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Biomedical subjects

A G Phillips

Publications and source records attributed to A G Phillips.

At least 127 records · Page 7Linked to original sources
PubMed1983

Strategies for studying the neurochemical substrates of drug reinforcement in rodents.

Results from three different experimental paradigms for studying drug reinforcement are reviewed. Rate-increasing effects of amphetamine on intracranial self-stimulation are abolished by lesions to ascending dopamine neurons. Rate-increasing effects of intracranial microinjection of opioids on self-stimulation are localized to the vicinity of dopamine cell bodies in the ventral tegmentum. Conditioned reinforcement produced with intracranial microinjection of opioids into the ventral tegmental area is blocked by the dopamine antagonist haloperidol and lesions to ascending dopamine pathways. Intravenous self-administration of cocaine is blocked by intracerebral microinjection of spiroperidol into the nucleus accumbens but not into the caudate nucleus. Ascending dopamine neurons appear to mediate some of the reinforcing properties of both psychomotor stimulants and opioids.

Amphetamine↗
PubMed1983

Low-frequency stimulation of the perforant path produces long-term potentiation in the dentate gyrus of unanesthetized rats.

Brief periods of high-frequency stimulation of hippocampal afferents produce long-term potentiation (LTP) of synaptic transmission, but the minimum frequency capable of inducing this alteration in synaptic efficacy has not been specified. The present study used the repeated measurement of input-output curves in the perforant path - dentate gyrus system of freely moving rats to monitor synaptic efficacy and found that stimulation at 0.2 Hz, but not 0.04 Hz produced LTP. These results suggest that the minimum stimulation frequency capable of producing LTP is lower than previously described. Possible reasons for the discrepancy between the present and previous findings are discussed, along with the implications of low-frequency potentiation.

Action Potentials↗
PubMed1982

Dopaminergic substrates of amphetamine-induced place preference conditioning.

The conditioned place preference paradigm was used to study the reinforcing properties of D-amphetamine. Rats were injected (i.p.) with D-amphetamine sulphate (0.5, 1.0 or 5.0 mg/kg) and 10 min later confined for 30 min to one side of a shuttle box in which each of the two compartments had distinctive features. On alternate (control) days they received saline injections and were confined for 30 min to the opposite side. At all doses D-amphetamine produced place preference for the distinctive compartment that previously had been associated with the drug. Pretreatment with haloperidol (0.15 or 1.0 mg/kg) antagonized the place preference produced by amphetamine (1.5 mg/kg). By itself, haloperidol (0.15 or 1.0 mg/kg) did not produce place aversion. In separate experiments the D-amphetamine-induced place preference was examined in rats that had received 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens. Animals with the greatest depletion of dopamine did not show preference for the compartment associated with D-amphetamine. Furthermore, the time spent on the amphetamine-reinforced side correlated significantly with the levels of dopamine remaining in the nucleus accumbens but not with the dopamine content in the striatum. Depletion of peripheral catecholamines by systemic injections of 6-OHDA did not affect D-amphetamine-induced place preference conditioning. Other groups of animals that received the dopamine receptor agonist, apomorphine, also developed a conditioned preference for the compartment that had been associated with the drug treatment. These findings support the view that the reinforcing effects of D-amphetamine are mediated by central dopamine-containing neurons, and in particular those of the mesolimbic system.

Animals↗
PubMed1982

Cocaine-induced place preference conditioning: lack of effects of neuroleptics and 6-hydroxydopamine lesions.

