Biomedical subjects

G F Koob

Publications and source records attributed to G F Koob.

At least 325 records · Page 18Linked to original sources

PubMed1986

Post-learning ethanol effects on a water-finding task in rats.

Ethanol's post-training facilitation of memory was examined using a latent learning paradigm known as the "water-finding task." Rats were assigned to one of two ethanol groups (E0.75 g/kg or E1.5 g/kg) or to a control group (saline) and individually placed in a novel open field containing a drinking tube. Following this exposure, subjects were immediately administered intraperitoneal (IP) injections of either the saline or ethanol and 48 hours later, re-introduced to the field. Initial latencies to contact the tube each time were recorded. A linear regression analysis of trial 2 latencies regressed onto trial 1 latencies indicated a statistically significant effect of ethanol on the relation between initial and subsequent latencies. Though the control rats' trial 2 latencies were completely random with respect to their previous speeds (rSAL = -0.07), the ethanol rats' trial 2 latencies were positively correlated with initial speeds (rE0.75 = 0.35, rE1.5 = 0.67). These results suggest that under conditions of post-training ethanol, trial 2 behavior is more similar to, or controlled by, trial 1 behavior and are consistent with the argument that, under certain training and testing contexts, ethanol can come to exert control over a response's recurrence.

Analysis of Variance↗

PubMed1986

The effects of verapamil on the locomotor-activating properties of corticotropin releasing factor (CRF) in the rat.

CRF was administered to rats following intracerebroventricular administration of the calcium antagonist verapamil. Treatment with verapamil elicited biphasic dose-response effects on rat locomotor activity: doses equimolar to CRF treatment slightly increased CRF-stimulated locomotion, while doses of verapamil ten times greater slightly depressed CRF-stimulated locomotion. These results suggest that CRF-stimulated locomotion, unlike other effects of CRF, is not mediated in a simple way by processes dependent on neuronal calcium influx.

Animals↗

PubMed1986

Subcutaneous administration of behaviorally effective doses of arginine vasopressin change brain AVP content only in median eminence.

The accumulation of [8-arginine]vasopressin (AVP) in brain areas inside the blood-brain barrier (thalamus-hypothalamus, amygdala with overlying temporal cortex, hippocampus and cerebral cortex) and outside the blood-brain barrier (median eminence of the hypothalamus and area postrema) was measured after subcutaneous injection of the hormone. The plasma concentrations of AVP peaked at 5 min after subcutaneous injection and declined in a biphasic manner over the next 115 min. The concentration of AVP in brain tissue samples peaked at 20 min after the subcutaneous injection of AVP; the decline of AVP in the areas protected by the blood-brain barrier followed the time course seen for plasma. The concentration of AVP in the brain areas not so protected also peaked at 20 min but these declined at rates that differed from other brain areas and plasma. The concentration of AVP in the plasma and in most brain areas depended on the dose administered, while those in the median eminence and in the area postrema did not. Water deprivation for 24 and 48 h significantly elevated both the plasma AVP concentration and the concentration of AVP in the hypothalamus and in the amygdala-temporal cortex samples. The increases in AVP after water deprivation are limited to these two regions and are quantitatively much lower than after peripheral administration. Furthermore, when the brains of anesthetized rats were perfused free of blood, there were no changes in regional brain AVP content after subcutaneous treatment with 5,000 ng/kg of AVP, except for the median eminence. These data suggest that circulating AVP does not enter the parenchyma of brain areas protected by the blood-brain barrier in sufficient quantities to be detected by our assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Neurochemical substrates for opiate reinforcement.

The studies reported herein summarize our work to date aimed at determining the neurochemical substrates for the reinforcing properties of opiates. Rats were trained to self-administer heroin intravenously in daily 3-hour sessions, and pharmacological blockade and neurotoxin-induced lesions were used to define the neurochemical substrates for this reinforcing action. Low-dose DA receptor blockade failed to alter heroin self-administration but significantly increased cocaine self-administration, presumably reflecting a decrease in the reinforcing effectiveness of cocaine. Destruction of presynaptic DA terminals within the N.Acc. produced extinction of cocaine, but not heroin, self-administration. Opiate receptor blockade with systemic naloxone increased heroin, but not cocaine, self-administration. Methylnaloxonium injections into the N.Acc. were effective in increasing heroin self-administration at doses one-eighth those observed for intracerebroventricular injections. Reinforcement has been explored using a place-preference procedure and a self-administration drug-substitution paradigm. Mu/delta agonists such as B-END readily produce a naloxone-reversible place preference. Fentanyl derivatives also produce place preference and substitute for heroin during self-administration. The kappa agonist U50-488 produces place aversion, not place preference, and does not readily substitute for heroin. Altogether, these results suggest that mu/delta receptor subtypes in the region of the N.Acc. may be an important neurochemical substrate for opiate reinforcement.

