Biomedical subjects

L Kokkinidis

Publications and source records attributed to L Kokkinidis.

At least 37 records · Page 2Linked to original sources

PubMed1993

Amphetamine and antidepressant drug effects on GABA- and NMDA-related seizures.

Research has shown a synergistic relationship between amphetamine sensitization and limbic system kindling. To explore the role of GABA and NMDA receptor activity in modulating the positive effects of amphetamine on epileptogenesis, alterations in GABA- and NMDA-related convulsions were examined after acute and chronic amphetamine administration. A single injection of d-amphetamine (7.5 mg/kg) significantly decreased latencies to generalized motor seizures induced 12 h later by the noncompetitive GABAA receptor antagonist picrotoxin (10 mg/kg). The increased sensitivity to clonus was specific to acute amphetamine treatment and was not evident following withdrawal from chronic drug exposure. Seizures induced by NMDLA (1,000 mg/kg), on the other hand, were not modified by acute amphetamine injection; however, the latency to clonus was reduced substantially after NMDLA injection to mice chronically preexposed to amphetamine. The short- and long-term amphetamine effects on GABA- and NMDA-associated convulsive activity were not paralleled by similar drug treatment schedules involving acute (20 mg/kg) and chronic administration of desipramine, zimelidine, and buproprion. These results suggest that amphetamine may be acting on inhibitory and excitatory amino acid systems independently of its monoaminergic properties. The implications of these findings were discussed in relation to amphetamine sensitization of mesolimbic functioning.

Amphetamine↗

PubMed1993

The effects of amygdaloid stimulation on amphetamine-elicited locomotor sensitization.

Systemic injection of d-amphetamine (1.0 mg/kg) resulted in a progressive increase in locomotor activity as a function of repeated daily drug administration. The magnitude of the stimulant-induced sensitization effect was enhanced by low-current electrical stimulation of the central nucleus of the amygdala during open-field testing. Amygdaloid stimulation in the absence of amphetamine treatment did not influence spontaneous locomotor activity, and there was no behavioral evidence of epileptogenesis following amygdaloid stimulation over the course of the experiment. However, with continued stimulation of the amygdala, early-stage convulsive activity was apparent in animals after approximately 40 days of testing, signifying the advancement of kindling evolution. These results suggest that the processes responsible for kindling acquisition, prior to the behavioral expression of epileptiform events, interact with the underlying substrates of amphetamine sensitization.

Amygdala↗

PubMed1992

Scopolamine increases nonreinforced behavior in an intracranial self-stimulation discrimination paradigm.

The effects of several doses of systemic scopolamine administration on brain-stimulation reward from the A10 nucleus of the ventral tegmental area (VTA) were evaluated. The intracranial self-stimulation (ICSS) task involved a two-hole nose-poke procedure allowing for the assessment of both reinforced (correct) and nonreinforced (incorrect) performance levels as a function of varying current intensities. Scopolamine (0.75, 1.5, and 3.0 mg/kg) was found not to alter the rate-intensity functions derived from descending and ascending presentation of seven current levels. However, when nonreinforced behavior was considered significant increases in error responding were evident following scopolamine injection. These results are consistent with the known disinhibitory and perseverative properties of scopolamine, and indicate that the previously reported positive actions of peripheral administration of anticholinergic drugs on ICSS likely involved a drug-induced rate-enhancement of reward-unrelated performance variables.

Animals↗

PubMed1992

Long-term influence of d-amphetamine on mesolimbic brain-stimulation reward: comparison to chronic haloperidol and naloxone effects.

Rate-intensity functions for brain-stimulation reward from the dopamine (DA) A10 cell region of the ventral tegmental area (VTA) were assessed following chronic exposure to d-amphetamine (10.0 mg/kg), haloperidol (1.0 mg/kg), and naloxone (20.0 mg/kg). A reward depression developed when animals were tested daily 24 h following injection of amphetamine and haloperidol. In the case of amphetamine, this effect was transitory and a full recovery of intracranial self-stimulation (ICSS) was evident 5 days after drug abstinence. Low-dose (0.5 mg/kg) amphetamine challenge administered 50 days postdrug treatment decreased current thresholds indicating a long-lasting sensitization of mesolimbic reward processes. The reward depression induced by chronic haloperidol exposure showed no signs of recovery during the abstinence period and ICSS rates remained significantly reduced after amphetamine challenge 50 days later. These behavioral observations suggest that under conditions of continued demand the functional aspects of neuroleptic-induced depolarization inactivation of VTA neurons are enduring. Chronic exposure to naloxone did not modify reward thresholds indicating that opioid hypoactivity may not be a factor in the ICSS depression induced by long-term amphetamine and haloperidol treatment. These data were related to the possibility that stimulant-induced sensitization of motivational processes may evolve as a compensatory response to the transitory development of withdrawal depression.

