Prefrontal cortex and neostriatum self-stimulation in the rat: Differential effects produced by apomorphine

In a dose-response experiment, the effects of intraperitoneal injections of the dopamine receptor agonist, apomorphine (0.075, 0.15, 0.3, 0.6 and 1.2 mg/kg) were studied on self-stimulation elicited from electrodes implanted in the medial and sulcal prefrontal cortex and caudate-putamen in the rat. From the medial and sulcal prefrontal cortex electrodes, apomorphine produced a dose-related decrease of self-stimulation rate which was consistent across animals. From the caudate-putamen electrodes, on the contrary, apomorphine produced a facilitatory effect in the majority of the animals at one or more doses, however, at other doses a decreased self-stimulation rate was observed. The clear and consistent effects of apomorphine on self-stimulation of the prefrontal cortex, together with other experimental evidence in the same line, suggest that dopamine is mediating self-stimulation of this cortical area.     

Differential effects produced by an anticholinergic on the neuroleptic inhibition of motor behaviour and self-stimulation of the prefrontal cortex in the rat

A specific dopamine receptor blocker, spiroperidol (0.016, 0.032, 0.064 and 0.128 mg/kg) alone or in combined treatment with the centrally acting anticholinergic, dexetimide (0.5, 1.0 mg/kg) was given intraperitoneally to rats pressing a lever for brain self-stimulation through electrodes implanted in the medial prefrontal cortex. The same treatment was also given to rats in which the spontaneous motor behaviour was measured. Spiroperidol produced a dose-related inhibition of both self-stimulation and spontaneous motor activity. Dexetimide, given to spiroperidol treated rats, was able to antagonize the motor impairment produced by spiroperidol, but prefrontal cortex self-stimulation remained decreased. These data support the suggested role for dopamine in self-stimulation of the prefrontal cortex in the rat.     

Behaviourally derived estimates of excitability in striatal and medial prefrontal cortical self-stimulation sites.

The refractory periods of the substrate underlying brain-stimulation reward were investigated in three rats with moveable electrodes implanted in the rostral caudate-putamen and the medial prefrontal cortex. Acquisition of caudate-putamen self-stimulation occurred within the first session, while self-stimulation for medial prefrontal cortex was observed only after three sessions of caudate-putamen stimulation. The currents required for self-stimulation ranged from 300 to 800 microA (0.1 ms pulse duration) across animals; the maximum response rates averaged roughly 40 bar presses per minute for both structures. Refractory period estimates were obtained from ten caudate-putamen and four medial prefrontal cortex sites. The time course of recovery had the following profile: the curves began to rise at 0.65 ms and 0.95 ms for caudate-putamen and medial prefrontal cortex stimulation, respectively, thereafter increasing to approach an asymptote at 6.00 ms for the caudate-putamen and 6.25 ms for the medial prefrontal cortex. The mean effectiveness value corresponding to the asymptotic portion of the curves was 73% for the caudate-putamen and 69% for the medial prefrontal cortex. Like other forebrain structures, the behaviourally derived refractory periods underlying caudate-putamen and medial prefrontal cortex stimulation, at least at these particular sites, are significantly longer than those observed in most medial forebrain bundle areas, both beginning and ending later. One interpretation for the similarity in their refractory period profiles and the apparent facilitating effect of caudate-putamen stimulation on acquisition of medial prefrontal cortex self-stimulation is that these two regions form part of the same reward substrate.     

Simvastatin reverses the downregulation of dopamine D1 and D2 receptor expression in the prefrontal cortex of 6-hydroxydopamine-induced Parkinsonian rats

Sprague-Dawley rats with unilateral lesion of the medial forebrain bundle by 6-hydroxydopamine showed marked decrease in the expression of dopamine D1 and D2 receptors in the prefrontal cortex. Simvastatin (10 mg/kg/day for 4 weeks) restored receptor expression to control levels. Given the association of dopaminergic dysfunction in the prefrontal cortex and cognitive deficits in Parkinson's disease, these findings may have implication in the treatment of cognitive decline in advanced Parkinson's disease.     

Cocaine enhances the reward value of medial prefrontal cortex self-stimulation.

Intracranial self-stimulation (ICSS) of at least some brain sites is thought to be mediated by mesolimbic dopamine (DA) neurons. However other ICSS sites, especially those in the medial prefrontal cortex (MFC), have been shown to be relatively insensitive to drugs (e.g. amphetamine, neuroleptics) that alter DA synaptic transmission. In the present study, rats with ICSS electrodes implanted in both the medial forebrain bundle (MFB) and the MFC were treated once per day for 10 days with cocaine (15.0 mg kg-1). Cocaine decreased the thresholds for both MFB (-51.4%) and MFC (-23.0%) ICSS. Cocaine also increased rates of responding for MFC but not MFB ICSS. These data provide additional support for the view that the MFC contributes to the rewarding effects of cocaine.     

