Possible role of alpha-2 and alpha-1 adrenoceptors in the experimentally-induced depression of the central nervous system

The alpha-2 adrenoceptor agonists clonidine and xylazine were employed in chicks and rats to induce a loss of the righting reflex, a sign for depression of the central nervous system. These effects of clonidine and xylazine were antagonized by yohimbine, idazoxan and CH-38083 (7,8-(methylenedioxi)-14-alpha-hydroxyalloberbane HCl), compounds having alpha-2 adrenoceptor antagonist properties. Prazosin, an antagonist for alpha-1 adrenoceptors, enforced the alpha-2 adrenoceptor agonist-induced depression in both species. 6-Hydroxydopamine treatment, which reduced the norepinephrine concentrations in the rat cerebral cortex by 76%, increased the duration of the loss of righting reflex induced by xylazine indicating that central postsynaptic alpha-2 adrenoceptors might also be involved in this behavioral alteration. The electrically-stimulated tritium release was also determined from the isolated rat cerebral cortex slices which had been preloaded with 3H-norepinephrine. Clonidine and xylazine inhibited the stimulation-induced tritium release and this inhibition was counteracted by yohimbine, idazoxan or CH-38083, but not by prazosin. We have concluded from the present data that stimulation of alpha-2 adrenoceptors with pre- and postsynaptic locations or inhibition of alpha-1 adrenoceptors in the central nervous system may shift the depression/vigilance balance to the direction of depression which might be accompanied by a decreased activity of cortical noradrenergic neural transmission.     

Altered histamine H3 receptor radioligand binding in post-mortem brain samples from subjects with psychiatric diseases

Background and purpose:

Histamine is a modulatory neurotransmitter in the brain. Auto- and hetero-histamine H₃ receptors are present in human brain and are potential targets of antipsychotics. These receptors may also display disease-related abnormalities in psychiatric disorders. Here we have assessed how histamine H₃ receptors in human brain may be affected in schizophrenia, bipolar disorder, major depression.

Experimental approach:

Histamine H₃ receptor radioligand binding assays were applied to frozen post-mortem prefrontal and temporal cortical sections and anterior hippocampal sections from subjects with schizophrenia, bipolar disorder, major depression and matched controls.

Key results:

Compared with the controls, increased H₃ receptor radioligand binding was found in dorsolateral prefrontal cortex of schizophrenic subjects (especially the ones who were treated with atypical antipsychotics), and bipolar subjects with psychotic symptoms. No differences in H₃ receptor radioligand binding were found in the temporal cortex. In hippocampal formation of control subjects, H₃ receptor radioligand binding was prominent in dentate gyrus, subiculum, entorhinal cortex and parasubiculum. Decreased H₃ binding was found in the CA4 area of bipolar subjects. Decreased H₃ binding in CA2 and presubiculum of medication-free bipolar subjects was also seen.

Conclusions and implications:

The results suggest that histamine H₃ receptors in the prefrontal cortex take part in the modulation of cognition, which is impaired in schizophrenic subjects and bipolar subjects with psychotic symptoms. Histamine H₃ receptors probably regulate connections between hippocampus and various cortical and subcortical regions and could also be involved in the neuropathology of schizophrenia and bipolar disorder.     

Pharmacological studies on the selectivity of HV-723, a new alpha-1 adrenoceptor antagonist

The pharmacological profile of a new alpha-1 adrenoceptor antagonist, alpha-ethyl-3,4,5-trimethoxy-alpha-(3-((2-(2-methoxyphenoxy)ethyl)amino) propyl) benzene-acetonitrile fumarate (HV-723), was studied in vitro. In dog mesenteric arteries, HV-723, prazosin and yohimbine competitively inhibited noradrenaline-induced contraction: the pA2 value of HV-723 (9.37) was apparently larger than that of prazosin (8.22) and yohimbine (7.18). However, HV-723 showed no or only a slight inhibition on the contractile responses to 5-HT, KCl and prostaglandin F2 alpha. HV-723 also showed potent alpha-1 adrenoceptor antagonist activity in the dog mesenteric and saphenous veins. However, HV-723 showed little antagonist activity on the pre- and postsynaptic alpha-2 adrenoceptors, beta-1 and beta-2 adrenoceptors and muscarinic receptors. HV-723 also inhibited the sympathetic contraction induced by electrical transmural stimulation in the dog mesenteric arteries, and the inhibition of HV-723 was about 10 times more potent than that of prazosin. However, 3H-noradrenaline release evoked by electrical stimulation was not influenced by HV-723. These results clearly show that HV-723 is a potent and selective alpha-1 adrenoceptor antagonist.     

