Biomedical subjects

G F Koob

Publications and source records attributed to G F Koob.

At least 199 records · Page 11Linked to original sources

PubMed1993

Neurotensin injected into the nucleus accumbens blocks the psychostimulant effects of cocaine but does not attenuate cocaine self-administration in the rat.

The neuropeptide neurotensin (NT) has been shown to modulate mesolimbic dopaminergic activity. Neurotensin injected into the VTA produces motor stimulation and release of dopamine in the nucleus accumbens. In contrast, when neurotensin is administered into the nucleus accumbens, it produces neuroleptic-like effects such as attenuation of the locomotor activity elicited by psychostimulants. In the present study, the hypothesis that neurotensin injected into the nucleus accumbens might modulate the psychostimulant and reinforcing actions of cocaine was tested. In experiment one, rats were trained to self-administer cocaine intravenously on an FR5 schedule of reinforcement. Following the establishment of baseline responding, rats were implanted with bilateral cannulae in the nucleus accumbens. One week later, rats were injected into the nucleus accumbens with various doses of neurotensin (4.2, 8.4 and 16.7 micrograms, total doses bilaterally) immediately prior to the self-administration session. No significant effects were found with any of the doses of neurotensin tested on the self-administration of cocaine. However, in experiment 2, neurotensin at doses of 4.2 and 16.7 micrograms injected into the nucleus accumbens significantly reduced the locomotor activation induced by an acute injection of cocaine (15 mg/kg i.p.) and a dose of 16.7 micrograms attenuated the locomotor activation induced by amphetamine (0.75 mg/kg i.p.). Thus, neurotensin in the nucleus accumbens appears to specifically modulate the acute locomotor activating properties of cocaine but not cocaine self-administration. Different mechanisms by which NT interacts with dopamine in the nucleus accumbens may provide a means of selectively altering psychostimulant motor actions without affecting psychostimulant reinforcement.

Amphetamine↗

PubMed1993

Functional impairment of hypothalamic corticotropin-releasing factor neurons with immunotargeted toxins enhances food intake induced by neuropeptide Y.

Previous work has shown that administration of corticotropin-releasing factor (CRF) into the lateral ventricle antagonizes the orexigenic effect of neuropeptide Y (NPY), and central injection of CRF antagonist, alpha-helical CRF(9-41) enhanced NPY-induced food intake in satiated rats. The aim of the present study was to determine the effects of selective inactivation of hypothalamic CRF neurons on food intake induced by NPY injection and to delineate which hypothalamic nucleus is involved in this NPY/CRF interaction related to the regulation of food intake. Impairment of CRF neuron function by immunotargeting of a ricin A chain toxin with a monoclonal antibody to CRF (CRF-MAb) has been previously reported. Administration of CRF-MAb/toxins into the paraventricular nucleus (PVN) two weeks prior to testing produced markedly enhanced eating induced by injection of NPY into the same nucleus. This effect was accompanied by a 60% decrease in CRF content within the hypothalamus and a 43% decrease of CRF in the median eminence, a site of projection of CRF neurons from the PVN. In contrast, injection of CRF-MAb/toxins into the ventromedial nucleus of the hypothalamus (VMH) did not modify the feeding induced by NPY injection into this hypothalamic area. Systemic pretreatment with the synthetic glucocorticoid dexamethasone at a dose known to downregulate the levels of CRF in the PVN also enhanced the feeding induced by intra-PVN injection of NPY. This suggests that an equilibrium between CRF and NPY neuronal function within the PVN may play an important role in the regulation of food intake. This interactive mechanism may provide some partial explanation of the eating disorders related to stress, in particular anorexia nervosa.

Animals↗

PubMed1993

Two discrete nucleus accumbens projection areas differentially mediate cocaine self-administration in the rat.