The conditioned place preference paradigm was used to investigate the reinforcing properties of cocaine. Rats were injected (i.p.) with cocaine hydrochloride (0.625-20 mg/kg) and then immediately confined for 30 min to one side of a shuttle box in which each of the two compartments had distinctive features. On alternate (control) days they received saline injections and were confined for 30 min to the opposite side. Cocaine produced a significant, dose-related preference for the distinctive environment that previously had been paired with the drug. Pretreatment with pimozide (0.5 or 1.0 mg/kg) or haloperidol (1.0 mg/kg), both of which blocked the locomotor stimulant effects of cocaine, failed to influence place preference produced by cocaine (5.0 mg/kg). In addition, neither 6-hydroxydopamine lesions of dopamine terminals in the nucleus accumbens nor 6-hydroxydopamine-induced destruction of central and/or peripheral noradrenergic systems affected cocaine-induced place preference conditioning. In other experiments it was found that injections of the local anaesthetic procaine, at doses that did not affect locomotor activity (25 and 50 mg/kg), also resulted in significant place preference conditioning. It is concluded that cocaine can produce place preference conditioning through a mechanism that is independent of its effects on catecholamine-containing neurons and that may be related to its local anaesthetic properties. It is noted, however, that if cocaine's local anaesthetic properties could be blocked selectively, the drug might still produce place preference conditioning through its enhancement of central dopaminergic function.

Animals↗
PubMed1982

Attenuation by haloperidol of place preference conditioning using food reinforcement.

The place preference conditioning paradigm was used to examine the reinforcing properties of food in hungry rats. Availability of food in one of two distinctive environments increased the amount of time they spent in the environment associated with food in a test when the animals were no longer food deprived and neither environment contained food. Pretreatment with haloperidol (0.1 or 0.2 mg/kg) during the conditioning phase blocked the establishment of place preference even though the animals consumed the food in the drugged state. The results are interpreted as demonstrating a role for dopamine-containing neurons in mediating the reinforcing properties of food.

Animals↗
PubMed1982

Effects of kainic acid lesions of the striatum on self-stimulation in the substantia nigra and ventral tegmental area.

Unilateral kainic acid lesions of the dorsal striatum provided evidence for a dissociation of neural substrates of brain-stimulation reward at sites in the ventral tegmental area and substantia nigra. The lesions caused a significant increase in current intensity thresholds at substantia nigra placements, whereas similar lesions had no effect on self-stimulation thresholds at sites in the ventral tegmentum. In addition, the rate-increasing effects of D-amphetamine (0.1-1.0 mg/kg) on self-stimulation were determined before and after lesions to the dorsal striatum. No significant changes in dose-response curves were observed at either loci. Amphetamine-induced rotation was used to confirm damage to the dorsal striatum and lesioned animals were observed to rotate towards the side of the lesion. In contrast, sham-lesioned animals showed turning away from the side stimulated electrically in previous tests. The results of the self-stimulation and rotation experiments are discussed in the context of neural substrates of reward and motor activity.

Animals↗
PubMed1981

Increased intracranial self-stimulation in rats after long-term administration of desipramine.

The effects of long- and short-term administration of the tricyclic antidepressant desipramine on intracranial self-stimulation in rats were studied with electrodes in the A10 region of the dopamine-containing cell bodies of the ventromedial tegmentum. Long-term desipramine administration resulted in a significant shift to the left in the ascending portion of the rate--current intensity function, indicating that the activity of the mesolimbic dopamine system was enhanced. These findings point to a possible dopaminergic mechanism of action of antidepressants and support speculations concerning the role of dopamine-containing neurons in the pathophysiology of depression.

Animals↗
PubMed1981

Intracerebral self-administration of amphetamine by rhesus monkeys.

Four rhesus monkeys received intracranial implantation of cannulae aimed at the orbitofrontal cortex. Electrical intracranial self-stimulation was obtained readily from insulated electrodes placed temporarily into the orbitofrontal cortex via the outer guide tubes. Subsequently, each subject acquired a panel press operant response to deliver 0.05 microliter of D-amphetamine (10-6 M) into the orbitofrontal cortex via an inner cannula. The rate of panel pressing increased over several daily test sessions and extinguished after substitution of the vehicle solution. One animal responded readily on a fixed ratio-10 schedule. Control injections into the nucleus accumbens and lateral ventricles failed to maintain self-administration behavior.

Animals↗
PubMed1981

The effects of pimozide during pairing on the transfer of classical conditioning to an operant discrimination.

