Systemic administration of CCK-8S, but not CCK-4, enhances dopamine turnover in the posterior nucleus accumbens: a microdialysis study in freely moving rats

The present study was carried out to examine the effects of peripheral administration of sulfatedcholecystokinin octapeptide (CCK-8S) on dopamine (DA) turnover in the posterior nucleus accumbens (PNAc) and the caudate-putamen (CP) in awake rats. Microdialysis was used to quantify the extracellular concentrations of DA and its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Intraperitoneal injections of CCK-8S (0.3 mg/kg b.wt.) caused a significant increase in DOPAC and HVA concentrations in the PNAc, but did not affect the DA level. Such increases in the metabolite contents were not found in the CP. Similar injections of vehicle (1% NaHCO3 solution, 1 ml/kg b.wt.) did not have an effect in either brain region. In an attempt to determine the type of receptor involved in the CCK-8S-induced changes, CCK tetrapeptide (CCK-4, 0.3 mg/kg b.wt.) known to have high affinity for CCKB subtype or vehicle (10% DMSO-saline, 1 ml/kg b.wt.) was administered intraperitoneally. Neither CCK-4 nor vehicle caused significant changes in any of extracellular DA, DOPAC and HVA contents in the PNAc. These results suggest that peripherally administered CCK-8S has stimulatory effects on the dopaminergic system in the PNAc, and raise the possibility that the effect appears to be mediated via CCKA receptors.     

Lesions of the amygdala, but not of the cerebellum or red nucleus, block conditioned fear as measured with the potentiated startle paradigm.

In Exp I, 97 male Sprague-Dawley albino rats were given 10 light–shock pairings on 2 successive days. At 24–48 hrs following training, groups of Ss received bilateral transection of the cerebellar peduncles, bilateral lesions of the red nucleus (which receives most of the cerebellar efferents), or bilateral lesions of the central nucleus of the amygdala. Controls were sham operated. At 3–4 days after surgery, Ss were tested for potentiated startle (PS [increased acoustic startle in the presence of the light previously paired with shock]). PS was blocked by lesions of the central nucleus of the amygdala but not by transection of the cerebellar peduncles or lesions of the red nucleus. Exp II, in which a visual prepulse test was used with 14 Ss, indicated that the blockade of PS observed in Ss with amygdala lesions could not be attributed to optic tract damage. Exp III, with 20 Ss, demonstrated that the absence of potentiation in Ss with amygdala lesions was not simply due to a lowered startle level ceiling, because these Ss could show increased startle with increased stimulus intensity and with administration of intraperitoneal strychnine, (0.75 mg/kg), a drug that increases startle. Results are consistent with the hypothesis that the amygdala is involved in fear conditioning. (64 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stimulus quality affects expression of the acoustic startle response and prepulse inhibition in mice.

The relationship between stimulus intensity and startle response magnitude (SIRM) can assess the startle reflex and prepulse inhibition (PPI) with advantages over more commonly used methods. The current study used the SIRM relationships in mice to determine differences between white noise and pure tone (5 kHz) stimuli. Similarly to rats, the SIRM relationship showed a sigmoid pattern. The SIRM-derived reflex capacity (RMAX) and response efficacy (slope) of the white noise and pure tone stimuli in the absence of prepulses were equivalent. However, the pure tone startle response threshold (DMIN) was increased whereas the stimulus potency (1/ES??) was decreased when compared to white noise. Prepulses of both stimulus types inhibited RMAX and increased DMIN, but the white noise prepulses were more effective. Both stimulus intensity gating and motor capacity gating processes are shown to occur, dependent on prepulse intensity and stimulus onset asynchrony. Prepulse intensities greater than 10 dB below the startle threshold appear to produce PPI via stimulus intensity gating, whereas a motor capacity gating component appears at prepulse intensities near to the startle threshold. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

CCKB receptors mediate CCK-8S-induced activation of dorsal hippocampus CA3 pyramidal neurons: an in vivo electrophysiological study in the rat

