D1 receptor-mediated inhibition of medial prefrontal cortex neurons is disrupted in adult rats exposed to amphetamine in adolescence.

Amphetamine (AMPH) exposure leads to changes in behavior and dopamine receptor function in the prefrontal cortex (PFC). Since dopamine plays an important role in regulating GABAergic transmission in the PFC, we investigated if AMPH exposure induces long-lasting changes in dopamine's ability to modulate inhibitory transmission in the PFC as well as whether the effects of AMPH differed depending on the age of exposure. Male Sprague-Dawley rats were given saline or 3 mg/kg AMPH (i.p.) repeatedly during adolescence or adulthood and following a withdrawal period of up to 5 weeks (Experiment 1) or up to 14 weeks (Experiment 2), they were sacrificed for in vitro whole-cell recordings in layer V/VI of the medial PFC. We found that in brain slices from either adolescent- or adult-exposed rats, there was an attenuation of dopamine-induced increases in inhibitory synaptic currents in pyramidal cells. These effects did not depend on age of exposure, were mediated at least partially by a reduced sensitivity of D1 receptors in AMPH-treated rats, and were associated with an enhanced behavioral response to the drug in a separate group of rats given an AMPH challenge following the longest withdrawal period. Together, these data reveal a prolonged effect of AMPH exposure on medial PFC function that persisted for up to 14 weeks in adolescent-exposed animals. These long-lasting neurophysiological changes may be a contributing mechanism to the behavioral consequences that have been observed in those with a history of amphetamine abuse.

The effects of abused drugs on adolescent development of corticolimbic circuitry and behavior.

Adolescence is a period of significant neurobiological change that occurs as individuals transition from childhood to adulthood. Because the nervous system is in a relatively labile state during this stage of development, it may be especially sensitive to experience-induced plasticity. One such experience that is relatively common to adolescents is the exposure to drugs of abuse, particularly alcohol and psychostimulants. In this review, we highlight recent findings on the long-lasting effects of exposure to these drugs during adolescence in humans as well as in animal models. Whenever possible, our focus is on studies that use comparison groups of adolescent- and adult-exposed subjects as this is a more direct test of the hypothesis that adolescence represents a period of enhanced vulnerability to the effects of drug-induced plasticity. Lastly, we suggest areas of future investigation that are needed and methodological concerns that should be addressed.

Effects of ethanol during adolescence on the number of neurons and glia in the medial prefrontal cortex and basolateral amygdala of adult male and female rats.

Human adolescents often consume alcohol in a binge-like manner at a time when changes are occurring within specific brain structures, such as the medial prefrontal cortex (mPFC) and the basolateral nucleus of the amygdala (BLN). In particular, the number of neurons and glia is changing in both of these areas in the rat between adolescence and adulthood (Markham et al., 2007; Rubinow and Juraska, 2009). The current study investigated the effects of ethanol exposure during adolescence on the number of neurons and glia in the adult mPFC and BLN in Long-Evans male and female rats. Saline or 3g/kg ethanol was administered between postnatal days (P) 35-45 in a binge-like pattern, with 2days of injections followed by 1 day without an injection. Stereological analyses of the ventral mPFC (prelimbic and infralimbic areas) and the BLN were performed on brains from rats at 100 days of age. Neuron and glia densities were assessed with the optical disector and then multiplied by the volume to calculate the total number of neurons and glia. In the adult mPFC, ethanol administration during adolescence resulted in a decreased number of glia in males, but not females, and had no effect on the number of neurons. Adolescent ethanol exposure had no effects on glia or neuron number in the BLN. These results suggest that glia cells in the prefrontal cortex are particularly sensitive to binge-like exposure to ethanol during adolescence in male rats only, potentially due to a decrease in proliferation in males or protective mechanisms in females.

Adaptations in medial prefrontal cortex function associated with amphetamine-induced behavioral sensitization.