The region of the nucleus accumbens and its connections have been implicated in the reinforcing actions of cocaine as measured by intravenous self-administration. Our previous work has demonstrated that ibotenic acid lesions of one of the output regions of the nucleus accumbens, the sublenticular region of the extended amygdala (SEA), resulted in significant decreases in the highest ratio obtained in rats self-administering cocaine. In the present study, the importance of another nucleus accumbens output, the subcommissural ventral pallidum (SVP), in mediating the self-administration of cocaine in the rat was explored. Animals were trained to self administer cocaine (0.75 mg/kg/inj) via an intravenous catheter on a FR5 schedule of reinforcement. Subsequently, subjects were either given bilateral intracerebral injections (0.5 microliter per side) of ibotenic acid (10 micrograms/microliter lesion group) or vehicle (sham group) into the SVP or into the SEA. Four days postlesion, cocaine self-administration on a FR5 schedule was resumed for 3 days. Next, a dose effect function was determined in one 3-h session. Finally, a progressive ratio probe in which the ratio requirement was increased after each reinforcement was tested. Lesions of both the SVP and the SEA produced significant changes in responding for intravenous cocaine on a FR5 schedule of reinforcement as compared to sham lesioned controls, although the effect was found to be greater for the rats bearing lesions of the SEA. While the lesions produced decreases in responding for cocaine at all doses tested in the dose-effect function, the rate of responding was still inversely proportional to the dose in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗

PubMed1993

Modulation of cocaine self-administration in the rat through D-3 dopamine receptors.

The reinforcing properties of cocaine are probably mediated by the mesocorticolimbic dopamine pathways in the central nervous system, but not all of the dopamine receptor subtypes involved in cocaine's reinforcing actions have been clearly identified. Recently, the D-3 receptor has been cloned, and its distribution in the brain has been found to be relatively restricted to limbic projections of the midbrain dopamine system. The D-3-selective compounds 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OHDPAT) and quinpirole potently decreased cocaine self-administration in the rat at doses that were not by themselves reinforcing. Moreover, three dopamine receptor agonists had affinities for binding to the D-3 receptor that correlated highly with their relative potencies in decreasing cocaine self-administration. The D-3 receptor may be involved in the reinforcing effects of cocaine and may be a useful target for the development of new pharmacotherapies for cocaine abuse.

Animals↗

PubMed1993

Corticotropin-releasing factor in the paraventricular nucleus modulates feeding induced by neuropeptide Y.

Central administration of neuropeptide Y (NPY) exerts a potent orexigenic effect in rats, whereas injection of corticotropin-releasing factor (CRF) suppresses food intake. Anatomical evidence of NPY-containing terminals located in close proximity to CRF-containing neurons and terminals of the hypothalamus and amygdala suggests possible interactions of these neuropeptide systems in food-intake regulation. The present study examined the effect of local administration of the CRF antagonist, alpha-helical CRF9-41, or peripheral treatment with dexamethasone on NPY-induced hyperphagia. Injection of a 250-ng dose of alpha-hel CRF within the paraventricular nucleus (PVN) of the hypothalamus significantly potentiated the feeding induced by a 500-ng dose of NPY injected into the same locus. In contrast, feeding induced by administration of the 500-ng dose of NPY into the ventromedial hypothalamus (VMH) was not modified by intra-VMH pre-treatment with a 250-ng dose of CRF antagonist. No effects of NPY or alpha-hel CRF on feeding were observed after administration into the central nucleus of the amygdala. Systemic pre-treatment with the synthetic glucocorticoid dexamethasone at a dose known to downregulate the function of CRF neurons in the PVN (100 micrograms/kg) enhanced feeding induced by intra-PVN administration of a 500-ng dose of NPY. These results suggest that hypothalamic CRF systems in the PVN exert inhibitory control over NPY-induced food intake.

Animals↗

PubMed1993

Central administration of corticotropin releasing factor induces long-term sensitization to D-amphetamine.

