reduced thyroid hormone concentrations.

Polychlorinated biphenyls (PCBs) are environmental contaminants, which accumulate in the food chain and are transferred to the offspring during prenatal development through the placenta and postnatally via breast milk. It is reported that PCBs exert effects on thyroid hormone levels and brain neurotransmitter levels. Both actions may alter neuronal development. The aim of the present study was to investigate, if PCB-induced effects on concentrations of catecholamines and serotonin can be attributed to PCB-induced reductions in thyroid hormone concentrations. In addition, binding to dopamine D(1) and D(2) receptors was examined. Time-mated Wistar rats were treated prenatally with 1 mg 3,4,3',4'-tetrachlorobiphenyl (PCB 77)/kg bodyweight or the vehicle. A third group serving as the positive control received perinatally 5 mg propylthiouracil (PTU)/l drinking water. There were no overt toxic signs in dams or offspring. Thyroid hormone measurements demonstrated effects in dams and offspring up to postnatal day 40. In particular, total T(4) in serum and in the thyroid were decreased in PCB- and PTU-treated dams and offspring. Only PTU exposed rats exhibited significantly increased concentrations of TSH in the serum and pituitary. Measurement of neurotransmitters revealed changes in the PCB-exposed offspring at PND 40, while PTU-treatment was without effect. Dopamine and DOPAC were increased in the medial prefrontal cortex. In adulthood, there were no PCB-related effects on thyroid hormones and neurotransmitters. Binding studies of dopamine D1 and D2 receptors demonstrated that PCB and PTU had no influence on receptor concentration and affinity. Comparison of PCB 77 exposed offspring to PTU exposed offspring demonstrated differential effects on TSH and neurotransmitter levels, the latter result indicating that not all PCB-induced effects on the nervous system can be ascribed to decreases in thyroid hormone concentrations.

Distribution of serotonin 5-HT(2A) receptors in afferents of the rat striatum.

Treatment with conventional antipsychotic drugs (APDs) is accompanied by extrapyramidal side effects (EPS), which are thought to be due to striatal dopamine D(2) receptor blockade. In contrast, treatment with atypical APDs is marked by a low incidence or absence of EPS. The reduced motor side effect liability of atypical APDs has been attributed to a high serotonin 5-HT(2A) receptor affinity coupled with a relatively low D(2) affinity. Despite the high density of 5-HT(2A) binding sites in the striatum, there are few detectable 5-HT(2A) mRNA-expressing neurons in the striatum. This suggests that most striatal 5-HT(2A) receptors are heteroceptors located on afferent axons. A combined retrograde tracer-immunohistochemistry method was used to determine the sites of origin of striatal 5-HT(2A)-like immunoreactive axons. 5-HT(2A)-like immunoreactive neurons in both the cortex and globus pallidus were retrogradely labeled from the striatum; very few nigrostriatal or thalamostriatal neurons expressed 5-HT(2A)-like immunoreactivity. Within the striatum, parvalbumin-containing interneurons displayed 5-HT(2A) immunolabeling; these neurons are the targets of cortical and pallidal projections. Our data indicate that cortico- and pallido-striatal neurons are the major source of 5-HT(2A) receptor binding in the striatum, and suggest that cortico- and pallido-striatal neurons are strategically positioned to reduce the motor side effects that accompany striatal D(2) receptor blockade or are seen in parkinsonism.

The distribution and origin of the calretinin-containing innervation of the nucleus accumbens of the rat.

