Bidirectional regulation of emotional memory by 5-HT1B receptors involves hippocampal p11.

Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.

Emotional memory impairments in a genetic rat model of depression: involvement of 5-HT/MEK/Arc signaling in restoration.

Cognitive dysfunctions are common in major depressive disorder, but have been difficult to recapitulate in animal models. This study shows that Flinders sensitive line (FSL) rats, a genetic rat model of depression, display a pronounced impairment of emotional memory function in the passive avoidance (PA) task, accompanied by reduced transcription of Arc in prefrontal cortex and hippocampus. At the cellular level, FSL rats have selective reductions in levels of NMDA receptor subunits, serotonin 5-HT(1A) receptors and MEK activity. Treatment with chronic escitalopram, but not with an antidepressant regimen of nortriptyline, restored memory performance and increased Arc transcription in FSL rats. Multiple pharmacological manipulations demonstrated that procognitive effects could also be achieved by either disinhibition of 5-HT(1A)R/MEK/Arc or stimulation of 5-HT4R/MEK/Arc signaling cascades. Taken together, studies of FSL rats in the PA task revealed reversible deficits in emotional memory processing, providing a potential model with predictive and construct validity for assessments of procognitive actions of antidepressant drug therapies.

Changes in brain cholinergic markers and spatial learning in old galanin-overexpressing mice.

The cholinergic forebrain system is involved in learning and memory, and its age-dependent decline correlates with a decrease in cognitive performance. Since the neuropeptide galanin participates in cholinergic neuron regulation, we have studied 19- to 23-month-old male mice overexpressing galanin under the platelet-derived growth factor B promoter (GalOE) and wild-type (WT) littermates by monitoring behavioral, neurochemical and morphological/histochemical parameters. In the Morris water maze test, old transgenic animals showed a significant impairment in escape latency in the hidden platform test compared to age-matched WT animals. The morphological/histochemical studies revealed that cholinergic neurons in the basal forebrain display a slight, age- but not genotype-related, alteration in choline acetyltransferase- (ChAT) immunoreactivity. The neurochemical studies showed an age-related decline in ChAT activity in the cerebral cortex of all mice, whereas in the hippocampal formation this effect was seen in GalOE but not WT animals. Expression of BDNF mRNA in the hippocampal formation, as evaluated by RT-PCR, was reduced in old animals; no age- or genotype-induced variations in NGF mRNA expression were observed. These data suggest that galanin overexpression further accentuates the age-related decline of the cholinergic system activity in male mice, resulting in impairment of water maze performance in old animals.

N-methyl-D-aspartate receptors in the medial septal area have a role in spatial and emotional learning in the rat.

Cholinergic and GABAergic neurons in the medial septal/vertical limb of the diagonal band of Broca (MS/vDB) area project to the hippocampus and constitute the septohippocampal pathway, which has been implicated in learning and memory. There is also evidence for extrinsic and intrinsic glutamatergic neurons in the MS/vDB, which by regulating septohippocampal neurons can influence hippocampal functions. The potential role of glutamatergic N-methyl-D-aspartate (NMDA) receptors within the MS/vDB for spatial and emotional learning was studied using the water maze and step-through passive avoidance (PA) tasks, which are both hippocampal-dependent. Blockade of septal NMDA receptors by infusion of the competitive NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) (0.3-5 microg/rat), infused 15 min prior to training, impaired spatial learning and memory at the 5 microg dose of D-AP5, while doses of 0.3 and 1 microg per rat had no effect. The impairment in spatial learning appears not to be caused by sensorimotor or motivational disturbances, or anxiogenic-like behavior. Thus, d-AP5-treated rats were not impaired in swim performance or visuospatial abilities and spent more time in the open arms of the elevated plus-maze. In the PA task, intraseptal D-AP5 infused 15 min before training impaired retention as examined 24 h after training. This impairment was observed already at the 0.3 microg dose, suggesting that NMDA receptors within the MS/vDB may be more important for emotional than spatial memory. In summary, the present data indicate that changes in septal glutamate transmission and NMDA receptor activity can influence activity-dependent synaptic plasticity in the hippocampus and thereby learning and memory.

Involvement of the 5-HT1A receptors in classical fear conditioning in C57BL/6J mice.