Corticotropin releasing factor (CRF) has been shown to initiate neuroendocrine and behavioral responses to stress. As stress and amphetamine (AMPH) show cross-sensitization, we investigated the role of endogenous CRF in behavioral sensitization to D-AMPH. In order to evaluate the participation of the central action and the pituitary-adrenocortical (PA) stimulatory effect of CRF, we compared the effects of repeated intracerebroventricular (i.c.v.) administration of CRF (0, 0.5, 2.5 micrograms/2 microliters), which have central and neuroendocrine consequences, with those of repeated subcutaneous administration of CRF (0, 0.1, 0.5, 2.5 micrograms/250 microliters), doses which only stimulate the PA axis, on the development of sensitization to AMPH-induced motor activation administered 1 week later. Repeated i.c.v. administration of CRF induced a long-lasting enhancement of the hyperactivity induced by 0.75 mg/kg peripheral administration of D-AMPH, whereas no sensitization to D-AMPH was observed following repeated subcutaneous administration of CRF. These results favor the hypothesis that a centrally mediated action of CRF is involved in the cross-sensitization of psychostimulants and stress.

Animals↗

PubMed1993

Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal.

Previous studies have shown that spontaneous exploration of the Elevated Plus Maze provides a sensitive measure of 'anxiety' induced by pharmacological or behavioral stressors. In particular, the percent time spent exploring the open arms of the plus maze is decreased during ethanol withdrawal, and this effect is antagonized by intracerebroventricular administration of 25 micrograms of alpha-helical CRF, a corticotropin-releasing factor antagonist (H.A. Baldwin et al., Psychopharmacology, 103 (1991) 227-232). The present study was designed to examine the effect of alpha-helical CRF infusion within the central nucleus of the amygdala during ethanol withdrawal. Rats were made dependent on ethanol by maintenance on an ethanol-containing liquid diet for 16 days, withdrawn from ethanol and tested on the elevated plus maze at 8 h post-ethanol access. In comparison with pair-fed control rats, ethanol withdrawn subjects spent significantly less percent time exploring the open arms of the plus maze. This decrease in open arm exploration was antagonized by administration of alpha-helical CRF (250 ng) bilaterally into the central nucleus of the amygdala, but not by intracerebroventricular administration of 250 ng of alpha-helical CRF. The ability of intra-amygdala alpha-helical CRF to antagonize decreased open arm exploration is unlikely to be due to changes in motor activity, since general activity on the maze was reduced in all EtOH withdrawal groups. These results suggest that the central nucleus of the amygdala may be an effective site for endogenous CRF systems to mediate anxious behavior associated with ethanol withdrawal.

Amygdala↗

PubMed1993

Destruction of the locus coeruleus decreases physical signs of opiate withdrawal.

The purpose of the present study was to investigate the role of the locus coeruleus in the development of opiate dependence. Two groups of rats each were subjected to either a electrolytic lesion of the locus coeruleus or a sham lesion. All animals were implanted with an intracerebroventricular (i.c.v.) cannula, and made physically dependent by subcutaneous insertion of two 75-mg morphine (base) pellets. Abstinence was precipitated by i.c.v. administration of methylnaloxonium (31-1,000 ng) 72 h after pellet implantation. Methylnaloxonium administered intracerebroventricularly induced a withdrawal syndrome characterized by the appearance of teeth chattering, mastication, rearing, wet dog shakes, jumping, piloerection, hyperactivity, ptosis and eye twitch. Withdrawal observed in the electrolytic lesion groups was less severe than in sham group. The presence of mastication, rearing, piloerection, hyperactivity, ptosis and eye twitch was significantly lower. These results support the hypothesis that the locus coeruleus has an important role in the expression of the physical signs of opiate dependence.

Animals↗

PubMed1993

Modulation of anxiety and neuropeptide Y-Y1 receptors by antisense oligodeoxynucleotides.

