Despite decades of research into the neurobiological basis of cocaine abuse, pharmacotherapeutic treatments for cocaine addiction have been largely ineffective. Converging evidence from preclinical research and from outpatient clinical trials suggest that treatment with amphetamine is efficacious in reducing cocaine intake. Although it has been suggested that amphetamine treatment reduces cocaine intake as an agonist replacement therapy, we have shown recently that multiple aspects of dopamine signaling are altered by cocaine self‐administration and returned to pre‐cocaine function by amphetamine treatment in the nucleus accumbens of male rats. Here, we sought to determine if these effects were also evident in female subjects, and across regions of the striatum. Female rats performed 5 days of cocaine self‐administration (1.5 mg kg−1 inj−1, 40 inj/day) and were treated with a single amphetamine (0.56 mg/kg) or saline infusion 1 hr prior to killing. We then used ex vivo fast‐scan cyclic voltammetry in the nucleus accumbens core or dorsolateral caudate‐putamen to examine dopamine signaling and cocaine potency. We found that in the nucleus accumbens core, cocaine self‐administration decreased dopamine uptake rate and cocaine potency, and both alterations were restored by amphetamine treatment. In the dorsolateral caudate‐putamen, neither cocaine self‐administration nor amphetamine treatment altered dopamine uptake; however, cocaine potency was decreased by self‐administration and returned to control levels by amphetamine. Together, these findings support a role for amphetamine treatment for cocaine addiction outside of agonist replacement therapy, and suggest that the development of cocaine tolerance is similar across sexes.

It has long been appreciated that adolescence represents a uniquely vulnerable period when chronic exposure to stressors can precipitate the onset of a broad spectrum of psychiatric disorders and addiction in adulthood. However, the neurobiological substrates and the full repertoire of adaptations within these substrates making adolescence a particularly susceptible developmental stage are not well understood. Prior work has demonstrated that a rodent model of adolescent social isolation (aSI) produces robust and persistent increases in phenotypes relevant to anxiety/stressor disorders and alcohol addiction, including anxiogenesis, deficits in fear extinction, and increased ethanol consumption. Here, we used extracellular field recordings in hippocampal slices to investigate adaptations in synaptic function and synaptic plasticity arising from aSI. We demonstrate that this early life stressor leads to enhanced excitatory synaptic transmission and decreased levels of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses. Further, these changes were largely confined to the ventral hippocampus. As the ventral hippocampus is integral to neurocircuitry that mediates emotional behaviors, our results add to mounting evidence that aSI has profound effects on brain areas that regulate affective states. These studies also lend additional support to our recent proposal of the aSI model as a valid model of alcohol addiction vulnerability.

Simultaneous use of stimulants and alcohol is a growing problem, particularly among older adolescents already prone to binge alcohol consumption. Adolescent rats consume high levels of alcohol when administered in a liquid diet and develop a strong alcohol withdrawal syndrome. We exploited this system to administer amphetamine in combination with alcohol and to test the effect of co-administration of amphetamine on alcohol withdrawal-induced hypoactivity and overall withdrawal severity. The presence of dietary amphetamine (≤40 mg/l) had no effect on consumption of control or alcohol-containing diets. Measured in an activity chamber, alcohol withdrawal hypoactivity was reduced significantly by co-administration of amphetamine with alcohol. Overall withdrawal severity was also reduced significantly when rats consumed amphetamine with alcohol. The results suggest that amphetamine co-use may mask physical signs of alcohol dependency and add to the importance of educational strategies pointing out the potential problems associated with co-use of stimulants and alcohol.

Fast scan cyclic voltammetry (FSCV) is an electrochemical technique that allows sub-second detection of oxidizable chemical species, including monoamine neurotransmitters such as dopamine, norepinephrine, and serotonin. This technique has been used to record the physiological dynamics of these neurotransmitters in brain tissue, including their rates of release and reuptake as well as the activity of neuromodulators that regulate such processes. This protocol will focus on the use of ex vivo FSCV for the detection of dopamine within the nucleus accumbens in slices obtained from rodents. We have included all necessary materials, reagents, recipes, procedures, and analyses in order to successfully perform this technique in the laboratory setting. Additionally, we have also included cautionary points that we believe will be helpful for those who are novices in the field.

Adolescent rats develop a severe alcohol withdrawal syndrome when fed alcohol as part of a liquid diet. The present study sought to correlate quantitative changes in neurotransmitter receptors with the severity of alcohol withdrawal symptoms. Membranes were isolated from brain fractions from rats fed an alcohol‐containing liquid diet beginning at P28 and continuing on into the adolescent period. Membranes were probed for specific receptors by Western blotting. During the period of up to 10 days, excitatory glutamate receptors (both AMPA and NMDA subtypes) increase significantly. This up regulation of glutamate receptors coincides with a time when the primary withdrawal behavior is anxiety‐like. By 14 days, adenosine A1 receptors decline significantly reaching a level 50% of that of pair‐fed controls. There are no corresponding changes in adenosine A2a receptors. Down regulation of A1 coincides with a time when 90% of the rats experience convulsions upon alcohol withdrawal. A detergent resistant (raft) fraction was isolated from brain membranes to determine which of these receptors may be located in lipid rafts. Initial analyses indicate all 3 receptors of interest are at least partially localized to lipid rafts. We conclude that the most severe alcohol withdrawal symptoms may occur in adolescents when up regulation of excitatory glutamate receptors coincides with down regulation of A1 receptors and thus with loss of the ‘brakes’ adenosine might normally apply to the glutamate system. Further studies will explore the potential role of lipid raft dynamics in these changes.