The nucleus accumbens of the rat consists of several subregions that can be distinguished on the basis of histochemical markers. For example, the calcium-binding protein calbindin D28k is a useful marker of the core compartment of the nucleus accumbens. Calretinin, another calcium-binding protein, is found in a dense fibre plexus in the accumbal shell and septal pole regions. The source of the accumbal calretinin innervation is not known. We examined the distribution of calretinin in the nucleus accumbens and used tract-tracing and lesion methods to determine the source of this calretinin innervation. Intense calretinin immunoreactivity was present in the medial shell, but the density of calretinin axons diminished sharply in the ventrolateral shell. Regions of dense calretinin immunostaining and those areas with calbindin-like immunoreactive cell bodies were generally segregated in the nucleus accumbens, although some overlap in the transition region between the core and shell was seen. Small clusters of calretinin-immunoreactive fibres were seen in the core, where they were restricted to calbindin-negative patches. Injections of the anterograde tracer biotinylated dextran amine into the paraventricular thalamic nucleus labelled fibres in calretinin-rich regions of the accumbens. Conversely, injections of Fluoro-gold into the accumbal shell retrogradely labelled numerous cells in the paraventricular thalamic nucleus that were calretinin-immunoreactive. Electrolytic lesions of the paraventricular thalamic nucleus reduced calretinin levels in the shell by approximately 80%. These data indicate that the calretinin innervation of the nucleus accumbens is derived primarily from the thalamic paraventricular nucleus, and marks accumbal territories that are largely complementary to those defined by calbindin.

DOI-Induced activation of the cortex: dependence on 5-HT2A heteroceptors on thalamocortical glutamatergic neurons.

Administration of the hallucinogenic 5-HT(2A/2C) agonist 1-[2, 5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) induces expression of Fos protein in the cerebral cortex. To understand the mechanisms subserving this action of DOI, we examined the consequences of pharmacological and surgical manipulations on DOI-elicited Fos expression in the somatosensory cortex of the rat. DOI dose-dependently increased cortical Fos expression. Pretreatment with the selective 5-HT(2A) antagonist MDL 100,907 completely blocked DOI-elicited Fos expression, but pretreatment with the 5-HT(2C) antagonist SB 206,553 did not modify DOI-elicited Fos expression. These data suggest that DOI acts through 5-HT(2A) receptors to increase cortical Fos expression. However, we found that DOI did not induce Fos in cortical 5-HT(2A) immunoreactive neurons but did increase expression in a band of neurons spanning superficial layer V to deep III, within the apical dendritic fields of layer V 5-HT(2A)-immunoreactive cells. This band of Fos immunoreactive neurons was in register with anterogradely labeled axons from the ventrobasal thalamus, which have previously been shown to be glutamatergic and express the 5-HT(2A) transcript. The effects of DOI were markedly reduced in animals pretreated with the AMPA/KA antagonist GYKI 52466, and lesions of the ventrobasal thalamus attenuated DOI-elicited Fos expression in the cortex. These data suggest that DOI activates 5-HT(2A) receptors on thalamocortical neurons and thereby increases glutamate release, which in turn drives Fos expression in cortical neurons through an AMPA receptor-dependent mechanism. These data cast new light on the mechanisms of action of hallucinogens.

Clozapine pretreatment modifies haloperidol-elicited forebrain Fos induction: a regionally-specific double dissociation.

RATIONALE: Acute administration of typical antipsychotic drugs, such as haloperidol, results in the induction of the immediate-early gene c-fos in the dorsolateral striatum. In contrast, the atypical antipsychotic drug clozapine, which lacks significant extrapyramidal side effect liability, does not induce Fos protein in the dorsal striatum. Several studies have attempted to define the mechanisms through which typical antipsychotic drugs induce striatal Fos, often by pretreating animals with specific receptor antagonists. Despite the broad receptor profile of clozapine, there has been no study of the effect of clozapine pretreatment on haloperidol-elicited striatal Fos expression. METHODS: We examined the effects of clozapine pretreatment of rats on haloperidol-elicited forebrain Fos expression, using both immunoblot and immunohistochemical methods. The effects of clozapine pretreatment were assessed in the dorsal striatum and in the different nucleus accumbens compartments, the septum, and the prefrontal cortex. RESULTS: Clozapine pretreatment markedly decreased haloperidol-elicited striatal Fos induction and blocked haloperidol-induced catalepsy. Clozapine also attenuated haloperidol-elicited Fos expression in the nucleus accumbens, but in the prefrontal cortex and ventrolateral septum the effects of haloperidol and clozapine were additive. CONCLUSIONS: An emerging body of literature suggests a high incidence of rapid relapse in schizophrenic patients when clozapine treatment is discontinued. This psychosis is relatively resistant to haloperidol and other neuroleptics, even in patients who had previously responded well to neuroleptics. The present data may shed light on the central sites associated with and perhaps model certain aspects of the relapse associated with clozapine discontinuation.