Tolerance to amphetamine''s facilitation of self-stimulation responding: Anatomical specificity

Further work on the phenomenon reported by Leith and Barrett, wherein tolerance was shown to develop to the well-known D-amphetamine-induced facilitation of self-stimulation, clearly indicates that the development of such tolerance is dependent on the location of the stimulating electrode. Thirty-seven Fisher or Harlan rats were trained to bar press for hypothalamic stimulation (60 Hz, AC). Following several sessions during which small doses of D-amphetamine were administered to demonstrate facilitation, the subjects were placed on a 4-day D-amphetamine regimen. During this time they were given three daily injections of continuously increasing doses of D-amphetamine (total 78 mg/kg). Subsequent tolerance was shown for electrodes stimulating dorsal or medial hypothalamic structures (H2 field of Forel, dorsal medial forebrain bundle, medial hypothalamic nuclei), but did not develop with ventral or lateral hypothalamic stimulation sites (fornix, ventral medial forebrain bundle).     

Supersensitivity to the reinforcing effects of cocaine following 6-hydroxydopamine lesions to the medial prefrontal cortex in rats

The effects of neurotoxic lesions to the medial prefrontal cortex on both the acquisition and maintenance of intravenous cocaine self-administration were examined. In one experiment, acquisition of intravenous cocaine self-administration (0.25, 0.5 or 1.0 mg/kg/infusion) was measured in separate groups of rats 14 days following either a sham or 6-hydroxydopamine lesion to the medial prefrontal cortex. For sham rats, the 1.0 and 0.5 mg/kg dose supported reliable self-administration as indicated by discriminative responding. These rats reliably chose a lever that resulted in the delivery of these doses of cocaine over an inactive lever. Reinforced response rates were reduced when 0.25 mg/kg was the available dose and there was a loss of discriminative responding for some of the rats suggesting that it was close to threshold for self-administration. For rats that sustained a 70% depletion of dopamine in the medial prefrontal cortex, the dose-response curve was an inverse function across the entire dose range tested. In contrast to the data from the control rats, lesioned rats had a high rate of reinforced responses and demonstrated good discrimination for all doses including 0.25 mg/kg/infusion, suggesting a supersensitive response to the initial reward effect of cocaine. Another group of rats was first screened for reliable cocaine self-administration (0.5 mg/kg/infusion) and then subjected to either the prefrontal cortical 6-hydroxydopamine or sham lesion. Dose-response curves for cocaine self-administration were compared 14 days following the infusions. The lesioned rats responded reliably for low doses of cocaine that were unable to maintain responding in sham rats. These data support the hypothesis that the medial prefrontal cortex plays an important role in cocaine self-administration.     

Differential effect of self-stimulation on dopamine release and metabolism in the rat medial frontal cortex, nucleus accumbens and striatum studied by in vivo microdialysis.

Changes in the extracellular levels of dopamine (DA) and its metabolites in the dopaminergic terminal regions, the medial frontal cortex (MFC), nucleus accumbens (NAC), and striatum (STR), were measured by microdialysis during self-stimulation of the medial forebrain bundle (MFB) in rats pretreated with the DA uptake inhibitor, nomifensine (1 mg/kg, i.p.). Self-stimulation of the MFB in nomifensine-pretreated rats caused an increase in the extracellular DA level in the MFC and NAC but not in the STR. Self-stimulation also increased the extracellular concentrations of the main DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) to a similar extent in the MFC and NAC and to a lesser extent in the STR. Thus, there was a regional difference in the neurochemical changes following self-stimulation with either the MFC or the NAC showing larger extracellular levels of DA, DOPAC, and HVA than the STR. Furthermore, these changes were observed on both hemispheres ipsilateral and contralateral to the stimulation. The results indicate that self-stimulation of the MFB preferentially activates the mesocorticolimbic DA systems, thereby bilateral increases in the release of DA and its metabolism being produced in their terminal regions, the MFC and NAC.     