The present study examined the involvement of the 5-HT(1A) receptors in classical fear conditioning using the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propyloamino)tetralin hydrobromide (8-OH-DPAT) and the selective "silent" 5-HT(1A) receptor antagonist (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo- hexane carboxamide trihydrochloride (WAY 100635). The drugs were administered both subcutaneously and bilaterally into the dorsal hippocampus of male C57BL/6J mice. The training was performed in a single trial in which a tone was followed by a footshock. The retention of context- and tone-dependent fear was examined in separate tests conducted either 1 or 24 hr after training. Subcutaneous 8-OH-DPAT (0.1-1.0 mg/kg), when injected before but not after training, caused a dose-dependent impairment of contextual fear in both 1 and 24 hr tests, whereas tone-dependent fear was less affected. Pretraining intrahippocampal injections of 5.0 microg but not 1.0 microg 8-OH-DPAT caused a severe deficit in contextual fear when tested 24 hr after training. When injected both subcutaneously and intrahippocampally, 8-OH-DPAT induced the 5-HT syndrome, indicative of postsynaptic 5-HT(1A) receptor activation at the dose ranges that impaired fear conditioning. However, the behavioral changes induced by 8-OH-DPAT at the time of training could not account for inhibitory effects of 8-OH-DPAT on fear conditioning. Neither subcutaneous (0.03 mg/kg) nor intrahippocampal (0.5 microg per mouse) WAY 100635 altered context- or tone-dependent fear. However, subcutaneous WAY 100635 blocked both the 5-HT syndrome and the impairment of fear conditioning induced by subcutaneous or intrahippocampal 8-OH-DPAT. In contrast, intrahippocampal WAY 100635 blocked the impairment caused by intrahippocampal but not subcutaneous 8-OH-DPAT, indicating the involvement of extrahippocampal 5-HT(1A) receptors in fear conditioning. It is concluded that the deficits in fear conditioning induced by 8-OH-DPAT are a result of postsynaptic 5-HT(1A) receptor activation that interferes with learning processes operating at acquisition but not consolidation. Furthermore, the dorsohippocampal 5-HT(1A) receptors play an important but not exclusive role in the limbic circuitry subserving contextual fear conditioning.

Heart rate dynamics and behavioral responses during acute emotional challenge in corticotropin-releasing factor receptor 1-deficient and corticotropin-releasing factor-overexpressing mice.

The role of corticotropin-releasing factor in autonomic regulation of heart rate, heart rate variability and behavior responses was investigated in two genetic mouse models: corticotropin-releasing factor receptor 1-deficient mice, and corticotropin-releasing factor-transgenic mice overexpressing corticotropin-releasing factor. Heart rate was recorded by radio-telemetry during novelty exposure and auditory fear conditioning. Locomotor activity and freezing served as behavioral indices. Locomotor activity and heart rate were invariably increased in response to novelty exposure in both corticotropin-releasing factor receptor 1-deficient mice and littermate wild-type controls. The heart rate responses during retention of conditioned auditory fear and the exponential relationship between heart rate and heart rate variability were unaffected by genotype. Moreover, conditioned fear responses inferred from multiple behavioral measures including freezing did not differ between corticotropin-releasing factor receptor 1-deficient and corticotropin-releasing factor receptor 1 wild-type control mice. Corticotropin-releasing factor-transgenic mice exhibited markedly reduced locomotor activity during novelty exposure when compared with littermate wild-type controls. Baseline and novelty-driven heart rate was slightly elevated in corticotropin-releasing factor-transgenic mice, whereas the novelty-induced increase of heart rate was not different between genotypes. In contrast, corticotropin-releasing factor-transgenic mice did not display a heart rate response indicative of conditioned auditory fear. It is concluded that corticotropin-releasing factor receptor 1-deficiency does not affect heart rate adjustment and behavioral responses to acute fearful stimuli. The resiliency of behavioral and cardiovascular patterns elevation argues against the involvement of corticotropin-releasing factor receptor 1 in acute emotional regulation on these two functional levels despite an absent corticosterone elevation in corticotropin-releasing factor receptor 1-deficient mice. It is hypothesized that the lack of a conditioned heart rate response in corticotropin-releasing factor-transgenic mice is attributable to an impairment of cognitive function. The results are compared with those of corticotropin-releasing factor receptor 2-deficient mice, and the role of the corticotropin-releasing factor system in cardiovascular regulation is discussed.

5-HT1A receptor mRNA and immunoreactivity in the rat medial septum/diagonal band of Broca-relationships to GABAergic and cholinergic neurons.

