Differential effect of morphine on dopaminergic neurons in frontal cortex and striatum of the rat

Inhibition of dopamine synthesis by a single injection of α-methyl-para-tyrosine (200 mg/kg, i.p.) was complete from 30 to at least 300 min after administration. When morphine (20 mg/kg) was given intraperitonealy 30 min after α-MpT treatment an enhanced decline of dopamine was observed in frontal parts of the cortex but not in the striatum. These results indicate that morphine affects dopaminergic neurons in frontal parts of the cortex in a way differently from those in the striatum of the rat. This may be caused either by a difference in the properties of dopaminergic nerve endings in both structures or by an effect of morphine on the input to the cortical system which is lacking in the striatum.     

The role of D1-dependent dopaminergic mechanisms in the frontal cortex in the rat latent response

The effects of microinjections of D1 selective dopaminergic substances into the medial frontal cortex (MFC) on information storage and proactive interference during delayed (the delay in 3 s) and non-delayed choice in Y-maze were studied. Bilateral microinjection of D1 receptor antagonist SCH 23390 (1 nM, 1 microliter) impaired both delayed and non-delayed choice. In contrast, microinjections of D1 receptor agonist SKF 38393 (1 nM) into the MFC significantly improved the delayed performance and did not influence the non-delayed choice. The effects of proactive interference caused by SCH 23390 and SKF 38393 injections were more pronounced in delayed choice condition than in the non-delayed task. Spatial bias in animal behavior was revealed after the SCH 23390 injections: during erroneous choices rats more frequently turned in the same direction as preferred in a rotation test. The results suggest that impairment of delayed performance in Y-maze observed under the blockade of D1-mediated neurotransmission in the MFC occurs due to enhancement of the processes of proactive interference and disinhibition of the spatial set.     

Lack of effect of bilateral locus coeruleus lesion and antidepressant treatment on gamma-aminobutyric acidB receptors in the rat frontal cortex

The aim of the present study was to investigate whether a disturbance of the central noradrenergic (NA) system could cause changes in gamma-aminobutyric acid_B (GABA_B) receptors in the rat frontal cortex. Manipulation of the NA projection to the frontal cortex was achieved by bilateral lesion of the locus coeruleus with 6-hydroxydopamine (6-OHDA) or chronic treatment with the NA reuptake blocker and antidepressant drug, desipramine. Precautions were taken to ensure that the GABA_B receptor assay was performed optimally and was not confounded by the presence of endogenously generated GABA. The results show conclusively that manipulation of the NA projection did not result in any significant change in the number (Bmax) or affinity (Kd) of GABA_B receptors in the frontal cortex. These results do not support the hypothesis that hypoactivity of the central NA system can lead to changes in cortical GABA_B receptors and that antidepressant drugs act by increasing GABA_B receptor binding in the frontal cortex.     

Venlafaxine enhances the effect of bupropion on extracellular dopamine in rat frontal cortex

Venlafaxine is recognised as an effective treatment for depression and is known to inhibit the reuptake of serotonin (5-HT) and noradrenaline (NA). Another antidepressant, bupropion, acts to inhibit dopamine (DA) and NA reuptake and is commonly co-administered with other antidepressants to improve the efficacy of the antidepressant effect. The present study was designed to investigate the acute effect of combining the 2 drugs on extracellular levels of 5-HT, DA, and NA in rat frontal cortex using brain microdialysis, with the drugs being administered by intraperitoneal injection (i.p). Bupropion (10 mg/kg body mass, i.p.) alone had no effect on extracellular 5-HT levels, whereas venlafaxine (10 mg/kg, i.p.) alone significantly elevated extracellular 5-HT over basal values. As expected, bupropion alone elevated extracellular dopamine above basal values at 40 min post-drug administration, and this effect lasted for a further 2 h. Venlafaxine alone did not statistically elevate extracellular dopamine. The co-administration of venlafaxine with bupropion resulted in a dramatic increase in extracellular dopamine, and this effect was significantly greater than that seen with bupropion alone. In the frontal cortex, NA was elevated by bupropion alone and venlafaxine alone, relative to the control animals. The combination of bupropion and venlafaxine resulted in a marked elevation of NA.     

