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Rats were trained to discriminate an injection of cocaine, 5.0 mg/kg, from an injection of saline, using a two-lever choice paradigm: one lever was correct after cocaine injection, the other lever was correct after a saline injection. After training, cocaine and methamphetamine were generalized to the cocaine lever, but phenethylamine (PEA) was only partially generalized. Cocaine was injected every 8 hrs, 20.0 mg/kg, and the discriminability of 5.0 mg/kg was tested every other day. Redetermination of the cocaine generalization curve after 6 days of chronic administration showed a shift to the right, from an ED50 of 4.1 mg/kg in the pre-chronic condition to 10.0 mg/kg. Tolerance did not develop to the behavioral effects of cocaine, measured by time to the first reinforcement and response rate. There was cross-tolerance to methamphetamine; however, no evidence for cross-tolerance to PEA was obtained. Following the acquisition of tolerance, chronic administration of cocaine was terminated, and the discriminability of 5.0 mg/kg was tested every other day for loss of tolerance. After 8 days the ED50 returned to 5.0 mg/kg.

In light of the limited and conflicting experimental data on food intake, body weight change and body energy metabolism following single-dose or long-term cocaine administration, the purpose of the present study was to further evaluate the dose-dependent acute and chronic (27 day) effects of two dose levels of cocaine on the following questions: i) Does chronic cocaine administration decrease food consumption and weight gain?; ii) To what extent does acute or chronic cocaine administration alter body carbohydrate stores (liver and skeletal muscle glycogen content)?; and iii). To what extent does acute or chronic cocaine administration affect plasma glucose and free fatty acid levels and thus hepatic glycogenolysis and adipose tissue lipolysis?

Cocaine, the principal biologically active alkaloid of Erythroxylon coca, acts as both a local anesthetic agent and an indirect-acting sympathomimetic. These two very different activities make research on and subsequent interpretation of cocaine's multiplicity of varied effects difficult. Not surprisingly, investigations into the central effects of cocaine have yielded mixed results. However, there is a certain body of evidence which points to the euphoric and self-administrating properties of cocaine as appearing to involve the acute activation of central dopamine neuronal systems . With chronic cocaine use, central neurotransmitter alterations have been observed to occur. Dopamine depletion has been hypothesized to result from the overstimulation of these central neurons and the excessive synaptic metabolism of the neurotransmitter. This depletion may underlie the dysphoric aspects of cocaine abstinence and cravings. The potential cardiotoxicity of chronic cocaine abuse has been welldocumented. The possible mechanisms for this remain unclear. The present study was designed to evaluate the effects of repeated daily administration of two different doses (15 and 30 mg/kg/day) of cocaine on male Sprague-Dawely rat cardiac norepinephrine levels. Seven time intervals of sustained dosing were acute (1 dose), 1, 2, 4, 8, 12 and 20 weeks. The catecholamine levels of the whole heart were measured using an HPLC with electrochemical detection. Cardiac norepinephrine levels were unaffected by an acute injection of either cocaine dose. The lower dose elicited a slight increase of 5.8% while the higher dose evoked a small decrease at the 1 week administration period. At 2, 4, and 8 weeks cardiac neurotransmitter levels decreased an average of 13% compared to control values for both doses. At 20 weeks, the catecholamine content was similar to that of the controls. It was observed that cocaine in regard to cardiac norepinephrine content failed to elicit a dose-dependent response. The lower dose of 15 mg/kg/day evoked a greater reduction than that of the higher dose, especially at the 12 week time increment ( -23% and -11%, respectively) which was statistically significant. This is one of the first studies to investigate the effects that repeated daily cocaine dosing has on cardiovascular biochemical pharmacology. It is difficult to postulate the possible etiology and functionality of this decrease. Previous studies have indicated that cocaine might cause alterations in tyrosine hydroxylase activity, the rate-limiting enzyme in the biosynthesis of catecholamines which could be responsible for the reduction observed.

The main purpose of this research was to investigate the phenomenon of tolerance to cocaine. Tolerance is operationally defined as a decreased drug effect due to prior history of drug administration. The animal model that was chosen to investigate tolerance to cocaine was the drug discrimination model, which is an animal analogue of human subjective drug effects. In the drug discrimination procedure, animals are trained to emit one behavior when injected with saline. In the present experiments, rats were trained to press one lever when injected with cocaine, 10 mg/kg, and a different lever when injected with saline for food reinforcement. Once rats are trained, they can accurately detect the cocaine stimulus greater than 95% of the time.

