Karen E. Sabol

Reserpine attenuates D-amphetamine and MDMA-induced transmitter release in vivo : a consideration of dose, core temperature and dopamine synthesis

Amphetamine releases dopamine through a transporter-mediated mechanism. The purpose of this report was to further our understanding of the intracellular pool from which amphetamine releases dopamine: the cytoplasmic pool, the vesicular pool, or both. Rats were treated with D-amphetamine (AMPH) (1.0 or 10.0 mg/kg) or an amphetamine analog, methylenedioxymethamphetamine (MDMA) (2.0, 5.0, or 10.0 mg/kg). Pre-treatment with 10.0 mg/kg reserpine (18 h prior to AMPH or MDMA) attenuated dopamine release for high and low AMPH doses; however the low-dose effect showed borderline significance. Pre-treatment with 10.0 mg/kg reserpine attenuated dopamine and serotonin release induced by MDMA. The dopamine effect was seen at all three MDMA doses; the effect on serotonin was only measured at the 10.0 mg/kg dose. Reserpine pre-treatment caused reductions in core body temperature; heating the rats to normal body temperature for 3 h prior to AMPH or MDMA, and during the 4 h post-treatment period partially reversed the reserpine-induced attenuation of dopamine release. However, the intermediate level of dopamine release for the reserpinized-heated animals was not significantly different from either the reserpine group (not heated) or the AMPH or MDMA alone groups. In a separate group of rats, the effects of reserpine and reserpine+heat on dopamine synthesis were measured. DOPA accumulation after treatment with the aromatic acid decarboxylase inhibitor NSD-1015 (100 mg/kg, 30 min before sacrifice), was greater in rats treated with reserpine compared to controls; heating the reserpinized rats did not significantly alter the amount of DOPA accumulation; however there was a trend towards further increase. These results suggest that D-amphetamine releases dopamine that is stored in both vesicles and the cytoplasm. Cooling may contribute to the attenuation of AMPH or MDMA-induced dopamine release observed after reserpine; however, AMPH or MDMA dependence upon vesicular stores most likely explains the diminished release after reserpine. The attenuation of AMPH or MDMA-induced transmitter release by reserpine is thought to be counteracted by a reserpine-induced replenishment of stores. Therefore, all doses of D-amphetamine may use vesicular stores; the degree to which new synthesis counteracts the vesicular depletion may be the variable which differentiates low from high doses of D-amphetamine.

Prenatal alcohol exposure causes attention deficits in male rats

Children with fetal alcohol spectrum disorder (FASD) are often diagnosed with attention-deficit/ hyperactivity disorder (ADHD). These children show increases in reaction time (RT) variability and false alarms on choice reaction time (CRT) tasks. In this study, adult rats prenatally exposed to ethanol were trained to perform a CRT task. An analysis of the distribution of RTs obtained from the CRT task found that rats with a history of prenatal ethanol exposure had more variable RT distributions, possibly because of lapses of attention. In addition, it was found that, similar to children with FASD, the ethanol-exposed rats had more false alarms. Thus, rats with prenatal ethanol exposure show attention deficits that are similar to those of children with FASD and ADHD.

Long-term effects of a high-dose methamphetamine regimen on subsequent methamphetamine-induced dopamine release in vivo

Rats were treated with a high-dose methamphetamine (METH) regimen (40 mg/kg/injection, four times at 2-h intervals) or a saline regimen (four injections at 2-h intervals). Temperature related measures taken during the high-dose METH treatment were maximum core temperature and minimum chamber temperature. Fourteen rats (METH N=7; Saline N=7) were implanted with in-vivo dialysis probes 4-7 weeks post-regimen (average=6 weeks). The next day, they received a challenge dose of METH (4.0 mg/kg) and dopamine release was measured. Results showed a significant decrease in challenge-induced dopamine release in rats previously treated with the high-dose METH regimen. These findings demonstrate a functional deficit in the dopamine system 6 weeks after high-dose METH treatment. Temperature-related measures taken during the high-dose regimen were not correlated with METH-induced dopamine release 6 weeks later. An additional group of rats were sacrificed 6 weeks after the high-dose regimen (METH N=12; Saline N=10), and their brains was analyzed for dopamine and serotonin concentrations. Tissue concentrations of dopamine were significantly depleted in striatum and nucleus accumbens/olfactory tubercle, but not septum, hypothalamus, or ventral mid-brain 6 weeks after the high-dose regimen. Tissue concentrations of serotonin were also significantly depleted in striatum, nucleus accumbens/olfactory tubercle, hippocampus, somatosensory cortex, but not septum, hypothalamus or ventral mid-brain. Significant correlations between the temperature-related measures and post-mortem neurotransmitter tissue concentrations were region and transmitter dependent.