Animals↗

PubMed1991

The effects of amphetamine preexposure on electrical kindling of the hippocampus and related transfer phenomena.

Earlier research has established that repeated amphetamine administration can interact synergistically with the processes responsible for the genesis of kindled seizures after intermittent electrical stimulation of the amygdala. In this study, the effects of amphetamine preexposure on primary hippocampal kindling, secondary kindling of the contralateral amygdala, and rekindling of the original hippocampal focus were evaluated. It was shown that amphetamine treatment did not modify kindling rates when electrodes were situated in the dorsal hippocampus. However, transfer kindling of the contralateral amygdala evolved after fewer afterdischarges, and rekindling of the dorsal hippocampus progressed significantly faster in amphetamine-pretreated animals. The effects of amphetamine on ventral hippocampal kindling were also determined, and it was found that although epileptogenesis developed more rapidly relative to the dorsal region of this structure, kindling rates were not affected by amphetamine preexposure. These results were related to the possibility that the amygdala might have a unique function in the relationship between kindling- and stimulant-induced sensitization effects.

Amphetamine↗

PubMed1991

Amphetamine sensitization and amygdala kindling: pharmacological evaluation of catecholaminergic and cholinergic mechanisms.

Chronic pharmacological experiments were conducted to evaluate the relationship between sensitization induced by repeated administration of amphetamine (AMPH) and electrical stimulation of the amygdala. While AMPH withdrawal did not influence the kindling process, AMPH administered during the kindling procedure increased the rate at which seizures evolved, and under these conditions withdrawal from chronic AMPH further facilitated the propensity to kindle. Haloperidol (HAL) treatment failed to block the stimulant-induced increase in kindling acquisition indicating that changes in dopamine (DA) are not necessary for the AMPH/kindling synergism to develop. Scopolamine dose-dependently retarded kindling evolution irrespective of prior AMPH pretreatment also ruling out a cholinergic mechanism in the kindling sensitization. Subsequent experiments assessed the interactive effects of AMPH and desipramine (DMI) on the kindling process. Animals chronically exposed to AMPH and switched to DMI treatment during the kindling procedure kindled faster than control subjects. In addition, withdrawal from DMI preexposure advanced the AMPH-induced increase in kindling rate. These results were discussed in terms of the role of norepinephrine-mediated inhibition of the kindling process, and were related to drug-elicited alterations in beta-adrenergic receptor functioning. Taken together, these findings implicate the amygdala as an important structure in the development of non-DA forms of AMPH sensitization.

Acetylcholine↗

PubMed1991

Sensitization of mesolimbic brain stimulation reward after electrical kindling of the amygdala.

The effects of partial kindling of the central amygdaloid nucleus on brain stimulation reward were evaluated. Intracranial self-stimulation (ICSS) rate intensity functions were determined using a two-hole nose-poke discrimination paradigm in rats implanted with electrodes in the A10 dopamine (DA) neuronal region of the ventral tegmental area (VTA), and in the medial forebrain bundle (MFB) at the level of the lateral hypothalamus. The kindling process did not influence ICSS baseline rates from either site. However, following stage 4 kindling, a low dose amphetamine challenge increased ICSS, resulted in a significant shift to the left of the rate intensity functions, and decreased reward thresholds. Analysis of the error scores which consisted of nonreinforced responses made during ICSS testing revealed that the interaction between kindling and amphetamine on ICSS was specific to changes in central reward processes, and could not be attributed to the influence of rate-enhancing performance variables. The kindling-elicited sensitization of mesolimbic DA reward functioning seen after amphetamine challenge was discussed in relation to the role of the central amygdala in the integration of stimulus-reward associations, and in the conditioning of affective emotional states.