Activation of 5-HT1A receptors results in a variety of physiological responses, depending on their localization on neurons with different phenotypes in the brain. This study investigated the localization of 5-HT1A receptor mRNA and 5-HT1A receptor immunoreactivity in cell bodies of the rat septal complex using in situ hybridization and immunohistochemistry. In adjacent sections of the medial septum/diagonal band of Broca (MSDB), the distribution of cell bodies expressing 5-HT1A receptor mRNA was closely related to cells labeled with oligonucleotide probes to GAD (glutamic acid decarboxylase), VAChT (vesicular acetylcholine transporter) or parvalbumin mRNA. Using antiserum to GAD and antibodies to GABA, 5-HT1A receptor immunoreactivity was demonstrated in a majority of GABAergic cells in the MSDB. 5-HT1A receptor-immunoreactive GABAergic cells in the MSDB were also demonstrated to contain the calcium-binding protein parvalbumin, a marker for septohippocampal projecting GABAergic neurons. In the lateral septum, 5-HT1A receptor immunoreactivity was colocalized with the calcium-binding protein calbindin D-28k, a marker for septal GABAergic somatospiny neurons. 5-HT1A receptor immunoreactivity was also detected in a subpopulation of VAChT-containing cholinergic neurons of the MSDB. In MSDB neurons, colocalization of 5-HT1A and 5-HT2A receptor immunoreactivities was demonstrated. These observations suggest that serotonin via 5-HT1A receptors may represent an important modulator of hippocampal transmission important for cognitive and emotional functions through actions on both GABAergic and cholinergic neurons of the rat septal complex. In addition, 5-HT may exert its effects in the MSDB via cells expressing both 5-HT1A and 5-HT2A receptors.

Medial septal galanin and acetylcholine: influence on hippocampal acetylcholine and spatial learning.

Neurochemical and behavioral studies in the rat have provided evidence for the view that galanin impairs learning via an inhibitory modulation of cholinergic neurons in the septohippocampal projection, believed to be important for learning and memory. To test this hypothesis, galanin was microinjected via a unilateral chronic cannula located in MS/dBB of rats. Infusion of galanin in the MS/dBB, which contains a high number of 125I-galanin binding sites, did not impair spatial acquisition or memory. On the contrary, spatial acquisition tended to be facilitated by 1 and 3 nmoles of galanin, while the 0.3 nmol dose had no effect. Intraseptal injections of scopolamine (10 microg/rat), a non-specific muscarinic antagonist, also failed to alter learning performance. In contrast, co-injections of galanin (3 nmol) and scopolamine (10 microg) resulted in a marked impairment of spatial acquisition. The effect of intraseptal galanin on basal acetylcholine release in the ventral hippocampus was examined by in vivo microdialysis and high-performance liquid chromatography. Both galanin (3 nmol/rat) and scopolamine (10 microg/rat) infused into the MS/dBB increased basal acetylcholine release in the ventral hippocampus. The combined injections of galanin and scopolamine resulted in an excessive increase in acetylcholine release. These results indicate, that galanin activates septohippocampal cholinergic neurons, suggesting that septal galanin may have a facilitatory role in spatial learning. Moreover, the level of muscarinic activity within the septal area appears to be critical for the effects of galanin on cognitive functions, since the combination of galanin and scopolamine produced a marked impairment in spatial learning, despite a marked increase in hippocampal acetylcholine release. In summary, a limited range of cholinergic muscarinic transmission may contribute to optimal hippocampal function, a finding that has important implications for therapeutic approaches in the treatment of disorders of memory function.

Behavioral and neurochemical studies on brain aging in galanin overexpressing mice.

To study possible involvement of galanin in brain aging quality, we have investigated behavioral, neurochemical and morphological parameters in aged mice overexpressing galanin under the platelet-derived growth factor B promoter (GalOE mice) compared to wild-type littermates (WT mice). The behavioral analysis in the forced swim test showed that old GalOE animals spent more time in immobility compared to WT. In the activity cage test, galanin overexpression counteracted the age-induced decrease in exploratory behavior. The neurochemical analysis showed a 30% decrease in noradrenaline overflow in the cerebral cortex of WT old mice that was not present in age-matched GalOE mice. Our results indicate that overexpression of galanin can influence several behavioral and neurochemical parameters in old mice.

Zimeldine: a review of its effects on ethanol consumption.