Athletes have continually sought to improve their physical performance. In order to accomplish this, athletes experiment with performance enhancing drugs, which are readily available to the athlete today. Cocaine, being one of them, is traditionally and popularly believed to increase muscular endurance and possess anti-fatiguing properties. The scientific literature as to whether cocaine is truly a performance enhancing drug is inconclusive. Moreover, few if any studies have been conducted on exercise performance following long term, repeated cocaine administration. The purpose of the present study was to determine the effects of 35 days of cocaine administration (25 mg/kg/day) on maximal endurance exercise capacity. Data were collected from six untrained male Sprague-Dawley rats. Resting and exercise heart rate and body temperature were recorded via radio telemetery. Running time to exhaustion was recorded via one weekly maximal treadmill exercise bout to exhaustion (26 m/min, at a 10% grade). Compared to saline controls, cocaine significantly decreased run time to exhaustion, following acute and chronic administration. Cocaine administration also significantly decreased maximal exercise heart rate. Chronic cocaine had minimal effects on resting heart rate and resting and exercise body temperature during maximal exercise conditions. These data indicate that daily, chronic cocaine administration significantly reduces endurance exercise capacity, and suggests that the decreased physical work capacity following cocaine is related to a decreased ability of the heart to function under maximal exercise conditions.

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The purpose of this study was to investigate whether a partial D₂-like dopamine agonist (i.e. terguride) would block the induction or expression of cocaine-induced behavioral sensitization in pre-weanling rats. The ability of terguride to induce behavioral sensitization was also examined, as partial D₂-like agonists have agonistic actions in cases of low dopaminergic tone.

Adolescence is a sensitive developmental period encompassing neural maturation that is critical for an individual’s behavioral transition into adulthood. Due to widespread physiological changes attributed to this period, adolescents are also vulnerable to the initiation of risky behaviors, such as drug experimentation and use, as well as the emergence of various neuropsychiatric disorders. The mesocorticolimbic dopamine (DA) system in the brain undergoes a transient peak in activity and continues to mature during adolescence, potentially mediating adolescent hypersensitivity to social, appetitive, and drug-associated rewards. Simultaneously, the serotonin (5-HT) system exerts its influence on the dopamine system throughout adolescence, a process vital for proper impulse control and emotional regulation in adulthood. Substance use disorders (SUDs) are multifaceted and are comprised of diverse maladaptive behaviors that promote compulsive drug seeking, including loss of control and the propensity to engage in drug use irrespective of personal risks and/or consequences. Drug addiction and substance use have a large negative impact globally both economically and with regards to public health outcomes, representing approximately 1.3% of the global burden of disease. Furthermore, dopamine reward pathways are heavily impacted by drug use, particularly with respect to stimulants, and the level of drug-induced dopamine release in the ventral striatum can be correlated with a drug’s perceived “high.” Certain experiences and adverse behaviors linked to refinement of monoamine connectivity in the brain during adolescence, such as heightened stress and sensation seeking, may predispose individuals for developing SUDs in adulthood. However, how drug reward sensitivity and associated activity of the dopamine system is altered in adulthood as a consequence of interfering with monoamine neurodevelopment during adolescence has not been clarified. To this end, I aim to understand how imbalanced monoamine development during adolescence contributes to stimulant-mediated behaviors in adulthood, specifically contextual reward associations, in relation to in vivo activity of the dopamine reward system. I introduce a sensitive peri-adolescent (PA) period in mice, during which blockade of the serotonin transporter (SERT) via fluoxetine administration during postnatal (P) days 22-41 leads to inhibited adult aggression and locomotor response to stimulants. Conversely, I describe a more refined PA (P32-41) period during which systemic dopamine transporter (DAT) blockade via GBR12909 administration leads to enhanced aggression and stimulant-induced locomotor activity in adulthood. Utilizing these behaviorally opposing models characterized in our lab, I describe the diverging effects of systemic DAT and SERT blockade from P32-41 on cocaine-induced locomotor response as well as cocaine-mediated contextual preference. I administered cocaine intraperitoneally (i.p.) at doses of 5 and 10 mg/kg, applying the open field test and cocaine conditioned place preference (CPP) paradigm to assess stimulant-induced locomotor response and environmental reward associations, respectively. Potentiation of serotonergic tone during P32-41 via fluoxetine administration leads to decreased cocaine-induced locomotor response and a lack of preference for a cocaine-associated context in adulthood at a dose of 10 mg/kg, compared to controls and PA GBR treated subjects. Conversely, potentiation of dopaminergic tone by administering GBR12909 during P32-41 is associated with enhanced cocaine-induced locomotor reactivity at 10 mg/kg and greater contextual preference at lower doses of cocaine (5 mg/kg), in comparison to PA fluoxetine treated mice and controls. To understand how in vivo VTA dopamine population activity is altered in both PA models during cocaine-associated behaviors in adulthood, I performed cocaine CPP while recording calcium signals in VTA dopamine neurons using fiber photometry in freely behaving subjects. Importantly, I utilize these recordings as a proxy for measuring changes in VTA dopamine activity as the subjects engage with a cocaine-paired environment. I found that PA DAT blockade was associated with greater baseline VTA dopamine activity in adulthood compared to controls, as well as heightened VTA dopamine activity while the subjects were in a cocaine-paired context during selected portions of the behavioral task compared to control subjects. Additionally, we found a significant positive correlation between the magnitude of preference for a cocaine-associated context and the frequency of VTA dopamine calcium signals recorded while the subject is engaged with a cocaine-paired environment. Adult mice following PA DAT blockade displayed a greater frequency of recorded VTA dopamine calcium signals while in a cocaine-paired environment compared to PA fluoxetine treated mice. Supporting our correlational analysis, I detected a decreased preference for a cocaine-paired context in PA fluoxetine treated subjects compared to both controls and PA GBR12909 mice, when using a dose of cocaine in between the previous concentrations tested (7.5 mg/kg). Interestingly, PA fluoxetine treated subjects showed transition-dependent differences in VTA dopamine calcium activity during the final five-minute portion of our behavioral task, displaying less activity shortly post-entry into the cocaine-paired environment compared to pre-entry. In congruence, PA fluoxetine subjects showed enhanced VTA dopamine calcium activity on the saline-paired side shortly post-entry compared to pre-entry. In collaboration with the Sulzer Lab, we also probed the effects of both PA manipulations on electrically evoked dopamine release in the ventral striatum of adult anesthetized mice using fast-scan cyclic voltammetry. Electrical stimulation was targeted to the midbrain and evoked dopamine release was recorded in the ventral striatum both at baseline and in response to cocaine injection, using the same 7.5 mg/kg dose applied in the calcium imaging study. Overall, we found a significant increase in dopamine release at baseline in the ventral striatum of adult PA GBR12909 treated subjects compared to both PA fluoxetine subjects and controls. Moreover, we found significantly greater cocaine-induced dopamine release in our PA GBR12909 mice compared to controls in adulthood. These findings are consistent with the imaging and behavioral data, highlighting the persistence of an elevated dopaminergic phenotype due to systemic PA DAT blockade. Conversely, systemic PA SERT blockade leads to behaviorally opposing effects and generally lower VTA DA activity dynamics in comparison to PA GBR12909 treated subjects in adulthood. The unique, combinatorial approach applied in this dissertation work further our knowledge of how sensitive developmental periods influence the emergence of complex behaviors in adulthood, which is vital to improving treatment approaches for neuropsychiatric disorders.