Neuroadaptations in the prefrontal cortex (PFC) are hypothesized to play an important role in the behavioral changes associated with repeated psychostimulant exposure, but there are few published studies that measure neuronal activity during the development and expression of sensitization. To address this, we recorded single neuron activity in the medial PFC (mPFC) of male rats that were exposed for 5 days to saline or amphetamine (AMPH; 1.0 mg/kg i.p.) and then given saline or AMPH challenges following a three-day withdrawal. We found that rats exposed to AMPH developed locomotor sensitization to the drug that emerged on the fifth treatment session and became statistically significant at AMPH challenge. This was associated with no change in baseline (i.e., pre-injection) activity of mPFC neurons across the treatment or challenge sessions. Following the first AMPH injection, mPFC neurons responded primarily with reductions in firing, with the overall pattern and magnitude of responses remaining largely similar following repeated treatment. The exception was in the minority of cells that respond to AMPH with increases in firing rate. In this population, the magnitude of excitations peaked during the fifth AMPH exposure and was still relatively elevated at the AMPH challenge. Furthermore, these units increased firing during a saline challenge that was given to assess associative conditioning. These results suggest that AMPH-induced adaptations in mPFC function are not as apparent as AMPH-induced adaptations in behavior. When mPFC adaptations do occur, they appear limited to the population of neurons that increase their firing in response to AMPH.

Behavior-related modulation of substantia nigra pars reticulata neurons in rats performing a conditioned reinforcement task.

Motor-control models of basal ganglia function have emphasized disinhibition through reduction of tonic, inhibitory output. Although these models have shed important light on basal ganglia operations, evidence emerging from electrophysiological studies of behaving primates suggests that disinhibition alone may not adequately explain the role of the basal ganglia in movement. To assess this role in the rat, the most frequently used subject in studies of basal ganglia function, we recorded neuronal activity in the primary output nucleus, the substantia nigra pars reticulata, during an operant task. After rats were trained to nosepoke into an illuminated hole for access to a 10% sucrose solution delivered through a spout, single- and multiple-unit activity was recorded during 60-120 nosepoke trials. Compared to the period 60 s before the start of the first trial in the task, 110 of 225 reticulata units increased firing >200% while 17 of 225 decreased to 40% of baseline. Of these 225 units, >60% responded coincident with specific task events such as nosepokes and spout licking. Most nosepoke-responsive units showed either excitation (>50%) or a combination of excitation and inhibition (>25%) rather than inhibition alone (>20%). Increases in firing were also common during approach and licking at the spout, with inhibitions alone comprising 30% of responses. In some units, there was evidence of reward-related responding, with changes occurring in anticipation of reward delivery or during the delivery of sucrose, but not the persistent licking that continued for several seconds after its offset. While 70% of units responded during both nosepokes and spout licking, changes in firing were typically unique depending on the motor behavior required (i.e. nosepoking vs. licking). Our results, which indicate a prominent role for increases in nigra reticulata activity during movement, add to growing evidence that although inhibitions may allow desired motor responses to emerge, excitations may help shape behavioral output by suppressing competing motor programs.

Operant-self-administration of ethanol in mice prenatally exposed to cocaine.

Prenatal drug exposure may affect postnatal response to the reinforcing effects of a broad array of drugs. This study investigated the effects of prenatal cocaine exposure on operant self-administration of ethanol. Eighteen male, C57BL/6J mice were divided into three groups. The first had been prenatally exposed to 30 mg/kg of cocaine twice per day while the other groups were offspring of mothers which were either pair fed and saline intubated or untreated. Once adults, the mice were trained and subsequently tested for reinforcement from ethanol. The prenatal cocaine group responded less than the two control groups, with the largest decrease during a progressive ratio schedule of reinforcement. There were no differences in responding as a function of ethanol concentrations. These findings suggest that prenatal exposure to cocaine may not affect reinforcement per se, but may decrease motivation, drive state or propensity to work for ethanol.

Behavior-related changes in the activity of substantia nigra pars reticulata neurons in freely moving rats.