Opioid-neuroleptic interaction in brainstem self-stimulation

Injection of morphine into the ventral tegmental area (but not dorsal to it) induced a dose-dependent decrease in the frequency threshold for midline metencephalic brain stimulation reward. Facilitating doses of ventral tegmental morphine also reversed, in 4 of 6 animals, the threshold-increasing effects of pimozide (0.35 mg/kg, i.p.). This reversal was itself reversed by naloxone (2 mg/kg, i.p.), suggesting a direct action of morphine at ventral tegmental opiate receptors. These data fit with electrophysiological evidence that ventral tegmental morphine stimulates or disinhibits dopamine impulse flow, which would result in increased synaptic dopamine concentrations and decreased synaptic pimozide effectiveness. In the remaining two animals, the combined neuroleptic-opiate treatment resulted in a complete cessation of responding that was not reversed by a 5-fold increase in stimulation frequency. This finding suggested a complete inactivation of the reward mechanism, which might be expected from the interaction of high doses of two drugs that are each known to be capable of producing depolarization inactivation of dopaminergic neurons. These data confirm that brainstem self-stimulation, like medial forebrain bundle self-stimulation, depends critically on the function of the mesocorticolimbic dopamine system.     

Prefrontal cortex lesions attenuate substantia nigra self-stimulation: a reward summation analysis

A curve-shift paradigm was used to assess the effects of lesions of the prefrontal cortex on self-stimulation from electrode sites in the substantia nigra. Combined lesions of the medial and sulcal cortical regions severely attenuated substantia nigra self-stimulation. These results are discussed in the context of the frontal cortex and the substantia nigra as belonging to a reinforcement system that is largely independent of the medial forebrain bundle system.     

Regional neuroleptic microinjections indicate a role for nucleus accumbens in lateral hypothalamic self-stimulation reward

Bilateral microinjections of the neuroleptic, cis-flupenthixol, were made into 56 forebrain targets distributed across various dopamine (DA) terminal fields in the forebrain. Drug effects on medial forebrain bundle (MFB) stimulation-produced reward were assessed with a rate-frequency procedure implemented in a runway paradigm in a discrete-trial fashion. This method generated independent measures of drug-induced changes in the MFB stimulation reward and operant motor/performance capacity. Control experiments were run with the inactive isomer, trans-flupenthixol. Results indicate a major role for accumbens DA in MFB reward, but not for the DA in caudate and medial frontal cortex. Few drug-induced motor/performance deficits were found at any site. In 14 selected subjects, 6-OHDA-induced chronic DA lesions were made at the same site as neuroleptic microinjection. These results confirmed the reward effects of acute DA receptor blockade, but produced a greater associated motor/performance impairment. Both behavioral effects of the lesion recovered within 2 weeks in many, but not all subjects.     

Serotonergic mediation of reward within the medial raphe nucleus: some persistent problems in interpretation.

Adult male Sprague Dawley rats were implanted with unipolar stimulating electrodes aimed at the medial forebrain bundle (MFB) or the medial raphe nucleus (MR). All MFB implanted subjects self-stimulated at high stable rates for at least three weeks. Only a minority (1/3) of MR rats self-stimulated at all. Rates for the MR group were considerably more variable, and could not be maintained for more than two weeks. Treatment with methysergide increased MFB self-stimulation but decreased MR self-stimulation. While this result suggests serotonergic mediation of self-stimulation this conclusion must be interpreted cautiously since parachlorophenylalanine (PCPA) reinstated self-stimulation in raphe animals which had spontaneously ceased responding.     

Spreading depression in the cortex differently modulates dopamine release in rat mesolimbic and nigrostriatal terminal fields

The effects of cortical spreading depression (SD) on evoked dopamine release in mesolimbic (nucleus accumbens) and nigrostriatal (nucleus caudatus) terminal fields were studied by in vivo voltammetry in anesthetized rats. Dopamine release was evoked by electrical stimulation of medial forebrain bundle (20 Hz, 100 pulses). Local application of 3 M KCl on the dura initiated SD in the cortex. It was found that SD modulated evoked dopamine release in subcortical structures at the same time when the wave of depression of cortical activity reached reciprocally connected subcortical areas. This cortical depression increased stimulated dopamine release in the nucleus accumbens and decreased dopamine release in the nucleus caudatus. In agreement with these results, electrical stimulation of the prefrontal cortex at 20 Hz, synchronized with medial forebrain bundle stimulation, decreased evoked dopamine release in the nucleus accumbens. Areas of the cortex which modulated dopamine release in these two terminal fields were spatially separated by at least 5 mm from each other. It is proposed that depression and activation of evoked dopamine release in the nucleus caudatus and nucleus accumbens following SD are indicative of tonic activation of the nigrostriatal and tonic inhibition of the mesolimbic dopaminergic terminals by cortex in normal conditions. SD in the cortex, modulating neurotransmitter release in subcortical structures, may have a general impact on redistribution of oxygen supply in these subcortical areas and on behavior associated with brain trauma, migraine, insult or seizures, i.e. the kind of neuropathology which may cause SD type phenomena also in human brain.     