Indiana University-Purdue University Indianapolis (IUPUI) / Alcohol and cocaine are commonly co-abused drugs, and those meeting criteria for both cocaine and alcohol use disorders experience more severe behavioral and health consequences than those with a single disorder. Chronic alcohol (ethanol) drinking increased the reinforcing and dopamine (DA) neuronal stimulating effects of ethanol within mesolimbic regions of the central nervous system (CNS) of alcohol-preferring (P) rats. The objectives of the current study were to determine if chronic continuous ethanol drinking produced: (1) alterations in the sensitivity of the nucleus accumbens shell (AcbSh) to the reinforcing effects of cocaine, (2) changes in the magnitude and time course of the local stimulating effects of cocaine on posterior ventral tegmental area (pVTA) DA neurons, and (3) a persistence of alterations in the stimulating effects of cocaine after a period of protracted abstinence. Female P rats received continuous, free-choice access to water and 15% v/v ethanol for at least 10 wk (continuous ethanol-drinking; CE) or access to water alone (ethanol-naïve; N). A third group of rats received the same period of ethanol access followed by 30 d of protracted abstinence from ethanol (ethanol-abstinent; Ab). CE and Ab rats consumed, on average, 6-7 g/kg/d of ethanol. Animals with a single cannula aimed at the AcbSh responded for injections of cocaine into the AcbSh during four initial operant sessions. Cocaine was not present in the self-infused solution for the subsequent three sessions, and cocaine access was restored during one final session. Animals with dual ipsilateral cannulae aimed at the AcbSh and the pVTA were injected with pulsed microinfusions of cocaine into the pVTA while DA content was collected for analysis through a microdialysis probe inserted into the AcbSh. During the initial four sessions, neither CE nor N rats self-infused artificial cerebrospinal fluid (aCSF) or 0.1 mM cocaine into the AcbSh. CE, but not N, rats self-administered 0.5 mM cocaine into the AcbSh, whereas both groups self-infused concentrations of 1.0, 2.0, 4.0, or 8.0 mM cocaine. When cocaine access was restored in Session 8, CE rats responded more on the active lever and obtained more infusions of 0.5, 1.0, 2.0, or 4.0 mM cocaine compared to N rats. Microinjection of aCSF into the pVTA did not alter AcbSh DA levels in N, CE, or Ab rats. Microinjections of 0.25 mM cocaine into the pVTA did not significantly alter AcbSh DA levels in N animals, moderately increased DA levels in CE rats, and greatly increased DA levels in Ab rats. Microinjections of 0.5 mM cocaine into the pVTA modestly increased AcbSh DA levels in N animals, robustly increased DA levels in CE rats, and did not significantly alter DA levels in Ab rats. Microinjections of 1.0 or 2.0 mM cocaine into the pVTA modestly increased AcbSh DA levels in N animals but decreased DA levels in CE and Ab rats. Overall, long-term continuous ethanol drinking by P rats enhanced both the reinforcing effects of cocaine within the AcbSh and the stimulatory and inhibitory effects of cocaine on pVTA DA neurons. Alterations in the stimulatory and inhibitory effects of cocaine on pVTA DA neurons were not only enduring, but also enhanced, following a period of protracted abstinence from ethanol exposure. Translationally, prevention of chronic and excessive alcohol intake in populations with a genetic risk for substance abuse may reduce the likelihood of subsequent cocaine use.