Amphetamine and morphine may produce acute-withdrawal related hypoactivity by initially activating a common dopamine pathway.

Rats given drugs of abuse such as amphetamine or morphine show longer-term effects, that is, signs of acute withdrawal, including hypoactivity, hypophagia, and blunted affect, sometime between 12 and 24h after treatment. This research explores the possibility that signs of acute withdrawal produced by different drugs of abuse are instigated by overlapping mechanisms. The specific objectives of the research were to see if amphetamine and morphine produced longer-term hypoactivity, and to see if any longer-term hypoactivity elicited by the drugs could be blocked by SCH23390, a dopamine D1 antagonist. Six groups of rats, with eight rats in each group, were exposed to a series of five-day tests. Near light onset of Test Day 1, each animal was given control administrations, consisting of a saline treatment (1.0ml/kg) followed 30m later by a saline posttreatment, and locomotor activity was monitored for the next 24h. On Test Day 3, each animal was given experimental administrations, and locomotor activity was again monitored for 24h. Each group received only one combination of experimental administrations across tests. Experimental administrations consisted of saline, amphetamine (2.0mg/kg), or morphine (5.0mg/kg), followed by saline or SCH23390 (0.05mg/kg). All administrations were subcutaneous. Amphetamine and morphine produced longer-term hypoactivity, having similar time courses and magnitudes. SCH23390 blocked the longer-term hypoactivity produced by both drugs. Saline and SCH23390 produced no changes in longer-term activity in their own right. The time course of amphetamine-elicited longer-term hypoactivity resembled that of amphetamine-elicited longer-term hypophagia observed in a prior study. Approximately 1/4 of the animals given amphetamine or morphine did not show longer-term hypoactivity ("low withdrawal" rats). Amphetamine and morphine may initiate the cascade of events resulting in signs of acute withdrawal by producing activation in a common pathway that uses dopamine as a neurotransmitter. Different signs of acute withdrawal (hypoactivity and hypophagia) may involve the short-term activation of the same common pathway. Low withdrawal rats may have a different vulnerability to amphetamine and may show differences in drug assessment outcomes relative to animals that manifest distinct signs of acute withdrawal.

Acute withdrawal-related hypophagia elicited by amphetamine is attenuated by pretreatment with selective dopamine D1 or D2 receptor antagonists in rats.

After receiving 2.0mg/kg amphetamine, rats show two phases of reduced food intake, short-term hypophagia, during the first several hours after treatment, and longer-term hypophagia, approximately 19 to 26 h after treatment. The longer-term hypophagia may be an indicator of an acute withdrawal. This study assessed whether D1 and D2 receptor activation were important early events in the elicitation of longer-term hypophagia. Throughout a series of five-day tests, rats could lever press for food pellets for one-hour periods beginning every 3h. On test day 1, rats were given a saline pretreatment, and 15 min later they were given a saline treatment. On test day 3, they were given a pretreatment of either saline or a selective dopamine receptor antagonist, and 15 min later they were given a treatment of either saline or amphetamine (2.0mg/kg). In Experiment 1, pretreatments included 3, 12, 31, and 50 µg/kg of the selective D1 receptor antagonist SCH 23390. In Experiment 2, pretreatments included 25, 50, and 100 µg/kg of the selective D2 receptor antagonist eticlopride. Distance moved was monitored for the first 6h following pretreatment-treatment combinations to obtain an indirect behavioral measure of receptor blockade (antagonist attenuation of amphetamine hyperactivity). Food intake at each meal opportunity was monitored throughout each five day test. Patterns of food intake following day 1 saline-saline and day 3 pretreatment-treatment were compared. The combination saline-amphetamine produced short-term and longer-term hypophagia. Combinations involving antagonist-saline did not produce longer-term changes in food intake. Pretreatment with 12 to 50 µg/kg of SCH 23390 produced substantial blockade of amphetamine hyperactivity and prevented amphetamine-induced acute-withdrawal-related longer-term hypophagia. Eticlopride produced a partial blockade of longer-term hypophagia. Both D1 and D2 receptor activation are required for full expression of longer-term hypophagia following amphetamine administration.

The effects of dose and repeated administration on the longer-term hypophagia produced by amphetamine in rats.