This review evaluates the literature and describes an extensive series of experiments which examined the effects of zimeldine , its metabolite norzimeldine and other serotonin and norepinephrine reuptake inhibitors on voluntary ethanol consumption in rats. The results of these experiments indicate that drugs which specifically inhibit serotonin reuptake are capable of decreasing voluntary ethanol consumption. The behavioral mechanism through which these drugs exert their effects seems to be extinction of the primary reinforcing properties of alcohol. These effects seem to be partially attenuated both by drugs which modulate the norepinephrine system as well as by the serotonin postsynaptic receptor blocker methergoline. The data presented in this review are discussed in terms of the involvement of the serotonin and norepinephrine systems in the mechanism of action of these drugs. In addition, several alternative hypotheses concerning the nature of the phenomenon are offered. Finally, the implications of these data for the possible development of a treatment procedure for problem drinkers is discussed.

Phencyclidine- and dizocilpine-induced hyperlocomotion are differentially mediated.

The dopamine (DA) D2 agonist quinpirole and the D2 receptor antagonists, haloperidol, raclopride, and remoxipride, were examined for their ability to block the locomotion induced by the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists phencyclidine (PCP) and dizocilpine, both given in equipotent doses. Quinpirole, given in a "DA D2 autoreceptor selective" dose (0.01 mg/kg), failed to influence the motor stimulation by PCP. On the other hand, the locomotor response induced by dizocilpine was significantly reduced by quinpirole. The three DA receptor antagonists blocked dose dependently the motor stimulation produced by both the low (2 mg/kg) and the high dose (3 mg/kg) of PCP. Haloperidol and remoxipride also blocked dose dependently and fully the stimulation produced by the low dose (0.1 mg/kg) of dizocilpine, whereas raclopride partially reduced the effect. The motor stimulation produced by the high doses of dizocilpine (0.2 mg/kg) and PCP (3 mg/kg) was reduced by haloperidol and raclopride only in cataleptogenic doses. Remoxipride, in contrast, fully blocked the effects of both PCP (3 mg/kg) and dizocilpine (0.2 mg/kg) in noncataleptogenic doses. These data suggest that different mechanisms of action may account for the motor stimulatory effects of PCP and dizocilpine. At the presynaptic level, PCP and dizocilpine may differ in the way they act on "regulatory" NMDA receptors controlling neuronal activity in midbrain neurons, and at the postsynaptic level they may interact with subtypes of NMDA receptors differentially coupled to subpopulations of D2 receptors.

Multiple 5-HT receptors in passive avoidance: comparative studies of p-chloroamphetamine and 8-OH-DPAT.

The aim of this study was to examine the involvement of multiple 5-HT receptors in passive avoidance (PA) with a focus on 5-HT1A, 5-HT2A, and 5-HT2C receptors. Because increases in 5-HT transmission result in concomitant multiple 5-HT receptor activation, the effects of the 5-HT releasing compound p-chloroamphetamine (PCA) were compared with those of the selective 5-HT1A receptor agonist 8-OH-DPAT in the rat. In addition, some results with the nonselective 5-HT2C/2B/1B receptor agonist mCPP are presented. When injected before PA training, 8-OH-DPAT, mCPP, and PCA produced a dose-related impairment of the 24-hour retention. The crucial involvement of the postsynaptic 5-HT1A receptors in the action of 8-OH-DPAT was confirmed. Thus, the 5-HT1A receptor antagonists WAY 100635 and (-)-pindolol blocked the PA deficit by 8-OH-DPAT. The impairment of PA caused by PCA was attenuated by WAY 100635 and (-)-pindolol, suggesting an involvement of the 5-HT1A receptor. In contrast, the 5-HT2A and 5-HT2C receptors were of negligible importance in the 24-hour retention deficit induced by PCA. However, the ability of the 5-HT2C receptor antagonist Ro 60-0491 to block the inhibitory effects of mCPP indicated an important regulatory role of the 5-HT2C receptor in PA. The nonselective 5-HT receptor antagonist methiothepin attenuated the PA deficit by PCA but lacked activity versus 8-OH-DPAT. These data provide evidence for the hypothesis that, in addition to the 5-HT1A receptor, other 5-HT receptor subtypes are involved in the inhibitory actions of PCA. Importantly, changes in dopamine transmission seemed not to contribute to the PA impairment by PCA. The behavioral alterations caused by the drug treatments at the time of PA training could not be related to the subsequent retention performance. In conclusion, multiple 5-HT receptors are involved in PA with roles that probably differ at various stages of information processing. These findings also suggest that there probably exists a functional distinction between 5-HT receptor subtypes in different types of aversive learning.

Adenosine A2A agonists: a potential new type of atypical antipsychotic.