Animals↗

PubMed1985

Locomotor behavior following kindling in three different brain sites.

Spontaneous and drug-induced interictal and post-ictal locomotor behavior of rats was investigated following electrical 'kindling' of different limbic structures at 3 brain sites which differ in the relative amount of innervation from dopamine cells of the ventral tegmentum: nucleus accumbens (N.Acc.), amygdala (AMYG), and dorsal hippocampus (DHPC). Kindling produced decreases in spontaneous post-ictal locomotion that did not appear to depend on the site of stimulation, but produced region specific attenuations in spontaneous interictal behavior as well as amphetamine-induced interictal and post-ictal responses. The most dramatic decreases were seen in N.Acc. kindled animals and the least dramatic were seen in rats kindled via DHPC. These data suggest that the mesolimbic dopamine system may participate in the changes in locomotion seen following kindled seizures, and may also provide a model for the study of human post-ictal and interictal behavior.

Amphetamine↗

PubMed1985

Blockade of nucleus accumbens opiate receptors attenuates intravenous heroin reward in the rat.

A quaternary derivative of naloxone, methyl naloxonium chloride (MN), was administered intracerebrally to rats trained to self-administer heroin intravenously. Increases in intravenous (IV) heroin self-administration rates were found following injections of low doses of MN into the nucleus accumbens (N.Acc), but not following injections of low doses of MN into the ventral tegmental area (VTA). These results were interpreted to suggest that the rewarding properties of IV heroin were decreased following N.Acc opiate receptor blockade. The relative insensitivity of the VTA to MN treatment was taken to suggest that VTA opiate receptors are either not essential or play a secondary role in mediating IV heroin self-administration. The present data support the notion that post-synaptic N.Acc opiate receptors play a crucial role in maintaining IV heroin self-administration.

Animals↗

PubMed1985

Chlordiazepoxide attenuates response suppression induced by corticotropin-releasing factor in the conflict test.

The role of corticotropin-releasing factor (CRF) in mediating the stress response was studied using a behavioral test in which anxiety or conflict influence performance. Rats implanted with intraventricular cannulae were tested in a Geller-Seifter conflict test modified for incremental shock. CRF produced a dose-dependent attenuation of punished and nonpunished responding in the conflict test. Chlordiazepoxide increased punished, but not unpunished, responding and produced a dose-dependent reversal of CRF-induced response suppression. CRF had no effect on tail flick or hot-plate analgesia tests. The results support the hypothesis that CRF produces behavioral effects consistent with "anxiety" or an increased responsiveness to stress.

Analgesics↗

PubMed1985

EEG effects of subcutaneous and intracerebroventricular injections of arginine vasopressin in the rat.

Several studies have suggested that arginine vasopressin (AVP) may act centrally as a neurohormone or neuromodulator to produce electrophysiological and behavioral effects. However, there are few reports of EEG effects of AVP in unanesthetized, behaving animals. In the present study the EEG effects of "behaviorally relevant" subcutaneous (SC) doses of AVP (6 micrograms/kg) known to raise blood pressure were compared to "behaviorally relevant" intracerebroventricular (ICV) doses (0.1-1.0 ng) and multiple "toxic" ICV doses (1.0 microgram) of AVP. Central injections of toxic doses of AVP produced behavioral arrest, bodily barrel rolling, and EEG slowing, but did not induce electrographic signs of seizure activity. Comparison of the spectral characteristics of the EEG revealed some similarities in the distribution of power between SC and the 1.0 ng ICV dose; whereas ICV doses of 0.1 and 0.5 ng produced power distributions that were different from those seen following saline or SC doses of AVP. The similarities in EEG activity between SC injections and the 1.0 ng ICV dose suggest a common brain state may be induced by the two routes of administration in those dose ranges.

Animals↗

PubMed1985

Low doses of methylnaloxonium in the nucleus accumbens antagonize hyperactivity induced by heroin in the rat.