Transfer of classical conditioning to operant learning was demonstrated by showing enhanced acquisition of an operant discrimination in a group of rats (n = 6) previously exposed to pairings of the discriminative stimulus with food as compared to control animals (n = 6). A group (n = 6) that received the classical conditioning sessions while under the influence of the neuroleptic, pimozide (1.0 mg/kg, IP) also showed enhanced acquisition of the discrimination when tested while undrugged but their performance was intermediate between that of the other groups for the first seven sessions. For the remaining sessions, the two groups that had received classical conditioning did not differ from each other and both groups discriminated better than the controls. These data may indicate a role for dopaminergic neurons in the mechanism by which the effects of classical conditioning influence operant responding.

Animals↗
PubMed1981

Disruption of autoshaped responding to a single of brain-stimulation reward by neuroleptic drugs.

Repeated pairing of the onset of a stationary light (CS) that signalled electrical stimulation of brain-stimulation reward sites in the mesencephalon (US) resulted in autoshaped approach behavior to the CS. After acquisition of approach to the CS two groups of rats were injected with either pimozide (0.15, 0.50, or 1.0 mg/kg) or haloperidol (0.05, 0.10, or 0.15 mg/kg) prior to test sessions consisting of 30 CS-US pairings. Both neuroleptic drugs caused a significant dose-related attenuation of the autoshaped CS-approach. A within-session analysis of responding after treatment with the high dose of each drug indicated that most responses occurred in the first 10 trials, a result that appears to rule out a direct effect of the drugs on sensory processes and orientation. The effect of repeated testing with pimozide (1.0 mg/kg) or haloperidol (0.15 mg/kg) was compared to three sessions with CS alone (extinction). Autoshaped CS-approaches declined gradually over the three extinction sessions, in contrast to the immediate and sustained disruption of approaching during the three drug sessions. These data suggest that neuroleptic-induced suppression of autoshaped CS-approach with brain-stimulation reward cannot be attributed solely to a block of reward processes. It is suggested that neuroleptic drugs disrupt neural mechanisms by which signals of impending reward release pre-organized response patterns.

Animals↗
PubMed1981

Differential effects of electrical stimulation of amygdala or caudate on inhibitory shock avoidance: a role for state-dependent learning.

The present study examined the disruptive effects of low-intensity electrical stimulation in the caudate or amygdala on retention of inhibitory shock avoidance. Caudate stimulation administered during a training trial disrupted inhibitory avoidance on a retest trial. However, animals receiving caudate stimulation during both training and retention trials displayed good retention of this behavior and did not differ significantly from implanted controls. These data suggest a role for state-dependent learning in mediating the disruptive effects of caudate stimulation on inhibitory shock avoidance. No evidence was found for state-dependent effects with amygdaloid stimulation. Animals receiving stimulation only during training or during both training and retest trials showed comparable disruption of inhibitory shock avoidance. These data provide evidence for locus-specific state-dependent effects of electrical brain-stimulation. The implications of these state-dependent effects are discussed with respect to the use of electrical brain-stimulation to study the neural substrates of memory.

Amygdala↗
PubMed1981

The acquisition of responding with conditioned reinforcement: effects of cocaine, (+)-amphetamine and pipradrol.

1 A procedure for examining the acquisition of a lever-pressing operant with conditioned reinforcement was used to compare the effects of three psychomotor stimulants. 2 Hungry rats were trained to associated and auditory tone (i.e., conditioned reinforcer) with food. Preference for the tone was then measured after treatment with pipradol (5, 10, 15 mg/kg), cocaine (1, 5, 10 mg/kg) or (+)-amphetamine (0.5, 1.5, 5.0 mg/kg). 3 In agreement with previous data, 10 mg/kg of pipradrol enhanced the effect of conditioned reinforcement whereas animals treated with any of the doses of (+)-amphetamine showed no effect. 4 Rats treated with cocaine (1 or 5 mg/kg) showed an effect of conditioned reinforcement but the effect was not significantly greater than in controls. 5 The present data suggest important differences in enhancement of responding for conditioned reinforcement by various drugs in the psychomotor stimulant class. These differences in turn may be related to the pharmacological actions of these compounds on release of catecholamines from different storage pools.