The systemic intraperitoneal (i.p.) administration of the adenosine A2A agonist CGS 21680 was found to dose-dependently antagonize spontaneous and amphetamine-induced (1 mg/kg i.p.) motor activity with similar ED50 values (about 0.2 mg/kg). The ratios between the ED50 values for induction of catalepsy and for antagonizing amphetamine-induced motor activity for CGS 21680, haloperidol, and clozapine were 12, 2, and > 30, respectively. Furthermore, CGS 21680 was comparably much stronger than haloperidol or clozapine at antagonizing the motor activity induced by phencyclidine (2 mg/kg subcutaneously) than motor activity induced by amphetamine (1 mg/kg i.p.). In conclusion, the present results show a clear "atypical" antipsychotic profile of the adenosine A2A agonist CGS 21680 in animal models.

A behavioral analysis of the spatial learning deficit induced by the NMDA receptor antagonist MK-801 (dizocilpine) in the rat.

This study analyzes whether the disruptive effects of the noncompetitive NMDA receptor antagonist MK-801 (0.01-0.1 mg/kg s.c.) on spatial learning can be dissociated from sensorimotor disturbances in the rat. Two different modifications of the Morris swim maze task with a hidden underwater platform were used: with or without local cue. Retention was tested either 24 h or 7 days after training as a probe trial (without platform). The present data indicate that MK-801 produces an impairment of spatial learning that cannot be dissociated from motor or sensory mechanisms. These findings support the view that NMDA receptors probably contribute to, but are not essential for, spatial learning in the water maze.

Test-dependent variations in the antinociceptive effect of p-chloroamphetamine-induced release of 5-hydroxytryptamine.

p-Chloroamphetamine (PCA), in doses that did not significantly impair motor performance in a rotating-wheel task, induced marked analgesia in rats tested with the hot-plate and flinch-jump methods. In the tail-flick test, moderate hyper- or hypo-analgesia was found to be dependent on dose. In hot-plate experiments the analgesia was attenuated by inhibition of uptake of 5-HT (with zimelidine), depletion of stores of 5-HT (with PCPA) and by lesioning of 5-HT-containing terminals (long-term PCA treatment). Blockade of serotonin receptors by metergoline produced hyperalgesia, but failed to reduce the analgesia induced by p-chloroamphetamine. Manipulation of catecholaminergic and opioid systems did not reduce the effect of p-chloramphetamine. It is concluded that induction of release of 5-HT by chloroamphetamine induces antinociception which varies in magnitude between tests, suggesting that different serotonergic mechanisms modulate complex and reflex responses to noxious stimulation. The failure of metergoline to antagonize the analgesia induced by p-chloroamphetamine suggests an involvement of 5-HT receptors different from the ones implicated in other types of behaviour mediated by 5-HT.

Limited involvement of central noradrenergic pathways in morphine-induced antinociception.

Lesioning of cerebral and spinal noradrenergic terminals by the neurotoxin DSP4 (50 mg/kg, 7 days prior to testing) significantly attenuated the effect of morphine (2.5-7.5 mg/kg) in rats tested with the hot-plate test. The effect of DSP4 was prevented by pretreatment with the selective inhibitor of uptake of NA, desipramine. Treatment with DSP4 did not attenuate the effect of morphine (5 mg/kg) in the flinch-jump and tail-flick tests, and did not by itself change the nociceptive thresholds in any of the tests. It is concluded that noradrenergic structures in the central nervous system play a limited role in analgesia induced by morphine.

Effects of subchronic treatment with imipramine, zimelidine and alaproclate on regional tissue levels of substance P- and neurokinin A/neurokinin B-like immunoreactivity in the brain and spinal cord of the rat.