The function of neuropeptide Y, one of the most abundant peptide transmitters of the mammalian brain, remains unclear because of a lack of specific receptor antagonists. An antisense oligodeoxynucleotide corresponding to the NH2-terminus of the rat Y1 receptor was constructed and added to cultures of rat cortical neurons. This treatment resulted in a reduced density of Y1 (but not Y2) receptors and diminished the decrease in adenosine 3',5'-monophosphate (cAMP) usually seen after Y1 receptor activation. Repeated injection of the same oligodeoxynucleotide into the lateral cerebral ventricle of rats was followed by a similar reduction of cortical Y1 (but not Y2) receptors. Such antisense-treated animals displayed behavioral signs of anxiety. Thus, specific inhibition of neurotransmitter receptor expression can be accomplished in the living brain and demonstrates that altered central neuropeptide Y transmission produces an anxiety-like state.

Animals↗

PubMed1993

The role of corticotropin-releasing factor in behavioural responses to stress.

Corticotropin-releasing factor (CRF), when administered directly into the CNS, can have activating properties on behaviour and can enhance behavioural responses to stress. CRF injected intraventricularly produces a dose-dependent increase in locomotor activity and increased responsiveness to an acoustic startle stimulus. However, this profile of activation changes to enhanced suppression of behaviour in stressful situations and includes increased freezing, increased conditioned suppression, increased conflict, decreased feeding and decreased behaviour in a novel open field. These effects of CRF are independent of the pituitary-adrenal axis and can be reversed by the CRF antagonist alpha-helical CRF(9-41). More importantly, the CRF antagonist can also reverse many behavioural responses to stressors. alpha-Helical CRF(9-41) reverses stress-induced fighting behaviour, stress-induced freezing, stress-induced suppression of feeding, stress-induced decreases in exploration of an elevated plus maze, fear-potentiated startle and the development of conditioned suppression. Intracerebral microinjections suggest that the amygdala may be an important site for the anti-stress effects of alpha-helical CRF(9-41). These results suggest that endogenous CRF systems in the CNS may have a role in mediating behavioural responses to stress and further suggest that CRF in the brain may function as a fundamental behavioural activating system. This CRF system may be particularly important in situations where an organism must mobilize not only the pituitary-adrenal system but also the CNS in response to environmental challenge.

Animals↗

PubMed1993

Withdrawal following cocaine self-administration decreases regional cerebral metabolic rate in critical brain reward regions.

The quantitative [14C]-2-deoxyglucose autoradiographic method was utilized to assess regional cerebral metabolic rate for glucose (rCMRglc) in rat brain during withdrawal from cocaine self-administration. RCMRglc was determined in 62 regions from brains of naive rats which were placed into an empty operant chamber for 12 hr continuously, and rats trained to self-administer cocaine during 3 hr training sessions and subsequently placed into the operant chamber for 12 hr continuously with or without access to cocaine. Animals placed into the chamber without access to cocaine were examined 6 hr later, while animals allowed access to the 12 hr cocaine binge were examined either 6 or 72 hr post-cocaine. Metabolic activity was reduced during withdrawal in the nucleus accumbens, olfactory tubercle, islands of Calleja region, basolateral and central amygdaloid nuclei, medial septum, piriform and cingulate cortices, rostral caudatoputamen, entopeduncular nucleus and the adjacent lateral hypothalamus, somatosensory, auditory, and motor cortices compared to the naive state. These effects were usually more severe at 72 than at 6 hr after binge exposure, with intermediate values observed in cocaine trained animals without binge exposure. The response was negatively correlated with the amount of cocaine consumed during binge exposure in the striatum, olfactory tubercle, piriform, cingulate, somatosensory, and motor cortices. Thus, the amount of cocaine consumed can affect the extent of metabolic depression after sustained drug exposure. The pattern of regional effects suggests that mesolimbic and rostral extrapyramidal dopamine terminal regions and certain of their efferent pathways are preferentially affected during cocaine withdrawal. The reduction of basal metabolic rate observed in these brain regions during cocaine withdrawal may become more severe with time despite the apparent recovery of certain behavioral-motivational responses.

Animals↗

PubMed1993

Animal models of drug craving.