Rats are hypophagic approximately 1-3 and 13-27h after receiving amphetamine (2.0mg/kg). This study examined how these short- and longer-term phases of hypophagia were affected by repeated administration of different amphetamine doses. Throughout eight five-day tests, the rats could lever press for food pellets for 1-hour periods beginning every three hours. On test day 1, the rats were treated with saline, and on test day 3, they were treated with a dose of amphetamine. Across tests, for one group, treatment on day 3 alternated between 0.0 (saline) and 0.5mg/kg amphetamine; for a second, group treatment on day 3 alternated between 1.0 and 2.0mg/kg amphetamine; and for a third group, treatment on day 3 was always 1.0mg/kg amphetamine. The patterns of food intake following day 1 saline and day 3 treatment were compared. Short-term food intake was abolished by 0.5, 1.0, and 2.0mg/kg amphetamine, and no tolerance was observed to this effect. Longer-term hypophagia was produced by 1.0 and 2.0 but not by 0.5mg/kg. Tolerance to longer-term hypophagia was seen when 1.0mg/kg alone was used as the day 3 treatment, but not when 1.0 and 2.0mg/kg were alternated across tests as the day 3 treatment. Short- and longer-term hypophagia were dissociated by threshold doses for elicitation and by differential tolerance. Occasional receipt of a higher amphetamine dose may sometimes increase the longer-term hypophagia produced by a lower dose.

Brief exposure to methamphetamine (METH) and phencyclidine (PCP) during late development leads to long-term learning deficits in rats.

Exposure to methamphetamine (METH) and phencyclidine (PCP) during early development is thought to produce later behavioral deficits. We postulated that exposure to METH and PCP during later development would produce similar behavioral deficits, particularly learning deficits in adulthood. Wistar rats were treated with METH (9 mg/kg), PCP (9 mg/kg), or saline during later development, postnatal days (PD) 50-51, and subsequent behavioral changes were examined including: locomotor activity during the acute drug state (PD 50-51) and the post-drug phase (PD 50-80); social interaction on PD 54-80; and spatial discrimination and reversal in adulthood (after PD 90). METH and PCP differentially affected locomotion during the acute state, but not during the post-drug phase. METH decreased social interaction throughout tests two weeks after drug treatment, whereas PCP decreased social interaction only during the first 8 min of tests. Neither METH nor PCP impaired initial acquisition of spatial discrimination. However, reversal was significantly impaired by PCP, whereas METH produced a mild deficit, compared to controls. Our data provide evidence that exposure to PCP and METH during later development lead to enduring cognitive deficits in adulthood. Selective impairment of reversal may reflect neurological damage in the prefrontal cortex due to early exposure to drugs.

Time-dependent effects of amphetamine on feeding in rats.

Following administration of a moderate dose of amphetamine, rats appear to pass through a sequence of physiological/psychological states, including stimulant and depressant states. The present research evaluated whether these states could be inferred from time-dependent changes in feeding-related measures. Male rats were housed in individual stations (light-dark 12-12 h, free access to water) where, at 3-h intervals, they could respond for food for 1 h. The work requirement was fixed ratio 1, and each lever press produced six 94-mg food pellets. When the pattern of responding for food stabilized across the light-dark cycle, a series of 6 or 7 tests was run. During each test, rats received a saline treatment (1.0 ml/kg, subcutaneously) followed by a 48-h monitoring period, and then they received an amphetamine treatment (2.0 mg/kg, subcutaneously) followed by a 72-h monitoring period. Different groups were treated at either light onset or light offset. Lever presses and head-in-feeding-bin responses were monitored throughout these tests. Administration of amphetamine at light onset and at light offset produced cumulative food intake functions having four regions: post-treatment hours 1-6 (hypophagia), 7-12 (normal intake), 13-27 (hypophagia), and 28 and beyond (normal intake). The sequence, duration, and quality of the amphetamine-induced changes in food intake resembled those formerly seen in cue state and activity, and provided further evidence of a transient withdrawal state 20-24 h post-amphetamine treatment.

Amphetamine-induced hyperlocomotion in rats: Hippocampal modulation of the nucleus accumbens.

Using lesions and infusions, the present study investigated the way in which and the extent to which the ventral hippocampus (vHIP) modulates amphetamine-induced hyperactivity in rats. Rats were lesioned (excitotoxic or sham) in the vHIP or were implanted with cannulae for subsequent infusions. A high dose (12.5 microg/microl) of N-methyl-D-aspartate (NMDA) was used to make excitotoxic lesions and a low dose (0.5 microg/microl) of NMDA to cause activation of the hippocampus. Lidocaine was used to inactivate the hippocampus. Lidocaine or a low dose of NMDA was infused into the vHIP in combination with either systemic injection or intra-accumbens infusions of amphetamine. The effects of these treatments on locomotor activity were measured by distance traveled in 10-min intervals for 40-60 min. Lesions and deactivation of the hippocampus attenuated amphetamine-induced hyperlocomotion, compared to the controls. Stimulation of the hippocampus augmented amphetamine-induced hyperlocomotion. The present findings provide evidence that the hippocampus exerts excitatory modulation on the expression of behavioral excitation produced by amphetamine, likely via the nucleus accumbens.