Prefrontal cortex serotonin, stress, and morphine-induced nucleus accumbens dopamine

Uncontrollable, but not controllable, stress produces a persistent potentiation of morphine-induced nucleus accumbens dopamine (DA) efflux and morphine-induced medial prefrontal cortex serotonin (5-HT) efflux. Here we investigate medial prefrontal cortex 5-HT mediation of this potentiation. Male Sprague-Dawley rats received bilateral medial prefrontal cortex microinjections of the neurotoxin 5,7-dihydroxytriptamine (5,7-DHT, 8 microg/microl/side), which selectively depleted medial prefrontal cortex 5-HT, or vehicle (Sham), and cannula implantation in the nucleus accumbens shell. After 2 weeks, rats received either uncontrollable stress or no stress. Microdialysis and morphine (3 mg/kg) treatment were performed the following day. Morphine produced an enhanced increase in DA in the Stress-Sham group that was completely blocked by 5,7-DHT lesions, suggesting that 5-HT in the medial prefrontal cortex mediates this potentiation.     

Unilaterally activated systems in rats self-stimulating at sites in the medial forebrain bundle, medial prefrontal cortex, or locus coeruleus

Rats with electrodes in either the posterior medial forebrain bundle (MFB), the anterior MFB, the medial prefrontal cortex, or the locus coeruleus self-stimulated during a 45 min period following the injection of [14C]2-deoxyglucose. They were then sacrificed and their brains prepared for autoradiography. The autoradiographs were analyzed for unilaterally activated neural systems, using a computerized image analyzing system to compare the darkness of neural structures on the stimulated side with the darkness of the same structures on the unstimulated side. There was extensive overlap in the neural structures unilaterally activated by stimulation in the anterior and posterior MFB; but there was no overlap between the structures activated by MFB stimulation and the structures activated by stimulation at either of the extradiencephalic sites; nor did the forebrain, diencephalic, and midbrain sites have any readily apparent bilateral effects in common. If there is a substrate common to MFB self-stimulation and extradiencephalic self-stimulation, its activation is not revealed by 2-deoxyglucose autoradiography.     

Contrasting effects of dopamine antagonists and frequency reduction on Fos expression induced by lateral hypothalamic stimulation

To help further identify the reward-relevant regions activated by electrical stimulation of the lateral hypothalamus, Fos expression was quantified in 23 brain regions in na?ve, awake rats following non-contingent stimulation with a frequency that supports self-stimulation (100 Hz), a frequency that supports only minimal responding (50 Hz) and a frequency that does not support self-stimulation (25 Hz). Fos expression was also examined in stimulated and unstimulated rats pretreated with SCH 23390 (a dopamine D1 antagonist) or spiperone (a D2-like antagonist), at doses known to greatly inhibit responding for self-stimulation. Lowering the stimulation frequency from 100 to 50 Hz reduced Fos labelling in all areas, except for a few cells immediately surrounding the electrode tip. No differences were observed between unstimulated rats and those receiving 25 Hz stimulation. This suggests that a critical threshold of stimulation is required before other reward-relevant regions in the midbrain and forebrain are recruited with higher frequency stimulation. Pretreatment with SCH 23390 (0.1 mg/kg) inhibited stimulation-induced Fos expression in some key dopamine terminal areas, such as the nucleus accumbens (core and shell) and medial caudate-putamen, but not in directly driven neurons near the stimulation site. In contrast, spiperone (0.1 mg/kg) did not affect the pattern of stimulation-induced Fos expression, but induced immunolabelling in the dorsolateral caudate-putamen, an area associated with the extrapyramidal side-effects of antipsychotic drugs. These results reveal the utility of Fos immunohistochemistry to show how different treatments that alter the rewarding impact of electrical brain stimulation achieve their effects at the neural level.     