As one of the primary targets of the striatum, the substantia nigra pars reticulata (SNr) has been hypothesized to play a role in normal motor behavior. Specifically, inhibition of usually high, tonic SNr output is predicted to correlate with motor activation. While support for this has come primarily from electrophysiological studies in primates performing goal-directed movements, we tested this hypothesis in rats behaving in an open-field arena. SNr single-unit activity was recorded during spontaneous bouts of open-field behavior (e.g., head and body movements, locomotion) and after rats were given D-amphetamine (1.0 mg/kg, s.c.), which reliably increases motor activity and elevates the firing of motor-related striatal neurons. Prior to drug administration, SNr neurons had either regular, slightly irregular or irregular firing patterns when animals rested quietly. During movement, some inhibitions were observed, but the majority ( approximately 79%) of analyzed units increased firing by as much as 38%. Regardless of the predrug behavioral response of the cell, amphetamine strongly inhibited firing rate ( approximately 90% below nonmovement baseline) and changed firing pattern such that all cells fired irregularly. Subsequent injection with the dopamine antagonist haloperidol (1.0 mg/kg, s.c.) reversed amphetamine-induced inhibitions in all tested cells, which supports a role for dopamine in this effect. These results suggest that the pattern of striatal activity established by amphetamine, which may be critical for determining the drug-induced behavioral pattern, is represented in the SNr regardless of the predrug behavioral response of the cell.

Modulatory effects of ascorbate, alone or with haloperidol, on a lever-release conditioned avoidance response task.

Pretreatment with ascorbate, a modulator of dopamine transmission in the striatum, enhances the ability of haloperidol, a dopamine antagonist, to induce catalepsy and block the motor-activating effects of amphetamine. The present study extended this line of work to a lever-release version of the conditioned avoidance response (CAR) task, which is highly sensitive to changes in striatal dopamine. Adult male rats were trained to avoid footshock by releasing a lever within 500 ms of tone onset. Ascorbate (100 and 1000 mg/kg, IP) or vehicle was tested either alone or in conjunction with haloperidol (0.01 and 0.05 mg/kg, SC). Compared to vehicle pretreatment, 1000 mg/kg ascorbate alone or in combination with haloperidol impaired CAR performance by increasing avoidance latency. Latency to escape footshock was not impaired, ruling out a generalized motor deficit. In contrast, 100 mg/kg ascorbate alone or in combination with haloperidol had no consistent effects on CAR performance, even at a haloperidol dose (0.005 mg/kg, SC) known to potentiate dopamine transmission by preferentially blocking autoreceptors. Collectively, these results support an antidopaminergic action of ascorbate on striatal function, but suggest that this effect requires relatively high systemic doses.

Selective serotonin reuptake inhibitors: effects of chronic treatment on ethanol-reinforced behavior in mice.

Several lines of evidence suggest that aspects of ethanol drinking are mediated, at least in part, by serotonergic (5-HT) neurotransmitter systems. Ethanol-preferring animals show decreases in serotonin function and receptor densities. In addition, serotonin uptake inhibitors have been shown to decrease ethanol consumption in animal models and in humans. However, the time course of these effects and their duration remain undetermined. In the present studies, C57BL/6J male mice were treated with one of three selective 5-HT reuptake inhibitors (SSRIs): fluoxetine, sertraline, or paroxetine. All three drugs produced initial decreases in operant lever pressing behavior for ethanol followed by a return to baseline on subsequent days. Immediately following 14 days of this initial treatment, subsequent treatment with higher SSRI doses was ineffective in decreasing ethanol-reinforced behavior. However, after a several week "washout period," SSRI pretreatment again produced an initial decrease in responding for ethanol, again followed by a return to baseline. Thus, suppression of ethanol drinking may be related to immediate changes in 5-HT function following treatment with SSRIs, and tolerance to this effect appears to develop rapidly.

Treatment of hyperemesis gravidarum with nasogastric feeding.

Hyperemesis gravidarum, an antepartem disorder characterized by severe nausea and vomiting, is usually a benign condition with a favorable outcome. Although no increase in fetal or maternal morbidity results, the disorder has deleterious effects on both nutrition and everyday life. The authors describe a treatment protocol for hyperemesis gravidarum that uses continuous infusion of an iso-osmolar tube-feeding product and their experiences with its use in 30 patients. Uniformly good symptom relief was obtained by this technique, thus avoiding the need for more invasive therapy. It is proposed that this treatment is a safe and effective means of managing severe nausea and vomiting during early pregnancy.