The sulphated octapeptide C-terminal fragment of cholecystokinin (CCK-8S) is present in high concentration in the mammalian brain, where it acts via two types of receptor denoted CCKA and CCKB. In the dorsal hippocampus, CCK-8S exerts a potent excitatory effect on pyramidal neurons. The present electrophysiological study was undertaken to determine which CCK receptor type mediates this neuronal activation. Using in vivo extracellular unitary recordings of CA3 pyramidal hippocampal neurons, we compared the effect of SNF-8702, a potent selective CCKB receptor agonist, to that of CCK-8S, and assessed the effects of selective CCKA and CCKB antagonists. CCK-8S and SNF-8702, microiontophoretically applied on the same neurons produced a similar degree and pattern of activation. Both CCK-8S- and SNF-8702-induced activations were suppressed by the microiontophoretic application of the CCKB antagonist CI-988, but not by that of the CCKA antagonist SR 27897. CCK-8S-induced activation was not significantly modified by the intravenous administration of the CCKA antagonists devazepide and SR 27897. However, it was reduced by the CCKB antagonist PD 135158, administered intravenously or intracerebroventricularly, and by the intravenous administration of the CCKB antagonist L-365,260. The intravenous administration of PD 135158 also reduced SNF-8702-induced activations. These results indicate that CCKB receptors mediate CCK-8S-induced activation of rat CA3 pyramidal neurons.     

The effect of post-training hypothalamic self-stimulation on sensory preconditioning in rats.

58 male hooded water-deprived rats experienced a preconditioning session (consisting of paired or unpaired presentations of a tone and a light) followed by either no self-stimulation, immediate self-stimulation, or self-stimulation delayed by 2 or 4 hrs. On the next 2 days, Ss experienced the conditioning phase in which the light was paired with a footshock. 24 hrs after the last conditioning trial, the transfer of the conditioned emotional response from the light to the tone was evaluated using a suppression-of-drinking procedure. Self-stimulation facilitated retention of the association between the tone and the light when it occurred within 2 hrs after preconditioning training, but not when it occurred 4 hrs after training. Immediate posttraining self-stimulation had no effect on Ss that experienced unpaired tone and light presentations during preconditioning training. Data suggest that the self-stimulation treatment strengthened the association between the tone and the light retroactively and noncontingently, and show that direct activation of the neural substrate of reinforcement can improve memory for associations formed between 2 neutral stimuli. (French abstract) (34 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of a Typical and an Atypical Antipsychotic on the Disruption of Prepulse Inhibition Caused by Corticotropin-Releasing Factor and by Rat Strain.

Male Wistar-Kyoto (WKY) and Brown Norway (BN) rats (11-12 weeks, n = 184) received an injection of saline, haloperidol, or clozapine, followed by an intracerebroventricular infusion of saline or corticotropin-releasing factor (CRF). Rats were tested for prepulse inhibition (PPI) of the acoustic startle response. BN rats showed less PPI than WKY rats, and neither antipsychotic alone enhanced PPI. In WKY rats, both haloperidol and clozapine attenuated the CRF-induced decrease in PPI. In CRF-treated BN rats, clozapine-enhanced PPI. A clozapine-induced decrease in startle amplitude was seen in CRF-treated BN rats but not in CRF-treated WKY rats. Although the disruption of PPI caused by exogenous CRF administration can be reversed by acute antipsychotic treatment, baseline PPI is not altered. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Age-related decline in auditory plasticity: Experience dependent changes in gap detection as measured by prepulse inhibition in young and aged rats.

Young adult and aged F344 rats were compared on a silent gap variant of the prepulse inhibition paradigm. Animals were tested using a 50-ms single tone cue, followed by 8 days of silent gap testing. The first 3 days of gap testing were long gaps (range 2 to 100 ms) followed by 5 days of short gaps (range 2 to 10 ms). The effects of gap length, prior experience, and age, on the magnitude and direction (facilitation vs. attenuation) of the acoustic startle response, were examined. The young rats showed stronger and more reliable acoustic startle responses (uncued trials) during all acoustic startle tasks as compared to the old. The younger animals also exhibited a more consistent attenuated response across cues and days. Depending on silent gap length, both reduction (inhibition) and enhancement (facilitation) of startle were observed. Finally, only the young adult animals showed an experience-related shift from facilitation to attenuation in response to very short silent gap cues, and this initial early facilitation predicted later attenuation following additional experience. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