Stress induces Fos expression in neurons of the thalamic paraventricular nucleus that innervate limbic forebrain sites.

The paraventricular nucleus of the thalamus (PVT) is a midline thalamic nucleus that responds strongly to exposure to various stressors. Many of the projection targets of PVT neurons, including the medial prefrontal cortex, nucleus accumbens, and central/basolateral nuclei of the amygdala, are also activated by stress. We sought to determine if PVT neurons that respond to stress are those that project to one or more of these forebrain sites. Retrograde tract tracing combined with immunohistochemical detection of Fos protein-like immunoreactivity was used to assess the activation of target-specific populations of PVT projection neurons by mild footshock stress in the rat. Stress markedly increased Fos protein-like immunoreactivity in PVT neurons, but without regard to the projection target of the thalamic neurons. Thus, the percentage of PVT cells that were retrogradely labeled from either the prefrontal cortex, nucleus accumbens, or amygdala, and that expressed Fos-like immunoreactivity did not differ substantially across the three forebrain sites. These data suggest that the PVT may have a role as a generalized relay for information relating to stress, and may serve an important role in the stress-induced activation of limbic forebrain areas.

5-HT2 receptor regulation of extracellular GABA levels in the prefrontal cortex.

Monoamines, including both dopamine and serotonin, synapse onto prefrontal cortical interneurons. Dopamine has been shown to activate these GABAergic interneurons, but there are no direct data on the effects of serotonin on GABA release in the prefrontal cortex. We, therefore, examined the effects of the 5-HT2a/c agonist 1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI) on extracellular GABA levels in the prefrontal cortex of the rat. Local infusions of DOI dose-dependently increased cortical extracellular GABA levels. In addition, systemic DOI administration resulted in Fos protein expression in glutamic acid decarboxylase67-immunoreactive interneurons of the prefrontal cortex. These data indicate that serotonin, operating through a 5-HT2 receptor, acutely activates GABAergic interneurons in the prefrontal cortex. These data further suggest that there may be convergent regulation of interneurons by dopamine and serotonin in the prefrontal cortex.

Psychostimulant-induced Fos protein expression in the thalamic paraventricular nucleus.

Lesions of glutamatergic afferents to the nucleus accumbens have been reported to block psychostimulant-induced behavioral sensitization. However, thalamic glutamatergic projections to the nucleus accumbens have received little attention in the context of psychostimulant actions. We examined the effects of acute amphetamine and cocaine administration on expression of Fos protein in the thalamic paraventricular nucleus (PVT), which provides glutamatergic inputs to the nucleus accumbens and also receives dopaminergic afferents. Immunoblot and immunohistochemical studies revealed that both psychostimulants dose-dependently increased PVT Fos expression. PVT neurons retrogradely labeled from the nucleus accumbens were among the PVT cells that showed a Fos response to amphetamine. D2 family dopamine agonists, including low doses of the D3-preferring agonist 7-OH-DPAT, increased the numbers of Fos-like-immunoreactive neurons in the PVT. Conversely, the effects of cocaine and amphetamine on PVT Fos expression were blocked by pretreatment with the dopamine D2/3 antagonist raclopride. Because PVT neurons express D3 but not other dopamine receptor transcripts, it appears that psychostimulants induce Fos in PVT neurons through a D3 dopamine receptor. We suggest that the PVT may be an important part of an extended circuit subserving both the arousing properties and reinforcing aspects of psychostimulants.

Disinhibition of the mediodorsal thalamus induces fos-like immunoreactivity in both pyramidal and GABA-containing neurons in the medial prefrontal cortex of rats, but does not affect prefrontal extracellular GABA levels.