The role of the lateral cortico-cortical prefrontal pathway in self-stimulation of the medial prefrontal cortex in the rat

Effects of electrolytic and kainic acid lesions at several stereotaxic planes of the lateral cortico-cortical prefrontal efferent pathway on self-stimulation of the medial prefrontal cortex were investigated. Electrolytic bilateral lesion of the sulcal prefrontal cortex, the first terminal area of this pathway, produced no effects on self-stimulation of the medial prefrontal cortex. However, bilateral electrolytic lesion of this pathway at the rostral part of the external capsule produced a permanent abolition of self-stimulation of the medial prefrontal cortex. These effects seemed selective since operant behaviour to obtain water, similar to that performed for self-stimulation and used as a control, was not affected by the lesion except on the 1st, 3rd (P less than 0.01) and 5th (P less than 0.05) days postlesion. Interestingly, bilateral microinjections of kainic acid (10 nmol in 0.8 microliters) at the same stereotaxic planes of the external capsule where electrolytic lesion was produced, had no effects on self-stimulation. These results suggest that fibres-of-passage through the external capsule are responsible for the abolition of self-stimulation. Bilateral electrolytic lesion of the entorhinal cortex, one of the caudal terminal areas of this descending set of fibres, produced a short transient decrease of self-stimulation of the medial prefrontal cortex. These results are discussed on the basis that complex, rather than single circuits are involved in maintaining self-stimulation in this neocortical area.     

Time course effects of MK-801: The relationship between brain neurochemistry and behavior

Separate groups of rats were given saline or MK801 treatments (0.3 mg/kg) and tested for locomotion activity levels for 10 min at 30, 60, and 120 min postinjection. At each postinjection time interval the MK-801 rats exhibited a marked hyperactivity that was unchanged across the three postinjection intervals. Ex vivo biochemical assays were performed to assess the neurochemical effects of MK-801 at each injection interval. In the striatum, a marked increase in dopamine metabolism was observed in the 120 injection group, but, otherwise, no other changes in striatum were detected. In contrast, a significant increase in dopamine metabolism was observed after 30 min in the medial prefrontal cortex, and this effect persisted across all postinjection intervals. At 120 min, however, the biochemical impact of the MK-801 treatment on medial prefrontal cortex broadened to include a decrease in purine metabolism and norepinephrine. Serotonin metabolism was unaffected in striatum or medial prefrontal cortex across all injection intervals, and there was no effect of MK-801 on plasma corticosterone levels.     

Increased dopamine and serotonin metabolism in rat nucleus accumbens produced by intracranial self-stimulation of medial forebrain bundle as measured by in vivo microdialysis

In the present study, we have used a newly developed microdialysis system to perfuse the nucleus accumbens (NAC) of conscious rats during spontaneous intracranial self-stimulation of the medial forebrain bundle (MFB). Chromatographic (HPLC-ECD) analysis of the perfusates showed that dopamine (DA) release increased, but with an unstable pattern during the actual period of self-stimulation. On the other hand, the main DA metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and a serotonin metabolite 5-hydroxyindoleacetic acid, were all markedly enhanced by self-stimulation, but with different time courses. These findings indicate that self-stimulation of the MFB in rats induces increases in both DA and serotonin activities in the NAC. Such changes may be involved in mediating self-stimulation of the MFB.     

Differential effects of haloperidol on phencyclidine-induced reduction in substance P contents in rat brain regions

We investigated the effects of a schizophrenomimetic drug, phencyclidine (PCP), on substance P (SP) contents in the discrete rat brain areas using an enzyme-immunoassay for SP. The acute intraperitoneal (i.p.) administration of PCP (10 mg/kg), which is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) type glutamate receptor and a dopamine uptake inhibitor, reduced the concentration of the peptide in the prefrontal cortex, limbic forebrain, striatum, and substantia nigra, but not in the ventral tegmental area, at 60 or 120 min postinjection. A selective noncompetitive NMDA antagonist, dizocilpine hydrogen maleate ((+)-MK-801) (1 mg/kg, i.p.), also caused a decrease in the SP content in the prefrontal cortex and limbic forebrain but failed to alter the content in the other areas studied 30 min thereafter. Dopamine agonists, methamphetamine (4.8 mg/kg, i.p.) and apomorphine (4.4 mg/kg, i.p.), diminished the SP contents in the striatum and substantia nigra 60 min after their injection without effects in the prefrontal cortex, limbic forebrain, and ventral tegmental area. Furthermore, pretreatment with haloperidol (1 mg/kg, i.p.), a D2 preferable dopamine receptor antagonist and a typical antipsychotic, blocked the ability of PCP to decrease the SP concentrations in the substantia nigra but not in the prefrontal cortex. PCP, therefore, might diminish the SP levels by NMDA receptor-mediated and dopamine-independent mechanisms in the prefrontal cortex and limbic forebrain, but by NMDA receptor-independent and dopamine-dependent mechanisms in the striatum and substantia nigra. The haloperidol-insensitive reduction of the frontal SP could be involved in certain neuroleptic-resistant symptoms of PCP-treated animals, PCP psychosis, or schizophrenia.