Amphetamine↗

PubMed1990

Behavioral evidence implicating dopamine in sensorimotor arousal and norepinephrine in the sedative effects of antidepressant drugs.

The effects of acute and chronic antidepressant treatment on acoustic startle were evaluated in three experiments. Administration of 2.5-10.0 mg/kg desipramine, amitriptyline, and nortriptyline depressed acoustic startle responding after repeated sensory stimulation. In contrast to the tricyclic drugs, the serotonin reuptake inhibitor zimelidine increased acoustic startle, and inhibition of dopamine reuptake following acute nomifensine and bupropion administration did not influence startle reactivity in the doses examined. The response reducing effects of desipramine and amitriptyline persisted following chronic exposure to these drugs, and these findings were discussed in relation to the inhibitory actions of the tricyclics on locus coeruleus neurons. A second major finding in this study was that animals challenged with d-amphetamine during desipramine and amitriptyline withdrawal showed a facilitated startle response. Enhanced startle reactivity to amphetamine was also observed following long-term exposure to iprindole, and a withdrawal hyperactivity of acoustic startle was evident after chronic treatment with amoxapine, bupropion, and nomifensine. These results agree with evidence that repeated administration of antidepressants increases dopamine neurotransmission which modulates sensorimotor arousal.

Acoustic Stimulation↗

PubMed1990

Postcocaine depression and sensitization of brain-stimulation reward: analysis of reinforcement and performance effects.

The effects of acute and chronic cocaine administration on intracranial self-stimulation (ICSS) were evaluated in a two-hole nose-poke discrimination paradigm. Analysis of ICSS rates as a function of current intensity revealed that cocaine increased rates of responding in a dose-dependent manner (5.0-20.0 mg/kg), resulted in a shift to the left of the rate-intensity function, and decreased thresholds for half-maximal responding. Brain-stimulation reward was modified by chronic exposure to cocaine, however, the direction of change was dependent on the schedule of drug administration. Repeated daily administration of cocaine (40.0 mg/kg) and ICSS testing 24 hr postinjection decreased rates and increased reward thresholds. A response depression was also observed when time-dependent variations in ICSS performance were evaluated after repeated cocaine administration. Using a different chronic cocaine/test schedule (30.0 mg/kg, twice daily), a sensitization of ICSS and decreased reward thresholds developed when rate-intensity functions were determined after 5-day drug intervals. These findings were discussed in terms of the role of dopamine in modulating central reward processes. It was suggested that depressed reward-system functioning might reflect reduced dopamine synthesis following cocaine withdrawal, and the ICSS sensitization was related to long-term compensatory changes in dopamine neurotransmission possibly involving presynpatic mechanisms.

Animals↗

PubMed1989

Alterations in amphetamine-induced locomotor activity and stereotypy after electrical stimulation of the nucleus accumbens and neostriatum.

The exacerbation of the locomotor and stereotypic effects of amphetamine after repeated drug administration is well documented. To elaborate on the involvement of the nigrostriatal and mesolimbic dopamine (DA) systems in modulating behavioral sensitization, locomotor activity and the time spent engaged in repetitive stereotyped behaviors following systemic amphetamine injection were assessed after electrical stimulation of the nucleus accumbens and neostriatum. It was found that exposure to repeated sessions of high frequency, low current stimulation of the anteromedial neostriatum and nucleus accumbens significantly enhanced the locomotor excitation induced by administration of 3.0 mg/kg of amphetamine. Stereotypic behaviors were also modified as a function of electrical stimulation of these brain regions, with the development of a significant decrease in the duration of focused head and body movements corresponding to the facilitated locomotor effects of the drug. Taken together, these data provide additional evidence demonstrating the interdependent relationship between amphetamine-elicited locomotor activity and stereotypy, and were discussed in terms of a functional interaction between mesolimbic and nigrostriatal systems in determining the behavioral profile of amphetamine administration.

Amphetamine↗

PubMed1988

The effects of long-term administration of antidepressant drugs on intracranial self-stimulation responding in rats.