An activity indicator of acute withdrawal depends on amphetamine dose in rats.

A moderate dose of amphetamine (AMPH) produces hypoactivity around 20 h post-administration. This hypoactivity may be an indicator of an acute withdrawal state. The purpose was to see how AMPH doses affected the expression of this hypoactivity and, by inference, AMPH-induced acute withdrawal. Rats were housed in individual open fields, with free access to food and water. Light-dark cycles were scheduled such that drug-elicited patterns could be readily detected. Animals first received a series of eight control treatments, and then a series of 10 experimental treatments spaced at 33-h intervals. Different experimental treatment groups received saline, 1.0 mg/kg, 2.0 mg/kg, or 4.0 mg/kg AMPH. The effects of these treatments on 33-h patterns of locomotor activity were observed. Control treatments produced no systematic time-dependent changes in activity beyond the first hour post-treatment. All doses of AMPH produced typical short-term effects: They markedly increased locomotion and/or stereotypy during the first 3 to 6 h post-treatment. Acute and chronic administrations of the 2.0 and 4.0 mg/kg doses also produced similar changes in longer term activity patterns: They produced hypoactivity 20 h later, followed by a recovery of activity around hour 25 post-treatment. The timing of amphetamine-induced hypoactivity and acute withdrawal may be independent of dose over a wide range of doses. Time-dependent changes in AMPH-induced state may influence motivation and drug-related assessments. The methodology described here may provide an easy and rapid way to investigate the determinants of AMPH-induced hypoactivity and acute withdrawal.

Development of acute withdrawal during periodic administration of amphetamine in rats.

Amphetamine (AMPH) administration appears to produce multiple time-dependent effects during the approximately 24-h period after administration. This study examined the development of these effects. Rats were housed in separate cubicles, had ad-lib access to food and water, and were continuously monitored. After a series of control treatments, different groups received AMPH (1.0 mg/kg ip) at either 33- or 24-h intervals. Light-dark cycles (12-12 h) were "staggered" by 3-h intervals across the rats in each group, so that the effects of AMPH could be readily detected in average activity profiles against the background of light-entrainable activity. Changes in activity indicated that AMPH produced a common sequence of effects on both 33- and 24-h-period schedules: psychomotor stimulation (Hours 1-3 postdrug), withdrawal (activity suppression near Hour 20 postdrug), and recovery (activity increase beginning around Hour 24 postdrug). Withdrawal and recovery effects developed during the first several AMPH administration cycles. These time-dependent changes during the approximately 24-h interval after AMPH administration could reflect changes in motivation and in susceptibility to processes thought to underlie the acquisition of drug abuse (such as the positive and negative reinforcing effects of drug receipt). Short- and long-term responsiveness to drug might then depend on when in the postdrug sequence administrations occur.

NMDA lesions in the medial prefrontal cortex impair the ability to inhibit responses during reversal of a simple spatial discrimination.

Although lesion studies suggest that the rat medial prefrontal cortex (mPFc) is involved in the process necessary for reversal of a particular set of contingencies, the nature of lesion-induced deficits is unclear. The involvement of rat mPFc in reversal of a simple spatial discrimination was examined in the present study. Our hypothesis was that lesion-induced deficits may reflect a failure to inhibit a learned instrumental response. Lister Hooded rats were trained on a spatial discrimination task (SD), which required a correct barpress matching the cue location, then they were trained on reversal of SD (SDR), which required a correct barpress opposite to the cue location. Rats with mPFc lesions showed a slower learning rate compared to the controls. However, behavior of the lesioned rats during early and later reversal differed. During the initial SDR, the lesioned rats showed a greater number of barpresses during the intertrial interval and a slightly higher percent correct responses than that of the controls. Our data suggest that damage to mPFc may produce a lack of response inhibition, leading to an increase in nondiscriminated bapresses, thereby yielding a 'facilitation' during early reversal. mPFc lesion did not affect either open field activity or prepulse inhibition (PPI), a frequently used measure of sensorimotor gating. Disruption of reversal learning following damage to mPFc is partly due to a failure to inhibit instrumental responses, rather than to disruption of other processes involved in sensorimotor gating or general activity.