Drug craving, the desire to experience the effect(s) of a previously experienced psychoactive substance, has been hypothesized to contribute significantly to continued drug use and relapse after a period of abstinence in humans. In more theoretical terms, drug craving can be conceptualized within the framework of incentive motivational theories of behavior and be defined as the incentive motivation to self-administer a psychoactive substance. The incentive-motivational value of drugs is hypothesized to be determined by a continuous interaction between the hedonic rewarding properties of drugs (incentive) and the motivational state of the organism (organismic state). In drug-dependent individuals, the incentive-motivational value of drugs (i.e., drug craving) is greater compared to non-drug-dependent individuals due to the motivational state (i.e., withdrawal) developed with repeated drug administration. In this conceptual framework, animal models of drug craving would reflect two aspects of the incentive motivation to self-administer a psychoactive substance. One aspect would be the unconditioned incentive (reinforcing) value of the drug itself. The other aspect would be relatively independent of the direct (unconditioned) incentive value of the drug itself and could be reflected in the ability of previously neutral stimuli to acquire conditioned incentive properties that could elicit drug-seeking and drug-taking behavior. Animal models of drug craving that permit the investigation of the behavioral and neurobiological components of these two aspects of drug craving are reviewed and evaluated. The models reviewed are the progressive ratio, choice, extinction, conditioned reinforcement and second-order schedule paradigms. These animal models are evaluated according to two criteria that are established herein as necessary and sufficient criteria for the evaluation of animal models of human psychopathology: reliability and predictive validity. The development of animal models of drug craving will have heuristic value and allow a systematic investigation of the neurobiological mechanisms of craving.

Animals↗

PubMed1993

Chronic ethanol produces a decreased sensitivity to the response-disruptive effects of GABA receptor complex antagonists.

Disruption of responding for food reinforcement may reflect the motivational state subsequent to the onset of an aversive event and has previously been shown to be sensitive to spontaneous withdrawal from ethanol and precipitated opiate withdrawal. The purpose of this study was to attempt to precipitate ethanol withdrawal with bicuculline methiodide, a competitive GABAA receptor antagonist, and Ro 15-4513, a benzodiazepine inverse agonist. A quantitative operant measure of food-motivated behavior was used to evaluate the reactivity of the GABAA-benzodiazepine receptor complex during chronic ethanol treatment in rats. In the present study, rats were trained to lever-press for food reinforcement on a fixed ratio 15 schedule and then maintained for 2 weeks on a liquid diet containing 35% ethanol-derived calories or a control liquid diet that was prepared isocalorically with sucrose. Chronic ethanol treatment attenuated the disruptive effects on operant responding that were produced by bicuculline methiodide (100 ng ICV) and Ro 15-4513 (3 and 6 mg/kg). The inability of these drugs to "precipitate" EtOH withdrawal may reflect the noncompetitive interaction of ethanol with the GABA-benzodiazepine-ionophore receptor complex. These data are consistent with recent biochemical studies indicating that chronic ethanol treatment modulates the GABAA-benzodiazepine-ionophore receptor complex by altering the expression of specific molecular components and inhibiting the activity of the receptor complex.

Animals↗

PubMed1993

D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat.

Previous work using systemic injections of dopamine receptor antagonists has established that dopamine D1 receptors may have a role in cocaine self-administration. The purpose of the present study was to test the hypothesis that these effects were mediated by dopamine D1 receptors in the region of the nucleus accumbens. Animals were trained to perform operant responses to self-administer cocaine via an IV catheter on a fixed-ratio 5 (FR 5) schedule of reinforcement. SCH23390, a selective D1 dopamine antagonist, significantly increased the self-administration of cocaine when injected into the nucleus accumbens. This increase in self-administration is thought to reflect decreases in the magnitude of the reinforcer, similar to the increase observed when the dose of cocaine is reduced. Similar doses of SCH23390 injected into the posterior caudate nucleus failed to alter cocaine self-administration. These data suggest that D1 receptors in the nucleus accumbens are important for the reinforcing properties of cocaine.

Animals↗

PubMed1993

Pituitary-adrenal axis responses to acute amphetamine in the rat.