Berbanes: search for novel alpha-2 adrenoceptor antagonists

We have previously described the alpha-2 adrenoceptor antagonist properties of berbanes and its stereoisomers. Of the compounds studied CH-38083 (2,3-methylenedioxy-11-betahydroxyalloberbane) has been selected for further analysis based upon its high affinity and selectivity for central and peripheral alpha-2 adrenoceptors. Structure activity relationship study revealed that the aromatic ring with its substituents at C-2 and C-3 positions, the nitrogen atom, the hydroxy group at C-11 position and the methoxycarbonyl group at C-12 position are important for the binding of the berbanes to the alpha-2 adrenoceptors. Using alloberbane derivatives for characterization of the alpha-2 adrenoceptors it was speculated that xylazine sensitive alpha-2 adrenoceptors in the rat vas deferens and in the guinea-pig ileum are similar, whereas xylazine sensitive and noradrenaline sensitive alpha-2 adrenoceptors of the guinea-pig ileum may belong to different subtypes. Correlation studies indicated that modification of the molecular structure of the alloberbanes can lead to either increased or decreased alpha-2 adrenoceptor antagonists activity without parallel changes in the alpha-1 adrenoceptor antagonist potency. The low affinity of CH-38083 for other receptor populations (muscarinic, histamine, dopamine receptors) makes this compound attractive for investigation of alpha-2 adrenoceptor-mediated neural processes in the central nervous system and periphery.     

Alpha up-beta down adrenergic regulation: a possible mechanism of action of antidepressant treatments

The presently reported findings: that spaced electroconvulsive treatment increases the density of alpha-1 adrenoceptor in the spinal cord as well as in the cerebral cortex of the rat, that treatment with various classes of antidepressant drugs, including antidepressant neuroleptics, affects in a similar manner alpha-adrenoceptors, elevating within 2 weeks the density of alpha-1, and depressing the density of alpha-2 subpopulation, and that prolonged imipramine treatment in investigated strains of rats does not depress the beta adrenoceptor density within 3 weeks, but only after 6-week-treatment such an effect is observed, are discussed together with our earlier results. It is suggested that the first effect of an antidepressant therapy may be a transient upregulation of alpha-2 adrenoceptors causing a decrease in noradrenaline utilization, but this is followed rapidly by an upregulation of alpha-1 adrenoceptors and depression of density of alpha-2 adrenoceptors. Eventually, adaptive beta adrenoceptor down-regulation follows. The final effect of an antidepressant therapy is a specific facilitation of neurotransmission regulated by alpha-1 adrenoceptors.     

Effects of prenalterol on beta adrenergic responsiveness and receptors in the cerebral cortex of the rat

The activity of the beta-adrenoceptor agonist, prenalterol, at beta adrenoceptors in the cerebral cortex of the rat and the effect of chronic intraperitoneal infusion of prenalterol on the biochemical responsiveness and density of cerebral cortical beta adrenoceptors was studied. Whereas isoproterenol caused a four-fold rise in the content of cyclic AMP in slices of cerebral cortex, prenalterol did not produce a significant increase in cyclic AMP. However, prenalterol inhibited the isoproterenol-stimulated increase in cyclic AMP in cortical slices in a concentration-dependent manner. Using an in vivo binding technique, prenalterol (3.8 mg/kg/hr) infused intraperitoneally through osmotic minipumps, penetrated the brain and significantly inhibited the binding of the beta adrenoceptor antagonist, [125I]iodopindolol (125I-IPIN), to cortical beta adrenoceptors. Infusion of prenalterol (3.8 mg/kg/hr) for 7 days resulted in a small (20%), but significant, reduction in the ability of isoproterenol to stimulate maximally the accumulation of cyclic AMP in slices of cerebral cortex. No alteration in the Bmax or KD of the binding of [125I]iodopindolol was observed in homogenates of cortex obtained from prenalterol-treated rats. Furthermore, no change was observed in the binding of the hydrophilic ligand [3H]CGP-12177 in homogenates of cortex. In this study, then, prenalterol exhibited properties in vitro of a beta adrenoceptor antagonist, but did cause modest desensitization of beta adrenoceptor responsiveness when administered continuously in vivo.     