The effects of subchronic (14 day) treatment with the inhibitors at the uptake of monoamines, zimelidine, alaproclate and imipramine, on regional levels of substance P (SP) and other tachykinins in tissue in the central nervous system of the rat were studied by radioimmunoassay. In the ventral spinal cord, in which substance P is known to exist together with 5-hydroxytryptamine (5-HT), in the terminals of descending neurones, treatment with the selective inhibitors of the uptake of 5-HT zimelidine (2 X 10 mumol/kg p.o.) or alaproclate (2 X 10 mumol/kg or 2 X 20 mumol/kg p.o.), increased the level of substance P-like immunoreactivity (SP-LI). The effect of alaproclate appeared to be dose-dependent. After treatment with imipramine (2 X 10 mumol/kg p.o.) only a tendency to increased levels of substance P-like immunoreactivity spinal cord was seen. Treatment with alaproclate, at the highest dose level, also elevated the concentration of neurokinin A/neurokinin B-like immunoreactivity (NKA/NKB-LI) in the ventral spinal cord. In the frontal cortex, in which separate monoaminergic and tachykinin-containing neurones interact, treatment with imipramine reduced the levels of SP-LI and NKA/NKB-LI, while treatment with alaproclate had the opposite effect. In the periaqueductal grey matter, treatment with zimelidine and alaproclate increased the levels of SP-LI and NKA/NKB-LI, while treatment with imipramine increased only the level of NKA/NKB-LI. In conclusion, subchronic treatment of rats with inhibitors of the uptake of monoamines induced changes in levels of tachykinin in frontal cortex, periaqueductal grey and spinal cord. The selective inhibitors of the uptake zimelidine and alaproclate, had similar effects on levels of tachykinin, while the inhibitor of the uptake of 5-HT and noradrenaline, imipramine induced changes in the frontal cortex, which were qualitatively different from the effects of zimelidine and alaproclate. Furthermore, the levels of different tachykinins were not always changed in parallel by the same treatment.

Galanin and spatial learning in the rat. Evidence for a differential role for galanin in subregions of the hippocampal formation.

Anatomical, neurochemical and behavioural evidence support a role for galanin in hippocampally mediated functions such as spatial learning and memory. To obtain more precise information on this role, galanin (3 nmol/rat) was infused via bilateral chronic cannulae into different areas of the hippocampal formation which are characterized by different galanin receptor subtypes and also by different galanin innervation patterns. The effects of infused galanin on spatial learning were examined in the Morris swim maze. Infusions of galanin into both the dorsal and ventral dentate gyrus, which mainly contain GAL-R2 receptor mRNA and a high degree of galanin-noradrenaline coexistence, significantly retarded spatial acquisition without affecting swim speed or performance in the visible platform test. This spatial learning deficit was fully blocked by pretreatment with the non-selective galanin antagonist M35. Analysis of retention performance suggested that the major effect of intrahippocampal galanin is mediated via a specific disruption of acquisition mechanisms of importance for performance in the probe trial. Galanin infused into the ventral CA1 (a mainly GAL-R1 receptor mRNA expressing region) or into anterior, ventral CA3 regions did not produce any deficits in spatial learning compared to control animals. These results suggest that galanin mediates its action on spatial learning mainly through the GAL-R2 receptor subtype in areas where most of the galanin is present in noradrenergic terminals. A possible role for the GAL-R1 receptor subtype in cognition in the dorsal and ventral hippocampus remains to be defined. The results suggest a differential functional role for galanin and galanin receptor subtypes within subregions of the hippocampal formation.

Selective depletion of norepinephrine in brain by N-2-chloroethyl-N-ethyl-2-bromobenzylamine fails to alter the voluntary consumption of ethanol in rats.

The effects of the selective norepinephrine neurotoxin, DSP-4, on the maintenance of voluntary consumption of ethanol was tested in male Long-Evans rats. The drug, DSP-4, produced a 51% reduction in whole brain levels of NE without affecting the consumption of ethanol. These results, however, do not rule out a role for NE in mediating this behavior.

Dopamine D2 receptors and dopamine metabolism. Relationship between biochemical and behavioural effects of substituted benzamide drugs.

The effect of the substituted benzamide dopamine D2 receptor antagonists sulpiride, raclopride, FLA 966(-), FLA 988(-), eticlopride and remoxipride as well as the "classical" dopamine antagonists, haloperidol and chlorpromazine, on the concentrations of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the brain of the rat was investigated. All compounds increased the turnover of dopamine, as defined by increased concentrations of DOPAC and HVA (without change in the concentration of dopamine) in the striatum in a dose-dependent manner. The doses of the compounds producing increased turnover of dopamine in the striatum were in the same range as those displacing the in vivo binding of [3H]spiperone in the striatum. In addition, for all the compounds tested in the study, an increase in the turnover of dopamine to about 300% of control was observed for doses antagonising the stereotypy produced by the dopamine agonist, apomorphine. On the other hand, no consistent relationship between increased turnover of dopamine and the doses of the compounds required to antagonise apomorphine-induced hyperactivity was found. This result was also found in limbic areas. Remoxipride and haloperidol had little or no effect on the turnover of dopamine in either the hypothalamus or substantia nigra at the ED50 doses of these compounds for antagonism of apomorphine-induced stereotypy.