After acute administration of amphetamine (AMPH), a characteristic behavioral response occurs in the rat, involving increased locomotion and stereotyped licking, grooming, and biting. AMPH administration also activates several neuroendocrine systems, including the pituitary-adrenal axis. Because recent evidence has supported a role for glucocorticoids in modulating the behavioral response to AMPH, the purpose of the present study was to examine the relationship between behavioral and hypothalamic-pituitary-adrenal (HPA) responses to AMPH and determine the physiological substrates responsible for the AMPH-induced release of adrenal steroids. AMPH administration produced the often-reported "inverted-U" shaped behavioral response. Specifically, locomotion was increased by low doses (0.5-1.0 mg/kg, SC) significantly more so than by the highest dose (5.0 mg/kg, SC), which instead elicited intense focused stereotyped movements. Plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone were increased by AMPH in a monotonic dose-response function, with highest levels measured in rats exhibiting the most intense stereotyped behaviors. Plasma ACTH levels then declined 10-30 min after AMPH administration, while AMPH-induced locomotion and stereotyped behavior persisted well beyond this period. In a parallel study, AMPH failed to elevate plasma levels of vasopressin, an important ACTH secretagogue, and AMPH reduced levels of corticotropin-releasing factor (CRF) immunoreactivity in the median eminence, providing indirect evidence of CRF release from this region. AMPH-stimulated ACTH and corticosterone release were prevented by immunoneutralization of CRF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1993

Corticotropin-releasing factor release from the mediobasal hypothalamus of the rat as measured by microdialysis.

Procedures were developed to permit the measurement of corticotropin-releasing factor in perfusate collected from microdialysis probes implanted in various brain areas of anesthetized and awake rats. Initially in vitro experiments were carried out to optimize the recovery of corticotropin-releasing factor and the radioimmunoassay conditions. Addition of a specific antiserum against corticotropin-releasing factor to the perfusion medium (artificial cerebrospinal fluid) increased the relative in vitro recovery over a range of different flow rates (1-10 microliters/min) using commercially available microdialysis probes with a membrane cutoff of 20,000 mol. wt. This procedure increased recovery from 3% to 6% at flow rate of 2.5 microliters/min, and from 4% to 8% at a flow rate of 5 microliters/min. In vivo experiments were performed with a flow rate of 3.3 microliters/min and 50-microliters fractions were used for radioimmunoassay. In each experiment, the standard curve of the radioimmunoassay was constructed from aliquots of the same medium used to perfuse the probe. Basal levels of corticotropin-releasing factor in dialysate collected from the mediobasal hypothalamus of anesthetized rats were estimated to be 0.75 +/- 0.07 fmol/50 microliters. Raising the concentration of potassium (60 mM) in the perfusate increased corticotropin-releasing factor levels to 2.04 +/- 0.37 fmol/50 microliters. Hypertonic stress induced by intraperitoneal injection of 1.5M NaCl (20 ml/kg) elevated the levels to 1.32 +/- 0.07 fmol/50 microliters. A marked increase of corticotropin-releasing factor levels was also produced by a 10-min pulse of the potassium-channel blocker 4-aminopyridine (10 mM) included in the perfusate. A second stimulation pulse with 4-aminopyridine, administered 2 h after the first pulse again increased the levels, with a mean ratio between the first and second pulse of 0.97. Corticotropin-releasing factor efflux produced by the second stimulation pulse was completely inhibited by perfusion with calcium-free medium containing calcium-chelating agent ethyleneglycol tetraacetic acid (10 mM). In separate experiments, microdialysis probes were implanted in several brain areas of anesthetized rats. Basal and potassium-evoked levels of corticotropin-releasing factor were measured in dialysate collected from the amygdala (1.20 +/- 0.22 and 2.05 +/- 0.48 fmol/50 microliters, respectively) and frontal cortex (0.51 +/- 0.10 and 1.64 +/- 0.15 fmol/50 microliters, respectively). Corticotropin-releasing factor levels in the dorsal part of the third ventricle and in the striatum were below the detection limits. In awake rats, corticotropin-releasing factor levels in the mediobasal hypothalamus were 0.98 +/- 0.03 fmol/50 microliters.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗

PubMed1993

Blockade of pituitary-adrenal axis activation induced by peripheral immunoneutralization of corticotropin-releasing factor does not affect the behavioral response to social defeat stress in rats.