Relationship between methamphetamine-induced behavioral activation and hyperthermia

Methamphetamine (METH) changes core temperature and induces behavioral activation. Behavioral activation is also known to change core temperature. The purpose of this report was to 1.) evaluate the extent to which the behavioral activation induced by METH showed a temporal relationship to METH-induced hyperthermia; and 2.) describe the temporal pattern of METH-induced hyperthermia over an extended dose range. Rats were treated with saline or METH (0.5-10.0mg/kg) in computer-controlled chambers with ambient temperature maintained at 24°C. Continuous telemetric core temperature measurements were made during a 7h test period. Behavioral observations were made once every 15 min using an 11-point scale ranging from 0 (quiet awake) to 10 (focused licking or biting). The onset of METH-induced behavioral activation occurred at 15-30 min after treatment for all doses and preceded core temperature increases; the onset of METH-induced hyperthermia ranged from 45 min post-treatment to 120 min post-treatment. This behavior-temperature delay was 15-30 min at the lowest (0.5 and 1.0mg/kg) and the highest (7.0, 8.0, and 10.0mg/kg) doses tested; the delay was increased between 1.0 and 4.0mg/kg METH (105 min delay at 4.0mg/kg) and then decreased again from 4.0 to 10.0mg/kg. The strongest relationship between core temperature and behavioral activation occurred at 180 min post-treatment. These data suggest that factors other than behavior are primarily responsible for the observed core temperature effects during the initial post-treatment period (60 min peak); possible effects from movement are masked. For the latter post-treatment period (180 min peak) the stronger relationship between temperature and behavior suggests a role for movement in METH-induced hyperthermia.

Trained and amphetamine-induced circling behavior in lesioned, transplanted rats.

Rats were trained to turn for water reinforcement and then were given unilateral 6- hydroxydopamine lesions. After lesion, rats showed deficits in trained turning both contraand ipsilateral to the side of the lesion, with contralateral turning more severely impaired. The lesioned rats were then transplanted with fetal mesencephalic dopamine tissue into striatum. A control group of lesioned rats were sham transplanted. Four weeks after transplant, 1.5 mg/kg D-amphetamine challenge injections were used to test the functioning of the transplants. In the control rats, D-amphetamine induced ipsilateral turning; in transplanted rats, D-amphetamine slowed the rate of ipsilateral turning or reversed the direction of amphetamine-induced rotation. Only rats which reversed their, amphetamine-induced turn direction after transplant were used for the rest of the experiment. Trained turning was assessed at 4, 8, 12 and 16 weeks post transplant. Transplants did not improve learned performance at any time post transplant. When D-amphetamine was administered in conjunction with the trained turning sessions, a low dose (0.12 mg/kg) enhanced contralateral trained turn rates, without affecting ipsilateral turn rates. Higher doses of amphetamine reduced ipsilateral turn rate in the transplanted animals. The results of this study suggest that transplants alone do not reinstate performance of conditioned rotation.

The effects of the β1 antagonist, metoprolol, on methamphetamine-induced changes in core temperature in the rat

Methamphetamine (METH) results in hyperthermia or hypothermia depending on environmental conditions. Here we studied the role of the β1 adrenergic receptor in mediating METHs temperature effects. Core temperature measurements were made telemetrically over a 7.5h session, two days/week, in test chambers regulated at either 18°C, 24°C, or 30°C ambient temperature. Rats were treated with the β1 antagonist metoprolol (5.0, 10.0, and 15.0mg/kg) alone (Experiment 1), or in combination with 5.0mg/kg METH (Experiment 2). In experiment 3, we combined a lower dose range of metoprolol (0.75, 1.5, and 3.0mg/kg) with 5.0mg/kg METH at 18°C and 30°C. Confirming prior findings, METH alone resulted in hyperthermia in warm (30°) and hypothermia in cool environments (18°C). Metoprolol alone induced small but significant increases in core temperature. In combination, however, metoprolol reduced METH-induced changes in core temperature. Specifically, at 30°C, 3.0, 5.0, 10.0, and 15.0mg/kg metoprolol decreased METH-induced hyperthermia; at 18°C, all six doses of metoprolol enhanced METH-induced hypothermia. Our metoprolol findings suggest that one component of METHs temperature effects involves increasing core temperature at all ambient conditions via β1 receptors. Since β receptors are involved in brown adipose tissue (BAT)-mediated thermogenesis, skeletal muscle-mediated thermogenesis, heart rate, and the metabolism of glucose and lipids, we discuss each of these as possible mechanisms for metoprolols effects on METH-induced changes in core temperature.