Enhancement of the murine primary antibody response by phenylephrine in vitro.

Phenylephrine was found to enhance the primary (immunoglobulin M) antibody response of murine splenocytes to sheep erythrocytes when added to splenocyte cultures at the time of in vitro immunization. The enhancement was seen at all times during the developing antibody response. One day after the peak response the enhancement was 78% above the control response, and was completely blocked by equimolar concentrations of the alpha adrenoceptor antagonist phentolamine. The alpha-1 adrenoceptor antagonist prazosin dose dependently antagonized the enhancement associated with phenylephrine one day after the peak response. These results suggest that phenylephrine prolongs the in vitro IgM antibody response by way of alpha-1 adrenoceptor activation. The adrenoceptors responsible for this pharmacologic response could not be demonstrated using direct radioligand binding techniques.     

Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive alpha2 adrenoceptor blockade: experimental evidence

Adjunctive treatment with the selective alpha2 adrenoceptor antagonist idazoxan augments the effect of conventional antipsychotics in treatment-resistant schizophrenics comparing favourably with clozapine. Clozapine has high affinity for alpha2 adrenoceptors. Previously, we found that adjunctive idazoxan treatment to the dopamine (DA) D2/3 antagonist raclopride enhanced raclopride-induced effects in an animal model of antipsychotic activity (conditioned avoidance response, CAR) and, similarly to clozapine, reversed the disruption of working memory induced by N-methyl-D-aspartate receptor blockade in rats with a concomitant increase in prefrontal DA efflux. To further investigate the significance of alpha2 adrenoceptor affinity for antipsychotic efficacy, we here investigated, in rats, the effects of adjunctive idazoxan treatment to low doses of a typical (haloperidol) and an atypical (olanzapine) antipsychotic drug, both lacking appreciable alpha2 adrenoceptor affinity, on (i) CAR; (ii) catalepsy; and (iii) DA output in the prefrontal cortex and the nucleus accumbens using microdialysis. Adjunctive treatment with idazoxan to haloperidol or olanzapine enhanced suppression of CAR to a level predicting sufficient antipsychotic activity, increased DA output preferentially in the prefrontal cortex, and reversed haloperidol-induced catalepsy. Our data confirm and extend our previous findings as well as clinical observations, and suggest that adjunctive alpha2 adrenoceptor blockade both typical and atypical antipsychotic drugs, lacking appreciable affinity for the alpha2 adrenoceptor, may contribute to a more advantageous therapeutical profile of these drugs in schizophrenia treatment, allowing for reduced DA D2 occupancy and reduction of unwanted side-effects.     

Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys.

The effects of systemically administered or iontophoretically applied clonidine (alpha-2 adrenergic agonist) and iontophoretically applied yohimbine (alpha-2 adrenergic antagonist) were examined on prefrontal cortical (PFC) neurons related to spatial working memory (SWM). Systemically administered clonidine (0.04 mg/kg) enhanced SWM-related PFC neuronal activity by 32.5 +/- 14.5%, (mean +/- SD; n = 25 neurons). The facilitatory effect of clonidine was antagonized by iontophoretically applied yohimbine. Iontophoretically applied clonidine enhanced SWM-related PFC neuronal activity by 38.2 +/- 18.6%, (n = 13 neurons), whereas similarly applied yohimbine suppressed it by 34.4 +/- 17.8% (n = 28 neurons). These results indicate that: a) systemically administered clonidine can facilitate SWM-related PFC neuronal activity through actions at alpha-2 adrenoceptors in the PFC; and b) conversely, blockade by yohimbine of alpha-2 adrenoceptors in the PFC suppresses SWM-related neuronal activity. The present study provides neurophysiological evidence that alpha-2 adrenoceptors in the PFC are involved in the cellular mechanisms underlying working memory.     