A discrimination procedure employing a two hole nose-poke technique was used to evaluate the effects of chronic administration of desipramine, amitriptyline, bupropion, nomifensine and zimelidine on intracranial self-stimulation (ICSS). Analysis of ICSS as a function of descending and ascending current presentation revealed that long-term exposure to desipramine significantly facilitated rates of responding from the medial forebrain bundle, and resulted in a shift to the left of the rate-intensity functions. The use of a discrimination paradigm allowed for the assessment of incorrect responses which proved to be a sensitive measure of the motor activating properties associated with electrical brain stimulation. These data indicated that the positive reinforcing effects of desipramine were not accompanied by concomitant increases in motor arousal. No changes in ICSS responding were evident after long-term treatment with amitriptyline, or the atypical antidepressants, bupropion, nomifensine and zimelidine. The implications of these findings were discussed in terms of the effects of these drugs on reward processes and the role of dopamine in the therapeutic efficacy of antidepressant drugs.

Animals↗

PubMed1987

Evidence for a relationship between amphetamine sensitization and electrical kindling of the amygdala.

Several schedules of long-term amphetamine administration were evaluated on the development of kindling from the amygdala. Consistent with earlier work involving the effects of chronic exposure to stimulant drugs, withdrawal from chronic amphetamine treatment had little or no effect on kindling. Facilitation of kindling was observed, however, under several schedules of drug treatment. The synergism between amphetamine and kindling was evident during drug schedules in which animals were maintained on drug treatment during the kindling procedure. Under these conditions, the facilitating effects of repeated amphetamine treatment varied as a function of prior experience with the drug. Our findings indicate a relationship between processes involved in amphetamine sensitization and kindling. These data have implications in relation to behavioral observations involving the development of postamphetamine depression during drug withdrawal, and amphetamine sensitization after drug challenge.

Amygdala↗

PubMed1987

Amphetamine-elicited perseverative and rotational behavior: evaluation of directional preference.

Four experiments examined the effects of d-amphetamine on lateralized direction preference, circling behavior, and perseveration. The nature as well as the magnitude of the behavioral response to amphetamine was dependent upon the testing situation. Whereas 5.0-10.0 mg/kg of the drug induced a robust circling behavior in a circular alleyway, it required 10.0 mg/kg of amphetamine to produce a significant turn preference in an open field exploratory situation. In a symmetrical Y-maze, mice displayed spontaneous alternation behavior characterized by an exploratory pattern involving different arm sequences. After amphetamine administration, spontaneous alternation was reduced and pronounced perseverative patterns of exploration were evident at dose levels similar to those that induced rotational behavior. Directional preferences could not account for the exploratory patterns in the Y-maze of animals in the undrugged state, or under the influence of amphetamine regardless of dose. Since lateralized motor asymmetries after amphetamine were limited by the behavioral context in which the effects of the drug were evaluated, it was argued that rotational behavior cannot be considered to be a simple mechanistic behavior. Rather, in addition to the expression of a side preference, it involves a drug-induced perseverative tendency. On the basis of these data, it was suggested that evaluation of the direction of turning in an open field is a less biased measure of spatial preference following amphetamine administration. It was further argued that perseverative behavior is a prepotent response to amphetamine and the possibility of lateralized attentional asymmetries was discussed.

Animals↗

PubMed1986

Amphetamine withdrawal: a behavioral evaluation.

The effects of withdrawal from long-term amphetamine treatment of intracranial self-stimulation, forced swim-induced immobility, shuttle escape performance, acoustic startle and locomotor activity were evaluated. Mice implanted with stimulating electrodes in the lateral hypothalamus demonstrated stable and reliable rates of self-stimulation responding. After exposure to a chronic schedule of amphetamine treatment response rates were severely depressed. In addition to modifying intracranial self-stimulation responding, amphetamine withdrawal increased the duration of immobility in a forced-swim situation. Although chronic amphetamine exposure induced pronounced behavioral changes in the intracranial self-stimulation and forced swim tasks, drug withdrawal had little effect on shuttle escape performance, acoustic startle and locomotor activity. Based on these findings it was suggested that the development of post-amphetamine depression in the self-stimulation and forced swim paradigms was not related to variations in motoric or arousal mechanisms resulting from amphetamine withdrawal, but rather involved drug-induced changes in motivational processes.