MK-329 blocks the inhibition of alcohol intake by CCK-8

Peripheral administration of sulfated cholecystokinin octapeptide (CCK-8) potently reduces alcohol intake, preference, and blood levels in rats. MK-329 (L-364,718 or Devazepide) acts at peripheral cholecystokinin (CCKA) receptors to antagonize CCK-8's physiological and behavioral effects, such as pancreatic stimulation and inhibition of feeding. We determined whether CCKA receptor blockade would also prevent CCK-8's alcohol satiety effect. Water-deprived female and male rats (n = 7 for each) received randomized combinations of intraperitoneal injections of MK-329 (0, 100, 200, or 400 micrograms/kg) followed by CCK-8 (0 or 4 micrograms/kg). Rats were then given access to 5% w/v ethanol for 30 min, followed by 30-min access to water, with food ad lib. MK-329 at all doses significantly (p < 0.05) reduced the suppression of alcohol intake and food intake by CCK-8. MK-329 alone increased alcohol intake at 400 micrograms/kg, and increased food intake, in females and males at 100 and 200 micrograms/kg, respectively. We concluded that CCK-8's alcohol and food satiation effects depend on specific, peripheral CCKA receptors, and satiation of alcohol consumption and drinking-associated feeding reflect an endogenous functional interaction of CCK-8 with CCKA receptors.     

Subamnesic cycloheximide treatment delays consolidation in mice.

In Exp I, groups of C57 BL/6J mice were given passive avoidance training and then administered different doses of cycloheximide (CYC) immediately, 30 min, or 1 hr after training. Only the highest dose (150 mg/kg) administered immediately or 30 min after training impaired memory when the mice were tested 72 hrs after training. In Exp II, Ss were given a nonamnesic administration of CYC (30 mg/kg) or saline immediately after training and another injection of CYC (15, 30, or 75 mg/kg) or saline 1 hr after training. The combinations of 30 mg/kg?+?30 mg/kg and 30 mg/kg?+?75 mg/kg impaired memory. Exp III demonstrated that brief carbon dioxide anesthetization initiated immediately after training impaired memory. In Exp IV, mice were given either saline or 30 mg/kg CYC immediately after training and then subjected to either air or CO? anesthetization 30 min after training. Only the group given 30 mg/kg CYC?+?CO? was amnesic when tested 72 hrs after training. Results indicate that the administration of a nonamnesic dose of CYC immediately after training renders the memory susceptible to disruption by additional doses of CYC or other amnesic treatments for a longer period of time than normal. It is suggested that CYC delays consolidation and prolongs the labile period of memory formation. (11 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Vasopressin dilates the rat carotid artery by stimulating V1 receptors

1. The effect of the intraperitoneal administration of cholecystokinin sulphated octapeptide (CCK-8S) (10 nmol/kg i.p.) on endogenous levels of several amino acids in five areas of the rat brain was analyzed. The olfactory bulb, hypothalamus, hippocampus, cerebral frontal cortex, and corpus striatum were evaluated. In addition, the effects of CCK-8S and PD 135,158 (1 mg/kg), a selective CCK(B) antagonist, on the performance of rats submitted to a dark/light transition test were also studied. 2. Upon administration of CCK-8S, the concentration of glutamate was reduced (27%) in the olfactory bulb. The same was observed when the levels of glycine (31%) or alanine (43%) were determined. No significant effects were produced by CCK-8S on cortical and hypothalamic levels. In the hippocampus, the concentration of both glutamate (27%) and taurine (29%) were reduced, whereas the levels of GABA in the striatum (29%) were increased. 3. After a single injection of CCK-8S, the time spent by the rats in the illuminated site of the dark/light transition test box, was not changed. On the contrary, the administration of PD 135,158 increased the time spent in the lighted compartment. 4. These results show that systemic administration of CCK-8S produced regional specific changes in brain amino acids, without producing any significant behavioral modification in the rat exposed to a dark/light box. In contrast, the selective CCKB receptor antagonist, PD 135,158, induces anxiolytic-like action in an animal model of anxiety.     

Modification of the acoustic startle response in hearing-impaired C57BL/6J mice: Prepulse augmentation and prolongation of prepulse inhibition.