Relationship of calmodulin and dopaminergic activity in the striatum

Increasing evidence suggests a relationship between dopaminergic activity in the striatum and the content of calmodulin (CaM), an endogenous Ca2+-binding protein. The content of CaM in striatal membranes is increased by treatments that produce supersensitivity in striatal membranes is increased by treatments that produce supersensitivity of striatal dopaminergic receptors such as chronic neuroleptic treatment or injection of 6-hydroxydopamine. Concomitant with the increase in CaM is a greater sensitivity of adenylate cyclase to dopamine and an increase in Ca2+-sensitive phosphorylation in the striatal membranes. Procedures that result in dopaminergic subsensitivity, such as amphetamine treatment, increase the cytosolic content of CaM that can subsequently activate Ca2+ and CaM-dependent phosphodiesterase activity. In vitro studies have demonstrated that CaM and Ca2+ can stimulate basal adenylate cyclase activity in a striatal particulate fraction as well as increase the sensitivity of the enzyme to dopamine. Ca2+ and CaM most likely affect the dopamine-sensitive adenylate cyclase by interacting with guanyl nucleotides, which are required for dopamine sensitivity. It is concluded that a change in CaM concentration and/or location occurs during conditions of altered dopaminergic sensitivity in the striatum. These changes in CaM coupled with potential alterations in the Ca2+ concentration could modulate the sensitivity of the dopamine system and many CaM-dependent enzymes.     

The frontal cortex and the criminal justice system

In recent decades, the general trend in the criminal justice system in the USA has been to narrow the range of insanity defences available, with an increasing dependence solely on the M'Naghten rule. This states that innocence by reason of insanity requires that the perpetrator could not understand the nature of their criminal act, or did not know that the act was wrong, by reason of a mental illness. In this essay, I question the appropriateness of this, in light of contemporary neuroscience. Specifically, I focus on the role of the prefrontal cortex (PFC) in cognition, emotional regulation, control of impulsive behaviour and moral reasoning. I review the consequences of PFC damage on these endpoints, the capacity for factors such as alcohol and stress to transiently impair PFC function, and the remarkably late development of the PFC (in which full myelination may not occur until early adulthood). I also consider how individual variation in PFC function and anatomy, within the normative range, covaries with some of these endpoints. This literature is reviewed because of its relevance to issues of criminal insanity; specifically, damage can produce an individual capable of differentiating right from wrong but who, nonetheless, is organically incapable of appropriately regulating their behaviour.     

Pharmacological modulation of dopaminergic transmission in the rat striatum in vivo

Inhibition of catechol-0-methyltransferase (COMT) activity by Tolcapone was shown to result in increase of the striatal DA extracellular content in unrestrained rats pretreated with L-3,4-dihydroxyphenilalanine combined with Carbidopa, the decarboxylation inhibiting agent. Tolcapone enhanced the increase of the DA level in the rat striatal dialysates produced by treatment of these animals with specific DA re-uptake blocker GBR 12909. The latter elicits stereotype behaviour in rats that is substantially enhanced by tolcapone. The DA turnover rate in the striatum was decreased by the GBR 12909. The data obtained suggest that the DA transporter of neuronal membrane plays a major role in the neurochemical homeostasis at synaptic level.     

Haloperidol effect on intracellular signals system coupled to alpha1-adrenergic receptor in rat cerebral frontal cortex.

The induction of intracellular signals coupled to alpha1-adrenoceptor by haloperidol, were studied in rat cerebral frontal cortex. The neuroleptic exerts a biphasic effect on nitric oxide synthase (NOS), inhibiting the enzymatic activity at low concentrations (10(-9) M), while higher concentrations (10(-5) M) increased it. Protein kinase C (PKC) and phosphoinositol turnover (PIs) were involved in these actions, as haloperidol induced PKC translocation at low concentrations, and increased PIs turnover at high concentrations. All the effects of haloperidol were blocked by the alpha-adrenoceptor antagonist prazosin and the phospholipase C (PLC) inhibitor NCDC. The possibility that a cross-talk between both enzymatic pathways depending on the neuroleptic concentration used in rat cerebral frontal cortex, is also discussed.     

Controlled cortical impact injury affects dopaminergic transmission in the rat striatum

The therapeutic benefits of dopamine (DA) agonists after traumatic brain injury (TBI) imply a role for DA systems in mediating functional deficits post‐TBI. We investigated how experimental TBI affects striatal dopamine systems using fast scan cyclic voltammetry (FSCV), western blot, and d‐amphetamine‐induced rotational behavior. Adult male Sprague–Dawley rats were injured by a controlled cortical impact (CCI) delivered unilaterally to the parietal cortex, or were naïve controls. Amphetamine‐induced rotational behavior was assessed 10 days post‐CCI. Fourteen days post‐CCI, animals were anesthetized and underwent FSCV with bilateral striatal carbon fiber microelectrode placement and stimulating electrode placement in the medial forebrain bundle (MFB). Evoked DA overflow was assessed in the striatum as the MFB was electrically stimulated at 60 Hz for 10 s. In 23% of injured animals, but no naïve animals, rotation was observed with amphetamine administration. Compared with naïves, striatal evoked DA overflow was lower for injured animals in the striatum ipsilateral to injury (p < 0.05). Injured animals exhibited a decrease in V_max (52% of naïve, p < 0.05) for DA clearance in the hemisphere ipsilateral to injury compared with naïves. Dopamine transporter (DAT) expression was proportionally decreased in the striatum ipsilateral to injury compared with naïve animals (60% of naïve, p < 0.05), despite no injury‐related changes in vesicular monoamine transporter or D₂ receptor expression (DRD₂) in this region. Collectively, these data appear to confirm that the clinical efficacy of dopamine agonists in the treatment of TBI may be related to disruptions in the activity of subcortical dopamine systems.     