Specific in vivo immunoneutralization of hypophysiotrophic corticotropin-releasing factor (CRF) and vasopressin (AVP) was used to investigate the respective roles of these circulating peptides in the hormonal response to a social stressor in Wistar rats. The effect of peripheral immunoneutralization on the behavioral response to the same social stressor was also studied. Stress was produced using social defeat in a resident-intruder paradigm, in which an intruder male rat, equipped with an indwelling IV catheter, was confronted with a dominant resident male rat. To minimize the physical component of the agonistic interaction, the intruder was protected immediately after the resident's first attack in a Plexiglas/wire-mesh enclosure. In the following time interval, the resident continued to threaten the protected intruder, which showed a significant increase in plasma immunoreactive adrenocorticotropic hormone (ACTH) and corticosterone levels compared to those measured in rats exposed to a control procedure. The hypothalamo-pituitary-adrenal (HPA) axis response to social defeat stress was totally abolished by pretreatment with an anti-CRF serum (0.3 ml IV) but not an anti-AVP serum (0.75 ml IV). An animal model for anxiety in rodents, the elevated plus-maze, was used to study the emotional response to social defeat stress in rats given anti-CRF serum or normal serum. A significant reduction of open-arm exploration was observed in defeated rats tested 10 min after the end of the agonistic interaction when compared with control animals for all antisera treatment group, indicating an "anxiogenic-like" emotional response to the social defeat stress. Pretreatment with anti-CRF serum did not affect the behavioral performance of defeated and control rats. These results suggest that: 1) social defeat stress produced an activation of the HPA axis in the rat which is mediated by hypophysiotrophic CRF but not AVP; and 2) the peripheral activation of the HPA axis induced by social defeat stress is not involved in the behavioral response to stress as measured in the elevated plus-maze.

Adrenocorticotropic Hormone↗

PubMed1993

Functionally selective neurochemical afferents and efferents of the mesocorticolimbic and nigrostriatal dopamine system.

In summary, evidence is presented that the mesocorticolimbic and nigrostriatal dopamine systems form functionally selective afferents to different parts of the basal ganglia and these inputs are paralleled by functionally selective outputs. The ventral striatal region of the nucleus accumbens and olfactory tubercle has a dopamine input that is critical for locomotor activation produced by psychomotor stimulant drugs and some non-drug states. These regions also appear critical for the reinforcing actions of psychomotor stimulants such as cocaine and amphetamine, and these regions may also be involved in the activation associated with non-drug rewards. Both psychomotor stimulant-induced locomotor activation and reinforcement may selectively involve dopamine D1 receptors. The functional efferents of this system appear to involve the region of the ventral pallidum and more specifically GABAergic mechanisms of the posterior medial (sublenticular) ventral pallidum. The relationship of this circuitry with the revised concept of the "extended amygdala" is an area of current work. The nigrostriatal dopamine system forms a functionally selective afferent system to the dorsal striatum and appears to be critical for the focused stereotyped behavior associated with high doses of psychomotor stimulants. This dopamine input also appears to be involved in non-drug-induced conditioned reaction time performance and may selectively involve dopamine D2 receptors. The functional efferents of this system appear to involve both direct and indirect GABAergic connections to the substantia nigra reticulata and dorsal pallidum, respectively. Activation of the GABAergic connection to the dorsal pallidum (indirect connection) appears to mimic the action of dopamine in the dorsal striatum, whereas activation of the GABAergic connection to the substantia nigra reticulata (direct connection) appears to modulate striatal dopamine function. These results show an important functional role for the globus pallidus in the output of the dorsal striatum and emphasize the parallel functional processing of both dorsal and ventral striatum.

Afferent Pathways↗