Stimulation of the mediodorsal and midline thalamic nuclei excites cortical neurons and induces c-fos expression in the prefrontal cortex. Data in the literature data suggest that pyramidal neurons are the most likely cellular targets. In order to determine whether cortical interneurons are also impacted by activation of mediodorsal/midline thalamic nuclei, we studied the effects of thalamic stimulation on (1) Fos protein expression in gamma-aminobutyric acid (GABA)-immunoreactive neurons and on (2) extracellular GABA levels in the prefrontal cortex of rats. Perfusion of the GABA-A receptor antagonist bicuculline for 20 minutes through a dialysis probe implanted into the mediodorsal thalamus induced Fos-like immunoreactivity (IR) approximately 1 hour later in the thalamus and in the medial prefrontal cortex of freely moving rats. Immunohistochemical double-labeling for Fos-like IR and GABA-like IR showed that about 8% of Fos-like IR nuclei in the prelimbic and infralimbic areas were located in GABA-like IR neurons. Fos-like IR was detected in three major subsets of GABAergic neurons defined by calbindin, parvalbumin, or vasoactive intestinal peptide (VIP)-like IR. Dual probe dialysis showed that the extracellular levels of GABA in the prefrontal cortex did not change in response to thalamic stimulation. These data indicate that activation of thalamocortical neurons indeed affects the activity of GABAergic neurons as shown by the induction of Fos-like IR but that these metabolic changes are not reflected in changes of extracellular GABA levels that are sampled by microdialysis.

Thalamic paraventricular nucleus neurons collateralize to innervate the prefrontal cortex and nucleus accumbens.

The prefrontal cortex and nucleus accumbens are primary recipients of medial thalamic inputs, prominently including projections from the thalamic paraventricular nucleus. It is not known if paraventricular neurons collateralize to innervate both the prefrontal cortex and nucleus accumbens. We used dual retrograde tract tracing methods to examine this question. A small population of paraventricular neurons was found to innervate the prefrontal cortex and medial nucleus accumbens. These data suggest that the thalamic paraventricular nucleus may coordinately influence activity in the prefrontal cortex and ventral striatum.

Behavioural pharmacology of the non-competitive NMDA antagonists dextrorphan and ADCI: relations between locomotor stimulation, anticataleptic potential and forebrain dopamine metabolism.

The effects of systemic administration of the non-competitive N-methyl-D-aspartate (NMDA) antagonists dextrorphan (10-40 mg/kg, i.p.) and [+/-]-5-aminocarbony-10,11-dihydro-5H-dibenzo[a,d]cycloheptan++ +-5,10-imine (ADCI) (25-70 mg/kg, i.p.) on basal ganglia-mediated behaviour and on forebrain dopamine metabolism were investigated in rats. Dextrorphan increased locomotor activity but did not induce stereotyped sniffing. ADCI failed to produce any significant motor stimulant and motor depressant actions. Both dextrorphan and ADCI dose-dependently antagonized catalepsy induced by the D-1 dopamine receptor antagonist SCH 23390 or the D-2 dopamine receptor antagonist haloperidol. Only the highest doses of dextrorphan and ADCI increased dopamine metabolism in the prefrontal cortex and/or in the nucleus accumbens, but not in the dorsal striatum. Our results show that dextrorphan and ADCI produce some of the behavioural effects (antagonism of experimentally induced catalepsy) and neurochemical actions (regionally selective stimulation of dopamine metabolism) that have previously been observed in the prototypical non-competitive NMDA antagonist, dizocilpine. The failure of ADCI to induce hyperlocomotion and stereotypy suggests that anticataleptic doses of ADCI may be devoid of the psychotomimetic actions commonly associated with non-competitive blockade of NMDA receptor function.

Modulatory role of catecholamines in the transsynaptic expression of c-fos in the rat medial prefrontal cortex induced by disinhibition of the mediodorsal thalamus: a study employing microdialysis and immunohistochemistry.