Age-dependent loss of NMDA receptors in hippocampus,striatum, and frontal cortex of the rat: Prevention by acetyl-l-carnitine

Acute i.p. administration of Acetyl-L-Carnitine (ALCAR), a component of several biological systems, has been found to modify spontaneous and evoked electrocortical activity in young rats, and, in the old rats, to improve learning ability and to increase the number of NMDA receptors in the whole brain. The present study was aimed at ascertaining the effect of chronic treatment with ALCAR added to drinking water on age-related changes in the different brain areas of rats. In twenty-four-month-old rats, ALCAR treatment for six months significantly impeded the decline in the number of NMDA receptors within the hippocampus, the frontal cortex and the striatum compared to the adult animal. This finding thus confirms the previously reported positive effect of ALCAR on the brain NMDA receptor system.     

Effects of alloxan-induced diabetes on dopaminergic receptors in rat striatum and anterior pituitary

The binding of [3H]-spiroperidol after 4 weeks of hyperglycemia was determined in the rat striatum and anterior pituitary. Alloxan-induced diabetes increased the number of dopaminergic binding sites in the striatum but not in the anterior pituitary. The interaction of metoclopramide with striatal dopaminergic receptors was slightly modified, while that of dopamine, bromocriptine and haloperidol was unaffected. These results suggest that chronic hyperglycemia exerts selective effects on nigrostriatal dopaminergic system in the rat.     

The effect of the cingulate cortex on the development of the frontal lobe in the human

In the study, measurements of cortical structures of the medial surfaces of cerebral hemispheres of adults were taken. Its aim was to test whether the examined values were correlated with one another, and if so, then to what degree. Studies were conducted on 100 brains of adult people. It was assumed that the span of the corpus callosum (the genual retrosplenial length) of the left and the right hemisphere of the given brain was constant. The results of measurements and their statistical analysis prove that in both hemispheres the parameters concerning the cingulate gyrus, mainly of its paragenual width, are situated within the limits of significance. The mean values of the length of this gyrus were bigger on the left hemisphere. Differences in size of the hemispheres appeared to be statistically insignificant. The mean arithmetic values of the fronto-occipital distance of the hemispheres were greater for the right hemisphere. The results suggest that certain changes in the values of the frontal lobes depend on changes in values concerning the cingulate gyrus. This fact may confirm suggestions of certain authors that limbic structures of man, encompassing also the cortex of the cingulate gyrus, are not retarded and that their effect on the development of the frontal lobes may be as considerable as the one of the gyri.     

Seasonal changes of SP and NKA in frontal cortex, striatum and testes in the rat. Role of maternal pineal gland

The concentrations of neurokinin A (NKA) and substance P (SP), members of tachykinins family, have been studied in all seasons of the year in frontal cortex, striatum and testes of male offspring 21-, 31-, or 60 days old of mother Wistar rats: control, pinealectomized (PIN-X) and pinealectomized + melatonin during pregnancy (PIN- X + MEL) kept under 12h:12h L:D. Control-offspring: in spite of having been kept under constant environmental conditions throughout the year, had marked differences in tachykinin concentrations. The highest tachykinin concentrations in the frontal cortex were found in summer and fall and the lowest in winter and spring. Maternal PIN-X resulted in alterations of this developmental pattern, mainly in PIN-X- and PIN- X + MEL-offspring in which the highest tachykinin concentrations at 21 and 31 days of age were only observed during summer. The alterations were observed up to 60 days of age for both tachykinins, when at this age control-offspring showed similar NKA concentrations. Seasonal variations were still observed in PIN-X- and PIN- X + MEL-offspring. In striatum and testes no mayor modifications throughout the four seasons of the year were found, with very few exceptions. PIN-X did not alter tachykinin concentrations, neither treatment with melatonin did it. In conclusion, our data clearly indicate for the first time that NKA and SP do indeed have seasonal rhythms in frontal cortex and that the maternal pineal gland plays a role in their entrainment already during fetal life.     

l-Glutamic acid,a neuromodulator of dopaminergic transmission in the rat corpus striatum