Picrotoxin in the medial prefrontal cortex impairs sensorimotor gating in rats: reversal by haloperidol

  Rationale: Neuropathological data indicate a GABAergic dysfunction in the prefrontal cortex and hippocampus of schizophrenics. On this basis, the construct validity of an animal model of schizophrenia was tested. Objective: This study assessed prepulse inhibition (PPI) of startle in rats after injections of the GABA antagonist picrotoxin into the prefrontal cortex and the ventral hippocampus. It was also tested if reductions in PPI are reversed by the dopamine antagonist haloperidol. PPI is a measure of sensorimotor gating and is impaired in schizophrenia patients. The hypothesis underlying this study was that blockade of prefrontocortical and hippocampal GABA receptors disrupts PPI in a dopamine- dependent way. This hypothesis was based on neuropathological data from schizophrenics indicating a loss of GABAergic neurons in the prefrontal cortex and hippocampus and on the observation that PPI is reduced in schizophrenics. Methods: Picrotoxin (0, 5, 10 ng/0.5 μl) was infused through chronically indwelling cannulae into the medial prefrontal cortex (mPFC), into the lateral prefrontal cortex and into the ventral hippocampus. The effect on PPI was measured directly after picrotoxin infusion. The neuroleptic compound haloperidol (0.1 mg/kg) was administered intraperitoneally 30 min before testing. Results: Picrotoxin in the mPFC dose-dependently reduced PPI and this effect was antagonized by systemic pretreatment with the dopamine antagonist haloperidol. No significant effects on PPI were observed after picrotoxin infusions into the lateral prefrontal cortex or into the ventral hippocampus. Conclusions: These findings indicate that acute blockade of GABA receptors in the mPFC impairs sensorimotor gating in a dopamine-dependent manner. Since PPI in rats has been shown to possess face, predictive, and construct validity as an animal model for some psychotic symptoms, we discuss the potential relevance of our findings for the pathophysiology of schizophrenia. Received: 16 August 1998 / Final version: 25 January 1999     

Post-pubertal adrenergic changes in rats with neonatal lesions of the ventral hippocampus

Lesions of the ventral hippocampus (VH) in neonatal rats result in post-pubertal alterations in a number of cognitive, social and motor behaviors that bear some analogy to schizophrenia. Increased sensitivity to stress and psychostimulants and prefrontal functional changes in the lesioned animals suggest an involvement of the mesocorticolimbic dopamine (DA) system. DA and norepinephrine (NE) interact in a number of ways in the medial prefrontal cortex (mPFC) to influence each other's functions. In order to assess the role of adrenergic system in the behavioral responses of neonatal VH (nVH) lesioned animals, we first examined cortical and subcortical bindings of alpha-1 and alpha-2 adrenergic receptors using [3H]-prazosin and [3H]-rauwolscine respectively, and the norepinephrine transporter (NET) using [3H]-nisoxetine. Sprague-Dawley rat pups, at post-natal day (PD) 7, received bilateral injections of ibotenic acid in the VH and were sacrificed pre (PD35)- and post (PD56)-pubertally. A significant increase in [3H]-prazosin binding was observed in the frontal and cingulate cortices of lesioned rats at PD56 without any significant change in the caudate putamen or nucleus accumbens. No significant difference was seen in [3H]-rauwolscine binding. A significant upregulation of NET binding was observed in subregions of the PFC and nucleus accumbens of PD56 lesioned rats. The functional relevance of changes in adrenergic markers on amphetamine-induced locomotor activity was examined by pre-treatment of PD56 rats with prazosin, an alpha-1 receptor antagonist. Prazosin at doses of 1.0 or 2.0 mg/kg ip significantly reduced amphetamine-induced locomotion in sham but not in PD56 lesioned animals. Taken together, these results suggest that alterations in prefrontal alpha-1 receptors likely contribute to altered behavioral responses observed in post-pubertal VH lesioned rats.     

