The effects of cocaine, amphetamine, and the dopamine D1 receptor agonist SKF 38393 on fear extinction as measured with potentiated startle: implications for psychomotor stimulant psychosis.

Using Pavlovian conditioned increases in the amplitude of the acoustic startle reflex as a behavioral indicator of fear motivation, the authors previously showed a resistance to extinction after repeated associations of cocaine with the fear-evoking conditioned stimulus (CS). In Experiment 1, acute administration of cocaine, amphetamine, and the dopamine (DA) D1 receptor agonist SKF 38393 produced a similar fear enhancement. In Experiment 2, a noncontingent injection of cocaine and SKF 38393 provoked a CS potentiation of acoustic startle in fear-extinguished laboratory rats. Potential behavioral, neurochemical, and neuroendocrine explanations for the effects of psychomotor stimulants on conditional fear were discussed. It was suggested that DA agonist drugs increase fear expression possibly by activating mesoamygdaloid associative neurocircuitry involved in excitatory conditioned fear reactions.

Contribution of ventral tegmental area dopamine neurons to expression of conditional fear: effects of electrical stimulation, excitotoxin lesions, and quinpirole infusion on potentiated startle in rats.

Potentiated startle was used in this study to determine the fear-motivational functions of the ventral tegmental area (VTA). In Experiment 1, electrical stimulation of the VTA increased acoustic startle amplitudes. In subsequent experiments fear-potentiated startle was assessed following axon-sparing N-methyl-D-aspartic acid (NMDA) lesions of the VTA and after bilateral intra-VTA infusion of the dopamine (DA) D2/3 receptor agonist quinpirole. The NMDA lesions produced substantial cell loss in the medial ventral tegmentum and suppressed fear expression. Similarly, inhibition of DA neuronal activity associated with locally administered quinpirole blocked fear-potentiated startle. It was suggested that VTA neurons and their forebrain DA projections regulate levels of aversive emotional arousal within the amygdala-based fear system.

Cocaine preexposure sensitizes conditioned fear in a potentiated acoustic startle paradigm.

The consequences of chronic cocaine administration on fear-potentiated startle were evaluated in two experiments. Cocaine treatment (40 mg/kg) for 7 days prior to fear acquisition (light + shock pairings) had an attenuating influence on the ability of the conditioned stimulus (CS) to increase acoustic startle. When cocaine was administered in the context of the CS, following fear conditioning, a marked enhancement of potentiated startle was observed. In contrast, an extinction of the fear response was seen in saline and procaine animals repeatedly exposed to the nonreinforced CS. The results from control subjects injected with cocaine either in the shock chambers (contextual cues) or in their home cage environment, suggest that the systemic effects of this stimulant served to intensify the fear-eliciting properties acquired by the CS during fear conditioning. These findings demonstrate a cocaine sensitization of conditioned fear, and were related to the emotional and psychological disturbances associated with long-term cocaine use.

Effects of scopolamine on the rewarding and seizure-inducing properties of amygdaloid stimulation.

The relationship between amygdaloid brain-stimulation reward and the evolution of seizure activity was evaluated in this study. Current levels that maintained optimal intracranial self-stimulation (ICSS) rates were found to be lower than the minimal current intensity required to elicit an afterdischarge (AD) from the central nucleus of the amygdala. After the ICSS session, AD thresholds (ADTs) were reduced to the same levels of current used to support ICSS. Assessment of seizure stage development during ICSS testing revealed that the emergence of early-stage epileptiform events following repeated amygdaloid stimulation suppressed ICSS performance. While administration of the antimuscarinic scopolamine did not prevent the stimulation-elicited reduction in AD thresholds, it was observed to inhibit seizure progression and increase ICSS rates. These results are consistent with the excitatory function of acetylcholine in epileptogenesis and were related to the possibility that different mechanisms underlie the rewarding and seizure-inducing properties of amygdaloid stimulation.

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.

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.

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.

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.

The effects of environmental enrichment on voluntary ethanol consumption and stress ulcer formation in rats.

The effects of exposure to an enriched environment on subsequent voluntary ethanol intake and response to restraint stress were examined. Rats at 21 days of age were reared in an enriched environment for 90 days. Non-enriched animals were reared individually in standard laboratory cages. Following an initial 36 day ethanol exposure period, voluntary ethanol (9% v/v) preference was assessed for 10 days. In addition, at the conclusion of the ethanol test session, animals were exposed to restraint stress for a 3 hr period. Results indicate that exposure to an enriched environment produces increased voluntary ethanol consumption as compared to non-enriched controls. Furthermore, animals reared in the enriched environment demonstrated reduced gastric ulcer severity in response to restraint stress. Ethanol per se did not affect ulcer formation.