Acoustic Stimulation↗

PubMed1986

Sensitization to amphetamine and tolerance to cocaine and phencyclidine stimulation in mice.

Amphetamine (1.0-7.0 mg/kg), cocaine (5.0-40.0 mg/kg) and phencyclidine (1.0-7.0 mg/kg) increased acoustic startle responding in mice. These drugs, however, had varying effects on habituation of the startle response after repeated exposure to the auditory stimulus. The primary effect of phencyclidine was to disrupt the habituation process, whereas increased startle responding after cocaine developed without modification of the habituation curve. Amphetamine facilitated acoustic startle at all doses, and after administration of 3.0 mg/kg a significant response sensitization as a function of repeated stimulus presentation was evident. Consistent with previous reports the excitatory effects of cocaine and amphetamine on acoustic startle were blocked by pretreatment with haloperidol. Haloperidol, which decreased startle responding, attenuated the facilitating effects of PCP on acoustic startle as well. Chronic exposure to amphetamine, cocaine and phencyclidine had differential effects on startle responding. The facilitating effects of amphetamine on startle were further enhanced after long-term exposure to the drug and the sensitizing effect of repeated amphetamine exposure was observed only when animals were tested with amphetamine. In contrast, tolerance developed after chronic exposure to both cocaine and phencyclidine, and the response attenuation was evident when animals were tested for acoustic startle after cocaine, amphetamine and phencyclidine.

Animals↗

PubMed1984

Effects of chronic intermittent and continuous amphetamine administration on acoustic startle.

Acoustic startle was evaluated after mice were exposed to two different schedules of long-term amphetamine treatment. Under one schedule, mice received two daily subcutaneous injections of d-amphetamine for 7 consecutive days, whereas the other consisted of continuous administration of amphetamine via a subcutaneously implanted minipump. The enhanced acoustic startle observed after a test dose of d-amphetamine (3.0 mg/kg) was further facilitated when animals were exposed to long-term intermittent amphetamine administration. In contrast, the enhanced startle response to amphetamine was attenuated when mice received chronic continuous exposure to amphetamine. Possible behavioral and neurochemical mechanisms that may be involved in the development of tolerance after continuous amphetamine administration, and reverse tolerance after intermittent amphetamine treatment were discussed.

Acoustic Stimulation↗

PubMed1983

Attenuation of perseverative behavior after repeated amphetamine treatment: tolerance or attentional deficits?

When permitted to explore an 8-arm radial maze, animals exhibited a systematic pattern of exploration characterized by preference for the most novel arms (spontaneous alternation) and entry into immediately adjacent arms (adjacent alternation). Acute treatment with moderate dosages of amphetamine reduced the proportion of both types of alternation responses and induced marked stimulus perseverance, i.e., consecutive entries between pairs of arms. Prior exposure to the apparatus enhanced the degree of perseverance ordinarily observed, and provoked perseverance after low doses of the drug. In contrast to acute drug treatment, perseverance was reduced after chronic amphetamine administration. However, chronic amphetamine treatment did not appear simply to reduce the potency of the drug. In contrast to the effects of apparatus pre-exposure on the degree of perseverance induced by acute amphetamine treatment, the degree of perseverance was not enhanced by pre-exposure to the maze in mice with a history of chronic amphetamine administration. Moreover, the exploratory pattern evident in chronically treated animals differed from that of control animals even when tested in the nondrug state. That is, animals chronically treated with amphetamine and tested with saline exhibited alternation scores which did not deviate from chance. These data suggest that chronic amphetamine treatment alters the way in which organisms attend, or respond, to environmental stimuli.

Amphetamine↗

PubMed1983

The effects of chronic amphetamine administration on the acquisition and extinction of an active and passive avoidance response in mice.

Long-term amphetamine treatment had no effect on the acquisition or retention of an active or passive avoidance response. In both tasks, however, mice withdrawn from chronic amphetamine administration showed a resistance to extinction relative to control animals. These findings were related to the effects of long-term amphetamine administration on attentional processes. Possible neurochemical mechanisms governing the attentional deficits induced by chronic exposure to amphetamine were discussed.

Animals↗