The effect of microinjection of a quaternary opiate antagonist methylnaloxonium (MN) in the lateral ventricle, ventral tegmental area (VTA) and nucleus accumbens (N.Acc.) was examined on the locomotor activation produced by a subcutaneous heroin injection (0.5 mg/kg) in the rat. At this dose heroin typically produced an initial depressant phase (0-30 min) followed by a prolonged hyperactivity (40-120 min). Lateral ventricular injections did not significantly reverse the initial depressant effects of heroin (0-30 min), and a dose of 4 micrograms was needed to reverse the subsequent hyperactivity (40-120 min). The most potent blockade was observed following injections into the N.Acc. where 0.1 microgram significantly reversed the initial depressant effects of heroin (0-30 min), and 0.25 microgram significantly reversed the subsequent hyperactivity (40-120 min). In the VTA, MN had the weakest effects, failing to reverse significantly the initial depressant effects of heroin (0-30 min), and only attenuating the subsequent hyperactivity at the highest doses. It is suggested that certain opiates act on the mesolimbic dopaminergic pathway at the level of the cell bodies in the VTA, but more critically in the N.Acc., possibly on opiate receptors postsynaptic to the dopamine neurons.

Animals↗

PubMed1985

Effects of intracerebroventricular administration of methyl naloxonium chloride on heroin self-administration in the rat.

A quaternary derivative of naloxone, methyl naloxonium chloride (MN), was administered intracerebroventricularly (ICV) to rats trained to self-administer heroin intravenously. MN produced a dose-dependent (0.5-4.0 micrograms) increase in responding for heroin. Since MN is unlikely to reach the peripheral circulation in these doses, these results were viewed as strongly supporting the hypothesis that central opiate receptors are solely responsible for mediating the reinforcing properties of heroin during self-administration. In addition, the present study suggests that intracerebral MN injections may prove to be a useful technique in the search for central substrates of heroin reward.

Animals↗

PubMed1985

Effects of naloxone on heroin-, amphetamine- and caffeine-stimulated locomotor activity in the rat.

We investigated the effects of naloxone on the locomotor activating properties of heroin (0.25 mg/kg SC), d-amphetamine (0.25 mg/kg SC) and caffeine (7.5 mg/kg SC). Naloxone eliminated heroin-stimulated locomotion at doses approximately six times lower than those that blocked amphetamine-stimulated locomotion. Caffeine-induced locomotor activation was insensitive to naloxone at all doses tested. These results suggest that central opiate systems are differentially involved in the behavioral activation produced by heroin, amphetamine and caffeine.

Amphetamine↗

PubMed1985

Separate neural substrates of the locomotor-activating properties of amphetamine, heroin, caffeine and corticotropin releasing factor (CRF) in the rat.

Destruction of dopamine terminals within the nucleus accumbens (N.Acc.) with 6-hydroxydopamine blocked the locomotor activating properties of d-amphetamine, but not caffeine or corticotropin-releasing factor (CRF). Infusion of muscimol into the region of nucleus accumbens efferent terminals in the substantia innominata and lateral preoptic region (SI/LPO) blocked amphetamine-, but not caffeine- or CRF-stimulated locomotion. These muscimol infusions also blocked heroin-stimulated locomotion. These results suggest that amphetamine, acting through a process dependent on N.Acc. dopamine transmission, stimulates locomotion by decreasing GABAergic activity within this N.Acc.-SI/LPO projection; heroin, known to act through a process dependent on N.Acc. opiate receptor activation, also stimulates locomotion by decreasing GABAergic activity within the SI/LPO; caffeine and CRF produce their activation through different neural substrates.

Amphetamine↗

PubMed1985

Vasopressin pressor antagonist injected centrally reverses behavioral effects of peripheral injection of vasopressin, but only at doses that reverse increase in blood pressure.

Previous work in rats (Ader, R. and De Wied, D., Psychon. Sci., 29 (1972) 46-48) has established that subcutaneously (s.c.) injected arginine vasopressin (AVP) prolongs extinction of active avoidance and that this effect could be prevented by pretreatment with the vasopressin antagonist analog [1-deaminopenicillamine, 2-(O-methyl)tyrosine]-beta-arginine vasopressin (dPtyr(Me)AVP). The purpose of the present study was to determine if peripherally administered AVP acts via a peripheral blood pressure effect or by a direct action in the central nervous system. We therefore tested the effects of the antagonist injected intracerebroventricularly (i.c.v.) on the prolongation of active avoidance and on blood pressure effects of s.c. injected AVP. The antagonist (i.c.v.) blocked the behavioral effects of systemically injected AVP only at dose sufficient to block the peripherally mediated pressor response of systemically administered AVP. The results show that peripherally injected AVP acts on peripheral systems and support our hypothesis that the peripheral visceral action of AVP contributed significantly to its behavioral action.