Morphine dependence and protracted abstinence: regional alterations in CNS radioligand binding

Rats (Fisher F-344) were given free access to a 10% sucrose solution containing 0.5 mg/ml morphine sulfate (controls received the sucrose vehicle only) as their sole source of fluid. Daily morphine intake averaged 119 +/- 21 mg/kg, an amount sufficient to induce physical dependence. After 18 days on this regimen, the control and dependent subjects were sacrificed. A protracted abstinence group was weaned from morphine by reducing its concentration in the vehicle by 20% over the next 5 days, followed by a 5-week drug-free period before sacrifice concurrent with the other groups. These subjects showed no signs of an abstinence syndrome. Binding assays for alpha-2 adrenergic sites (3H-clonidine), beta-1/beta-2 adrenergic sites (3H-dihydroalprenolol), and dopaminergic (D2)/serotonergic (5-HT2) sites (3H-spiroperidol) were performed on tissue from frontal cortex, hippocampus, striatum, and brainstem. No alterations in 3H-clonidine or 3H-dihydroalprenolol binding were observed in dependence or protracted abstinence, suggesting that noradrenergic systems are well-regulated both during dependence and in protracted abstinence. 3H-spiroperidol binding was significantly elevated in the striatum (D2 sites) and hippocampus (5-HT2 sites) during dependence. Hippocampal 3H-spiroperidol binding returned to control levels in protracted abstinence, reflecting a morphine-induced change in 5-HT2 binding sites which had normalized by 5 weeks post-drug. Striatal 3H-spiroperidol binding was significantly decreased below control levels after withdrawal, suggesting that alterations of D2 sites in this structure may play a role in protracted abstinence.     

Assessment of the role of adrenoceptor function in ischemia-induced impairment of 2-deoxyglucose uptake and CA1 field potential in rat hippocampal slices.

The release of catecholamines, dopamine and noradrenaline has been suggested to play a role in mediating ischemic damage in susceptible brain regions, the hippocampus and striatum. We now provide evidence that suggests a role for adrenoceptors in the deficit of 2-deoxyglucose uptake and CA1 field potential induced in hippocampal slices by hypoxia/hypoglycemia (ischemia). Treatment with alpha 1- or beta-adrenoceptor agonists or cAMP potentiated an ischemia-induced decline of both 2-deoxyglucose uptake and CA1 field potential in hippocampal slices, whereas alpha 1- or beta-adrenoceptor antagonists, or alpha 2-adrenoceptor agonists produced a remarkable neuroprotective action against these deficits. The results indicate that stimulation of adrenoceptors may play a detrimental role in the development of ischemic damage, and suggest a neuroprotective action for adrenoceptor antagonists, which may lessen the functional deficits induced by ischemia.     

Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats

Performance on working memory tasks, a measure of prefrontal cortical function, is impaired by exposure to mild stress as well as the anxiogenic drug, FG7142. Previous studies have shown that like stress, FG7142 increases catecholamine release in the prefrontal cortex (PFC) and that high levels of dopamine (DA) D(1) and norepinephrine (NE) alpha-1 receptor stimulation underlie the FG7142-induced cognitive impairment. Both the FG7142-induced DA turnover and working memory deficit can be blocked by pretreatment with the nonselective NE alpha-2/imidazoline I1 receptor agonist, clonidine. The present study examined the alpha-2 adrenoceptor subtype underlying this reversal in FG7142-induced working memory deficits by comparing the efficacy of clonidine with the more selective alpha-2A adrenoceptor agonist, guanfacine. The anxiogenic drug, FG7142 (0, 10, 20, or 30 mg/kg), dose-dependently impaired delayed alternation performance. Clonidine pretreatment (0.1 mg/kg, 30 min prior to FG7142) partially reversed the FG7142-induced impairment while guanfacine pretreatment (0.11 mg/kg) completely blocked the FG7142-induced impairment. Neither clonidine nor guanfacine had any effect on performance when administered alone. This study suggests that stimulation of the NE alpha-2A receptor subtype is sufficient to ameliorate the cognitive deficit induced by FG7142. Clonidine's sedative and hypotensive side effects limit its therapeutic usefulness; however, selective alpha-2A receptor agonists may be effective in treating prefrontal cognitive deficits in stress-related neuropsychiatric disorders with fewer side effects.     