Animals↗
PubMed1980

The effect of pimozide on the establishment of conditioned reinforcement.

The effect of pimozide on conditioned reinforcement was determined by comparing rate of lever pressing for a tone in groups previously treated with or without the drug when the tone was paired with food. Eight groups of six to eight rats each received three phases of training in a two-lever box. The pre-exposure phase measured the operant rate of pressing the two levers, one of which produced a 3s tone. In the conditioning phase, with the levers absent, the tone was paired with food over four sessions. The test phase again measured the rate of pressing the two levers. In an undrugged experimental group (i.e., Paradigm group), the number of presses on the tone lever significantly increased from the pre-exposure to the test phase, thereby confirming that the procedure could establish conditioned reinforcement. A control group receiving tones and pellets randomly during the conditioning phase also showed conditioned reinforcement but a group receiving negatively correlated tones and pellets did not. Groups receiving the dopamine-receptor blocker pimozide (1.0 mg/kg) prior to each conditioning session failed to show conditioned reinforcement in the test session. Control groups ruled out state dependent learning and drug-induced performance impairments as explanations of this pimozide-related effect. These data may indicate a possible role for dopamine neurons in mediating the control of behavior by certain positive reinforcing stimuli.

Animals↗
PubMed1980

The effects of pipradrol on the acquisitionof responding with conditioned reinforcement: a role for sensory preconditioning.

Previous studies have shown that pipradrol enhances the acquisition of responding with conditioned reinforcement. The present experiments replicated this finding and assessed the possible role of nonspecific stimulus change, feeding in the test environment and prior exposure to the conditioned stimulus. The test procedure consisted of three phases: Operant rates of pressing two levers, one of which produced a 3-s tone, were measured in the pre-exposure phase; the tone was paired with food in the four conditioning sessions; and conditioned reinforcement was demonstrated in the test phase by a relative increase in pressing the tone lever. A group (N = 8) receiving food but no tone during the conditioning phase also increased responding on the tone lever in the test phase and this effect was enhanced in a group (N = 8) receiving pipradrol prior to the test. A group (N = 8) receiving neither tones nor pellets during conditioning and pipradrol prior to test failed to show a change in lever bias, ruling out the possibility that pipradrol produced a nonspecific enhancement of responding for stimulus change. It was hypothesized that the conditioned reinforcement effect seen in the food-alone groups resulted from sensory preconditioning. According to this hypothesis, the tone was conditioned to environmental stimuli during the pre-exposure phase; subsequent presentation of pellets resulted in a learned association between environmental stimuli and food, leading to increased responding for the tone in the test phase. The results of two control experiments supported this view. One group (N = 8) received no tone in the pre-exposure phase, pellets alone in the conditioning phase and then pipradrol prior to test. The second group, but under altered environmental stimulus conditions, and then was given pipradrol prior to test. Neither group showed evidence of conditioned reinforcement. It was concluded that pipradrol enhanced acquisition of responding with conditioned reinforcement even if the conditioned reinforceing stimulus was established with sensory preconditioning procedures.

Acoustic Stimulation↗
PubMed1980

Reinforcing effects of morphine microinjection into the ventral tegmental area.

A neural substrate for the reinforcing property of an opiate drug was identified in the ventral tegmental area (VTA) by establishing conditioned reinforcement to salient environmental stimuli paired with intracerebral microinjections of morphine. Bilateral microinjections of morphine into the VTA in doses of 0.2 microgram and 1.0 microgram produced a subsequent change in place preference to a distinctive compartment previously associated with the stimulant effects of morphine. Microinjection of 1.0 microgram morphine at sites 2.5 mm dorsal to the VTA had no effect. Pretreatment with naloxone (2 mg/kg) antagonized the reinforcing effects of 1.0 microgram morphine as this group showed no significant change in place preference. Nor did control groups receiving microinjections of sterile physiological saline. Taken together, these data suggest that opiate receptors, located in the ventral tegmental area, play an important role in mediating the reinforcing effects of morphine. The possible involvement of dopaminergic neurons in these effects is discussed.

Animals↗