A superfusion system was used to study the effects of neuroexcitatory amino acids upon spontaneous and depolarization-evoked release of exogenously taken up and newly synthesized [³H]dopamine by rat striatal slices. Neither l-glutamate nor other aminoacids such as l-aspartate and d-glutamate (5 × 10^?5 M) modified the spontaneous release of exogenous [³H]dopamine from rat striatal slices. In contrast, these neuroexcitatory aminoacids did potentiate spontaneous release of striatal [³H]dopamine newly synthesized from [³H]tyrosine. A different pattern of effects emerged when depolarization-evoked release of dopamine was studied. Only l-glutamate (5 × 10^?6-1 × 10^?4 M) potentiated dopamine release under these experimental conditions in a rather specific and stereoselective manner. In addition, similar results were obtained regardless of whether depolarization-induced release of exogenous or newly synthesized [³H]dopamine was studied. The effect of l-glutamate on depolarization-induced release depended both upon the degree of neuronal depolarization and upon the presence of external Ca²⁺ in the superfusion medium and it was blocked by l-glutamate diethylester. Furthermore, this effect of l-glutamate seemed quite specific with regard to regional localization within the brain as it was only demonstrated in slices from striatum and not in slices from olfactory tubercle or hippocampus. It is suggested that during depolarization a Ca²⁺-dependent event occurs at the striatal membrane level which changes the sensitivity of the dopamine release process to neuroexcitatory aminoacids in such a way as to render it relatively more specific and stereoselective towards l-glutamate stimulation. The findings reported have led us to propose that l-glutamic acid could play a role as a neuromodulator of dopaminergic transmission in the rat corpus striatum.     

The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity

Atypical antipsychotics show preferential 5-HT 2A versus dopamine (DA) D2 receptor affinity. At clinical doses, they fully occupy cortical 5-HT2 receptors, which suggests a strong relationship with their therapeutic action. Half of the pyramidal neurones in the medial prefrontal cortex (mPFC) express 5-HT 2A receptors. Also, neurones excited through 5-HT 2A receptors project to the ventral tegmental area (VTA). We therefore hypothesized that prefrontal 5-HT 2A receptors can modulate DA transmission through excitatory mPFC-VTA inputs. In this study we used single unit recordings to examine the responses of DA neurones to local (in the mPFC) and systemic administration of the 5-HT 2A/2C agonist 1-[2,5-dimethoxy-4-iodophenyl-2-aminopropane] (DOI). Likewise, using microdialysis, we examined DA release in the mPFC and VTA (single/dual probe) in response to prefrontal and systemic drug administration. The local (in the mPFC) and systemic administration of DOI increased the firing rate and burst firing of DA neurones and DA release in the VTA and mPFC. The increase in VTA DA release was mimicked by the electrical stimulation of the mPFC. The effects of DOI were reversed by M100907 and ritanserin. These results indicate that the activity of VTA DA neurones is under the excitatory control of 5-HT 2A receptors in the mPFC. These observations may help in the understanding of the therapeutic action of atypical antipsychotics.     

Lack of effect of chronic desipramine treatment on dopaminergic activity in the nucleus accumbens of the rat

The binding of [³H]SCH 23390 to dopamine (DA) D₁-receptors was measured in the nucleus accumbens of rats treated chronically with desipramine for 14 days. DA D₁ — and D₂-receptor binding using [³H]SCH 23390 and [³H]spiperone, respectively as ligands, was determined in rats treated for 28 days. NeitherB _max norK _d values were influenced by chronic desipramine treatment. In addition, chronic desipramine treatment (28 days) did not influence the dose dependent, quinpirole (10–1000 nM)-mediated inhibition of the electrically stimulated release of [³H]DA and [¹⁴C]ACh from nucleus accumbens slices or the dose dependent increase in [³H]DA release and decrease in [¹⁴C]ACh release in the presence of 1 and 10 M nomifensine. Therefore, our results suggest that the effect of chronic antidepressant treatment cannot be attributed to changes in either DA D₁₁-or D₂-receptor binding or DA D₂-receptor function in the nucleus accumbens.     

N-Acetyl-aspartyl-glutamate in the rat dorsal striatum: topographical distribution and effect of sensorimotor cortex lesions

The dipeptide N-acetyl-aspartyl-glutamate (NAAG) has been proposed as putative neurotransmitter of some corticostriatal projections. To further explore this possibility, endogenous NAAG levels were measured in various microdissected striatal regions in normal animals and in those with bilateral lesion of sensorimotor cortex. In intact rats there was a rostro-caudal gradient for NAAG, with highest concentrations in the more caudal portions of the striatum without significant differences between the medial and lateral regions. Decortication induced no significant changes in peptide concentration in any of the striatal regions or in the respective crude synaptosomal (P2) fractions. However, decorticated animals showed a large degree of deafferentation as evidenced by a marked and significant decrease in [³H]glutamate uptake as well as in glutamate levels measured in striatal homogenates or in crude synaptosomal fractions. No changes in striatal dopamine levels were observed in lesioned animals. Thus, these findings are not in favor of the existence of corticostriatal projections arising from the sensorimotor cortex using NAAG as neurotransmitter.