We studied the interaction of catecholaminergic and thalamic afferents of the medial prefrontal cortex (PFC) by analyzing the effects of catecholamine depletion on thalamus-induced c-fos expression in the PFC of freely moving rats. Thalamic projections to the PFC were pharmacologically activated by perfusing the GABA-A receptor antagonist bicuculline (0.03 mM or 0.1 mM) through a dialysis probe implanted into the mediodorsal thalamic nucleus. Bicuculline perfusion induced Fos-like immunoreactivity in the thalamic projection areas, including the PFC, and in the thalamic nuclei surrounding the dialysis probe. 6-Hydroxydopamine lesions of the ventral tegmental area causing a 70-80% depletion of catecholamines in the PFC did not influence the increase in the number of Fos-like immunoreactive nuclei in the prefrontal cortex in response to thalamic stimulation. However, densitometric image analysis revealed that the intensity of Fos-like immunoreactivity in the PFC of lesioned rats perfused with 0.1 mM bicuculline was higher than in correspondingly treated controls. The behavioral activity to bicuculline perfusion, an increase of non-ambulatory activity (0.03 mM) followed by locomotion and rearing (0.1 mM), was not changed in 6-hydroxydopamine-lesioned rats. It is suggested that the thalamically induced c-fos response is directly mediated by excitatory, presumably glutamatergic, transmission and not indirectly by an activation of catecholaminergic afferents of the PFC. The increase in the intensity of Fos-like immunostaining in strongly stimulated, catecholamine-depleted rats suggests that catecholamines modulate the degree to which thalamic activity can activate the PFC of awake animals.

6-Hydroxydopamine lesion of locus coeruleus and the antiparkinsonian potential of NMDA-receptor antagonists in rats.

Behavioral and neurochemical effects after bilateral 6-hydroxy-dopamine locus coeruleus- (LC) lesion were examined in rats and compared to sham-lesioned controls. Behavior after treatment with the antiakinetic drugs dizocilpine, amantadine, memantine or L-DOPA as well as joint treatment of these drugs with haloperidol were tested in an open field with holeboard and in an experimental chamber. Under saline spontaneous activity (open field with holeboard) and sniffing (experimental chamber) were reduced after lesion. Injection of the proparkinsonian drug haloperidol decreased sniffing in all rats but to a greater extent in LC-lesioned rats. In combination with haloperidol none of the tested drugs could completely compensate for the motor deficits induced by the lesion. Neurochemical data revealed a reduced content of noradrenaline in the prefrontal cortex and in the posterior striatum of LC-lesioned rats. These results indicate that loss of LC neurons intensifies parkinsonian symptoms induced by blockade of dopamine D2-receptors, and lowers the antiakinetic potential of dizocilpine, amantadine, memantine or L-DOPA.

Behavioral and neurochemical actions of the strychnine-insensitive glycine receptor antagonist, 7-chlorokynurenate, in rats.

The present study investigated if blockade of the modulatory glycine receptor of the NMDA receptor complex influences the expression of behavior (sniffing stereotypy and locomotion) and dopamine metabolism in rats as it has been shown for NMDA receptor antagonists. The glycine receptor antagonist, 7-chlorokynurenate (7-chloro-4-hydroxyquinoline-2-carboxylic acid), induced a dose-dependent sniffing stereotypy but had no effect on locomotion when it was given i.c.v. The glycine receptor agonist, D-cycloserine (D-4-amino-3-isoxazolidinone), antagonized the sniffing stereotypy. 7-Chlorokynurenate had no influence on dopamine metabolism in the striatum and the nucleus accumbens, but moderately decreased the metabolism in the prefrontal cortex. Comparison of behavioral and neurochemical outcomes suggests that the failure to induce locomotion correlates with the unchanged dopamine metabolism in the basal ganglia, while sniffing stereotypy does not. These results show that blockade of the glycine receptor of the NMDA receptor complex induces a behavioral and neurochemical profile similar to that of competitive NMDA receptor antagonists.

Behavioural and neurochemical interactions of the AMPA antagonist GYKI 52466 and the non-competitive NMDA antagonist dizocilpine in rats.