Increased binding of cortical and hippocampal group II metabotropic glutamate receptors in isolation-reared mice

Post-weaning social isolation in rodents induces behavioral alterations, including hyperlocomotion, depression- and anxiety-like behaviors, aggression, and learning and memory deficits. These behavioral abnormalities may be related to the core symptoms in patients with neuropsychiatric disorders, such as schizophrenia and depression. In view of the recent studies that the group II metabotropic glutamate receptor (mGluR2/3) is involved in neuropsychiatric disorders, the present study examined the effect of isolation rearing on the binding of the mGluR2/3 antagonist [(3)H]LY341495 to mGluR2/3 in the mouse brain by in vitro autoradiography. The [(3)H]LY341495 binding in the prefrontal cortex, cerebral cortical layers I-III and hippocampus was significantly increased by rearing in social isolation while the binding in other brain regions was not altered. A saturation binding study of hippocampal membranes from isolation-reared mice revealed that the B(max) value increased significantly without any changes in the K(d) value. Moreover, the mGluR2/3 antagonist MGS0039 (1.0mg/kg, intraperitoneally) decreased the immobility time of isolation-reared mice in the forced swim test. These results suggest that isolation rearing causes an increase in mGluR2/3 densities in the prefrontal cortex and hippocampus and that the increased receptor function may contribute to pathogenic mechanisms for depression-like behavior of the isolation-reared mice.     

Selective deficits in spatial working memory in the neonatal ventral hippocampal lesion rat model of schizophrenia

The neonatal ventral hippocampal lesion (NVHL) manipulation is a neurodevelopmental animal model of schizophrenia that produces abnormalities in the prefrontal cortex and nucleus accumbens, both efferent targets of the hippocampus, and leads to spatial working memory impairments. To investigate the neuroanatomical basis of spatial working memory in NVHL animals, we assessed performance in two radial arm maze tasks known to be differentially sensitive to the two hippocampal efferent pathways, and measured levels of neuronal activation (Fos immunoreactivity [Fos-IR]) in the prefrontal cortex and nucleus accumbens following task performance. Neonatal rats (postnatal day 6–8) received excitotoxic lesions of the ventral hippocampus (n = 25), or a sham procedure (infusions of artificial cerebrospinal fluid; n = 22). Upon reaching adulthood, animals were trained in either a non-delayed random foraging task or a spatial delayed win-shift task. NVHL animals were impaired on the spatial delayed win-shift task, which depends on communication between hippocampus and prefrontal cortex, but were unimpaired on the non-delayed random foraging task, which requires connections between hippocampus and nucleus accumbens. Fos-IR in the nucleus accumbens was greater in NVHL animals than in shams following the random foraging task, despite similar levels of performance, while no group differences in Fos-IR in either the nucleus accumbens or prefrontal cortex were observed following win-shift performance. These results suggest that although the NVHL manipulation disrupts development of hippocampal efferents to both the prefrontal cortex and the nucleus accumbens, the disruption of hippocampal–prefrontal pathways has the dominant behavioral effect on spatial performance in NVHL rats.     