Modification of acoustic startle amplitude by a 10-ms tone prepulse (S1) was evaluated as a function of the interstimulus interval (ISI) between the onset of S1 and the onset of the startle-evoking stimulus (S2). Subjects were normal-hearing 1-month-old C57BL/6J (C57) mice and CBA/CaJ mice and 5-month-old C57 mice with high-frequency hearing loss. With a 2-ms ISI, 5-month-old C57 mice (but not the normal-hearing mice) exhibited pronounced prepulse augmentation (PPA) of startle: Amplitudes were much larger when S1 was present. Prepulse inhibition (PPI) occurred with ISls of 10–100 ms in all subject groups. With long ISls of 200 and 500 ms, however, PPI was strong only in 5-month-old C57 mice and only with S1 frequencies of 8, 12, and 16 kHz. Physiological studies of neural plasticity have shown that frequencies of 8–16 kHz become "over-represented" (more neurons responding) in the central auditory system of C57 mice, suggesting a link with prolonged PPI observed here. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of putative satiety peptides on feeding and drinking behavior in golden hamsters (Mesocricetus auratus).

Intraperitoneal cholecystokinin octapeptide (CCK-8 [0.1–5 μg/kg]) reduced feeding in Syrian hamsters in a dose-related fashion, except for males tested during the light phase of the illumination cycle. Proglumide (200 or 400 mg/kg), a putative CCK receptor antagonist, did not alter spontaneous food intake and did not reverse the suppression of feeding resulting from CCK-8. Bombesin (BBS [0.5–20 μg/kg]), thyrotropin releasing hormone (TRH [5–200 μg/kg]), and calcitonin (CC [2–22 μg/kg]) produced a dose-related suppression of food intake. BBS appeared to do so specifically. In contrast, TRH appeared to reduce feeding by temporarily debilitating the Ss and CC by evoking behavior (increased locomotor activity) incompatible with feeding. Intracerebroventricular (icv) injections of CCK-8, BBS, and CC produced dose-related inhibition of feeding, but only CCK-8 appeared to affect feeding behavior selectively. Reduced feeding after icv BBS was associated with excessive grooming, and icv CC, like systemic CC, increased locomotor behavior. (72 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Loss of emotional experience after traumatic brain injury: Findings with the startle probe procedure.

The authors used affective modulation of the eyeblink startle response to examine the impact of traumatic brain injury (TBI) on emotional reactions to pictures. Participants were 13 individuals with severe TBI and 24 controls. Participants were presented with pictures that differed in affective valence (e.g., mutilated bodies, erotic couples, and household objects) while the eyeblink startle response to an acoustic probe was measured. Startle amplitude was used to assess valence of emotional response, and startle latency was used to index interest in the pictures. Subjective ratings of the affect and arousal elicited by the various pictures were also obtained. TBI impaired startle potentiation to unpleasant pictures but not startle attenuation to pleasant pictures. Further, subjective ratings indicated that TBI participants found unpleasant pictures less arousing than did controls. The results are consistent with recent evidence of differential impairment in negative versus positive emotions after TBI and are discussed in relation to 2 competing explanations of startle modulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Emotional state and initiating cue alter central and peripheral motor processes.

Evidence indicates that voluntary and involuntary movements are altered by affective context as well as the characteristics of an initiating cue. The purpose of this study was to determine the contribution of central and peripheral mechanisms to this phenomenon. During the presentation of pleasant, unpleasant, neutral, and blank images, participants (N = 33) responded to auditory stimuli (startle, 107 dB startle or 80 dB tone) by initiating a bimanual isometric contraction of the wrist and finger extensor muscles. Analyses of electromyography and force measures supported the hypothesis that exposure to unpleasant images accelerates central processing times and increases the gradient of slope of peripheral movement execution. In addition, startle cues as compared with tone cues accelerated and magnified all temporal and amplitude indices. Collectively, these findings have noteworthy implications for (a) those seeking to facilitate the speed and force of voluntary movement (i.e., movement rehabilitation), (b) understanding the higher incidence of motor difficulty in individuals with affective disorders, and (c) those seeking to regulate emotional input so as to optimize the quality of intended movements. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Olfactory-Mediated Fear Conditioning in Mice: Simultaneous Measurements of Fear-Potentiated Startle and Freezing.