Animals↗

PubMed1985

The effects of chronic lithium on the EEG and locomotor response to drug challenge in rats.

Adult male Wistar rats were given lithium as a dietary supplement or a control diet for a period of eight weeks. Spectral analysis of cortical EEG activity revealed a significant shift in the amplitude and variance of the theta rhythm in rats administered lithium. A significant increase in the locomotor response to morphine over time but not to saline or caffeine was seen in lithium treated rats as compared to controls. The modulation of the locomotor response to morphine seen following lithium administration suggests the possibility that modification of a brain opioid system may contribute to the clinical response to lithium.

Animals↗

PubMed1985

Arginine vasopressin, stress, and memory.

Arginine vasopressin (AVP) has been shown to have several non-renal actions including the potentiation of learned avoidance behavior in rats and improvement in cognitive functioning in humans. Research in our laboratory has confirmed these behavioral effects in rats using both peripheral and central injection of AVP. We have begun to examine the physiological basis for these effects. Peripheral administration of a vasopressor AVP antagonist reversed the prolongation of extinction produced by peripherally administered AVP in both active and passive avoidance, but also reversed the aversive unconditioned effects of AVP. However, central administration of the vasopressor AVP antagonist reversed peripheral effects of AVP only at doses shown to act peripherally to reverse vasopressor effects of AVP. An osmotic stress in doses known to liberate endogenous AVP mimicked the behavioral effects of exogenously administered AVP, and this stress effect was reversed by the AVP antagonist. These results support our hypothesis of separate but parallel AVP systems in the pituitary and brain with a role in behavioral adaptation to certain types of stress.

Animals↗

PubMed1985

Corticotropin-releasing factor and behavior.

Corticotropin-releasing factor (CRF) has behavioral activating effects when injected intracerebroventricularly in rats. CRF dose-dependently increased activity in a familiar photocell cage environment. This activation persisted after hypophysectomy, opiate receptor blockade, and low-dose dopamine receptor blockade, which suggests a unique mechanism of action. CRF also improved acquisition of a visual discrimination task. In aversive situations such as an open field test CRF produced behavioral changes consistent with increased emotionality. These results suggest that CRF liberated directly into the central nervous system may have a neurotropic action important for mobilizing behavioral responses to stress.

Amygdala↗

PubMed1985

Stimulant and anxiogenic effects of corticotropin releasing factor.

Corticotropin releasing factor (CRF) injected intracerebroventricularly in doses from 15-150 pmoles (10-1000 nanograms) produced a prolonged locomotor activation in rats previously habituated to a test cage environment. This CRF activation persisted following hypophysectomy, opiate-receptor blockade and low dose dopamine receptor blockade suggesting a unique mechanism of action. In aversive, stressful situations such as a novel open field test and an operant conflict test CRF produced behavioral changes consistent with increased "emotionality." In the rat conflict test, this "anxiogenic" effect of CRF could be reversed by low doses of the anti-anxiety drug chlordiazepoxide. These results suggest that CRF liberated directly into the central nervous system may have an endocoid action important for mobilizing behavioral responses to stress.

Animals↗

PubMed1985

Effects of chronic dietary lithium on behavioral indices of dopamine denervation supersensitivity in the rat.

The present study was designed to test the hypothesis that chronic lithium (Li) treatment could alter the behavioral manifestations of dopamine (DA) denervation supersensitivity. Rats were maintained on a Li diet continuously for 4 weeks before and 4 weeks after bilateral chemical denervation of DA terminal fields in the nucleus accumbens (N.Acc.) and the caudate nucleus (CN). We examined the behavioral responses of these animals to apomorphine (0.1 mg/kg s.c.) treatment 2 and 4 weeks postdenervation. Animals exposed to similar chemical denervation but maintained on a control diet exhibited well-documented "supersensitive" behavioral responses to apomorphine: N.Acc. denervated animals demonstrated increases in ambulatory sniffing, rearing and locomotor activity; CN-denervated animals demonstrated increases in rearing and focused sniffing in one location but no increases in locomotor activity. Compared to these control-fed animals, Li-diet animals receiving either CN- or N.Acc-denervation demonstrated a significantly decreased "supersensitive" behavioral response to apomorphine. N.Acc.-denervated animals receiving Li showed less apomorphine-induced locomotor activity. CN-denervated animals receiving Li showed less focused behavior which became evident as actual increases in locomotor activity after apomorphine. These results suggest that chronic dietary Li modifies postsynaptic mechanisms to suppress elements of the behavioral manifestations of supersensitive mesolimbic and nigrostriatal DA activity.

Animals↗