Interaction of morphine but not fentanyl with cerebral α2‐adrenoceptors in α2‐adrenoceptor knockout mice

Objectives α₂‐Adrenergic and μ‐opioid receptors belong to the rhodopsin family of G‐protein coupled receptors and mediate antinociceptive effects via similar signal transduction pathways. Previous studies have revealed direct functional interactions between both receptor systems including synergistic and additive effects. To evaluate underlying mechanisms, we have studied whether morphine and fentanyl interacted with α₂‐adrenoceptor‐subtypes in mice lacking one individual α₂‐adrenoceptor‐subtype (α₂‐adrenoceptor knockout). Methods Opioid interaction with α₂‐adrenoceptors was investigated by quantitative receptor autoradiography in brain slices of α_2A‐, α_2B‐ or α_2C‐adrenoceptor deficient mice. Displacement of the radiolabelled α₂‐adrenoceptor agonist [¹²⁵I]paraiodoclonidine from α₂‐adrenoceptors in different brain regions by increasing concentrations of morphine, fentanyl and naloxone was analysed. The binding affinity of both opioids to α₂‐adrenoceptor subtypes in different brain regions was quantified. Key findings Morphine but not fentanyl or naloxone provoked dose‐dependent displacement of [¹²⁵I]paraiodoclonidine from all α₂‐adrenoceptor subtypes in the brain regions analysed. Binding affinity was highest in cortex, medulla oblongata and pons of α_2A‐adrenoceptor knockout mice. Conclusions Our results indicated that morphine interacted with α₂‐adrenoceptors showing higher affinity for the α_2B and α_2C than for the α_2A subtype. In contrast, fentanyl and naloxone did not show any relevant affinity to α₂‐adrenoceptors. This effect may have an impact on the pharmacological actions of morphine.     

Neonatal damage of the ventral hippocampus impairs working memory in the rat.

We investigated if a developmental lesion of the ventral hippocampus, studied previously as an animal model of schizophrenia, impairs performance in working memory tests related to the prefrontal cortex. Adult rats with a neonatal or adult excitotoxic lesion of the ventral hippocampus were tested in a continuous delayed alternation and a discrete paired-trial variable-delay alternation task. Performance of rats with the neonatal lesion was impaired as compared with control rats on both tasks, whereas performance of rats with the adult lesion was not altered in either task. The pattern of impaired performance, that worsened with increasing delays in neonatally lesioned rats, resembled that reported previously in animals with adult lesions of the medial prefrontal cortex. These results indicate that an early developmental, but not adult hippocampal, insult impairs performance in tasks sensitive to the integrity of the prefrontal cortex, and suggest that working memory may be compromised by neonatal damage of the ventral hippocampus.     

Combined alpha2 and D2/3 receptor blockade enhances cortical glutamatergic transmission and reverses cognitive impairment in the rat

The alpha(2) adrenoceptor antagonist idazoxan enhances antipsychotic efficacy of classical dopamine D(2) antagonists in treatment-resistant schizophrenia. The mechanisms are not fully understood, but we have previously shown that the combination of idazoxan with the D(2/3) receptor antagonist raclopride, similarly to clozapine but not classical antipsychotic drugs, augments dopamine efflux in the prefrontal cortex, and also generates an enhanced suppression of the conditioned avoidance response. We have now investigated the effects of clozapine, raclopride, idazoxan and the combination of raclopride and idazoxan on (i) electrically evoked excitatory post-synaptic potentials and currents in pyramidal cells of the rat medial prefrontal cortex, using intracellular electrophysiological recording in vitro, (ii) the impaired cognitive function induced by the selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, using the 8-arm radial maze test, (iii) the in-vivo D2, alpha(2A) and alpha(2C) receptor occupancies of these pharmacological treatments, using ex-vivo autoradiography. Whereas neither idazoxan nor raclopride alone had any effect, the combination exerted the same facilitation of glutamatergic transmission in rat prefrontal pyramidal neurons as clozapine, and this effect was found to be mediated by dopamine acting at D(1) receptors. Similarly to clozapine, the combination of idazoxan and raclopride also completely reversed the working-memory impairment in rats induced by MK-801. Moreover, these effects of the two treatment regimes were obtained at similar occupancies at D(2), alpha(2A) and alpha(2C) receptors respectively. Our results provide novel neurobiological and behavioural support for a pro-cognitive effect of adjunctive use of idazoxan with antipsychotic drugs that lack appreciable alpha(2) adrenoceptor-blocking properties, and define presynaptic alpha(2) adrenoceptors as major targets in antipsychotic drug development.