This study demonstrates that mice display olfactory-cued fear as measured with both freezing and fear-potentiated startle. Following a preconditioning test to measure any unconditioned responses to odor, mice received 5 pairings of a 10-s odor with a 0.25-s, 0.4-mA footshock. The next day, startle and freezing were measured in the presence and absence of the odor. Both fear measures increased after training with amyl acetate (Experiment 1) and acetophenone (Experiment 2). The enhancement of startle did not occur when the same number of odors and shocks were presented in an unpaired fashion (Experiment 3). Furthermore, mice were able to discriminate between an odor paired with shock and a nonreinforced odor (Experiment 4). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Changes with ageing in the modulation of murine lymphocyte chemotaxis by CCK-8S, GRP and NPY

The general immunodepression found in ageing organisms may be related to changes in the neuroimmune network. In the present study, the migration capacity of lymphocytes from BALB/c mice of three different ages: young (12 +/- 2 weeks), adult (24 +/- 2 weeks) and old (72 +/- 2 weeks), has been assayed in vitro in response to three neuropeptides: sulfated cholecystokinin octapeptide (CCK-8s), gastrin-releasing peptide (GRP) and neuropeptide Y (NPY) in a physiological range of concentrations (10(-8)-10(-12) M). The capacity of migration to a chemical gradient or chemotaxis was studied by the Boyden's technique using f-met-leu-phe at 10(-8) M as chemoattractant. The results show a different response of lymphocytes to the different neuropeptides, as wells as to age, concentrations and locations studied. However, some similarities were found, for instance the three neuropeptides inhibited chemotaxis in thymus. The stimulatory effects that GRP and NPY exerted in young and adult mice were not observed in old animals. CCK-8s inhibited the chemotaxis in every organ studied, with the effect being more striking in old mice. Our conclusion is that stimulatory effects of the neuropeptides disappear or become inhibitory with ageing.     

Group II metabotropic glutamate receptors within the amygdala regulate fear as assessed with potentiated startle in rats.

The contribution to fear and fear learning of amygdala Group II metabotropic glutamate receptors was examined in rats. Pretest intra-amygdala infusions of the Group II receptor agonist LY354740 (0.3 or 1.0 μg/side) significantly disrupted fear-potentiated startle. The same rats were unimpaired when later tested without drug. The Group II receptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (3.0 μg/side) mimicked the effect of LY354740, and coadministration of the Group II receptor antagonist LY341495 (0.3 μg/side) prevented it. Pretraining LY354740 (0.3 μg/side) infusions also blocked learning. The effects on learning and performance were significantly less pronounced in rats with misplaced cannulas. Thus, Group II metabotropic receptors within or very near the amygdala regulate fear and fear learning and are a potential target for anxiolytic compounds. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Estrogen and estrogen-progesterone treatments counteract the effect of scopolamine on reinforced T-maze alternation in female rats.

Determined if steroid hormone treatments would attenuate the effect of the muscarinic receptor blocker scopolamine on a memory task. Ovariectomized rats were trained first to alternate for food reward between the arms of a T maze. Following training, Ss treated with scopolamine hydrobromide (0.2 mg/kg, ip) did not alternate correctly between the arms of the T maze and responded at chance levels. However, when estradiol benzoate (25 μg) was administered 72, 48, and 24 hrs before testing alone or in combination with progesterone (500 μg) administered 48 hrs before testing, Ss alternated successfully between the arms of the T maze following scopolamine administration. Results indicate that gonadal steroids can completely counteract the impairment of T maze performance induced by scopolamine in female rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acoustic startle response in young and aging C57BL/6J and CBA/J mice.

C57 mice demonstrate progressive age-related hearing loss during the 1st yr, whereas CBA mice lose little sensitivity through 18 mo of age. The acoustic startle response (ASR) was measured to determine behavioral correlates of aging with and without presbycusis. Stimuli were tone pips with frequencies of 4–24 kHz at intensities of 70–200 dB SPL. ASR thresholds increased with age, and startle amplitudes became smaller. Changes in startle parameters were more pronounced in C57 mice, with middle to high frequencies severely affected. Startle latencies at and above ASR threshold increased with age in C57 mice. CBA data indicate that aging has little effect on ASR parameters; the C57 data show that hearing loss is a cogent factor. ASR parameters of C57 mice are altered to a greater extent than expected, on the basis of the elevations of absolute sensory thresholds, particularly for middle frequencies. Both peripheral and central mechanisms may account for the discrepancy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)