The behavioural and neurochemical effects of the N-methyl-D-aspartate (NMDA) antagonist dizocilpine and the alpha-amino-3-hydroxy-5-methylisoxazole- 4-propionic acid (AMPA) antagonist GYKI 52466, given alone or in combination, were investigated in rats. Locomotor activity was increased by dizocilpine (0.2 mg/kg), but not by GYKI 52466 (2.4 mg/kg). Dizocilpine-induced hyperlocomotion was reduced by co-administration of GYKI 52466. In dizocilpine-treated rats dopamine (DA) metabolism (measured as DOPAC [dihydroxyphenylacetic acid] or DOPAC/DA in post mortem brain tissue) was increased in the prefrontal cortex and nucleus accumbens. In GYKI 52466-treated rats serotonin was reduced in the prefrontal cortex and nucleus accumbens while DA metabolism was not affected. In rats treated with dizocilpine plus GYKI 52466, DA metabolism was increased only in the prefrontal cortex, but not in the nucleus accumbens, when compared with vehicle-treated animals. These data confirm that AMPA and NMDA antagonists do not have synergistic effects on locomotor activity. A differential role of NMDA and AMPA antagonists in the control of mesolimbic DA neurons will be discussed here.

Deficient sensorimotor gating after 6-hydroxydopamine lesion of the rat medial prefrontal cortex is reversed by haloperidol.

The present study sought to test the hypothesis that dopamine in the prefrontal cortex exerts an inhibitory influence on subcortical dopamsine systems and that depletion of prefrontal dopamine may affect behaviour via an increase in dopamine release in the basal ganglia. We used prepulse inhibition of the acoustic startle response, i.e. the inhibition of the acoustic startle response by a preceding non-startling stimulus, as the behavioural test, because this phenomenon of sensorimotor gating is modified in opposite directions by dopamine in the prefrontal cortex and in the basal ganglia. Rats were tested for prepulse inhibition before and after injections of the neurotoxin 6-hydroxydopamine into the medial prefrontal cortex. We attempted to differentiate the contributions of prefrontal dopamine and noradrenaline by pretreating the animals with desipramine (6-OHDAMI rats) or bupropion (6-OHDABUP rats), selective inhibitors of noradrenaline and dopamine reuptake respectively. 6-Hydroxydopamine lesion reduced prefrontal dopamine by 90% and noradrenaline by 80% in 6-OHDADMI rats, while prefrontal dopamine was reduced by 54% and noradrenaline by 95% in 6-OHDABUP rats. The ability of an acoustic prepulse (75 dB, 10 kHz) to inhibit the response to a startle pulse (100 dB noise burst) was maintained in sham-lesioned rats and in 6-OHDABUP rats. However, there was a marked reduction of prepulse inhibition (by 26%) in the 6-OHDADMI rats. Systemic administration of the dopamine antagonist haloperidol (0.05 mg/kg), which did not affect prepulse inhibition in sham-lesioned and in 6-OHDABUP rats, antagonized the lesion-induced deficit in prepulse inhibition in 6-OHDADMI rats.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Hydroxydopamine lesions of the medial prefrontal cortex of rats do not affect dopamine metabolism in the basal ganglia at short and long postsurgical intervals.

Dopamine (DA) in the medial prefrontal cortex (mPFC) has been implicated in the regulation of subcortical DA function. To further characterize the potential interaction between cortical and subcortical DA systems, the short- and long-term neurochemical consequences of 6-hydroxydopamine (6-OHDA) lesions of the mPFC of rats were investigated in the mPFC and in its subcortical target structures. 4 to 5, 10 to 12 and 32 to 36 days after infusion of 6-OHDA, DA was depleted to a larger extent than noradrenaline and serotonin. No lesion-induced changes of DA and its metabolites were detected in subcortical structures. These results show that prefrontal 6-OHDA lesions produce immediate and long lasting depletions of prefrontal monoamines, especially of DA, without increasing basal DA metabolism in the striatum and nucleus accumbens.