In 1989, the National Institute on Drug Abuse (NIDA) established its Medications Development Program. This program has concentrated on developing pharmacotherapies for opiate and cocaine dependence and, more recently, for methamphetamine and cannabis dependence. The major goals of this program are to optimize existing treatments and to expand treatment options for physicians and patients. This review will concentrate on the development of pharmacotherapies for the following substance abuse disorders: opiate, cocaine, methamphetamine, and cannabis dependence. Left untreated, opiate and stimulant dependence are responsible for significant morbidity and mortality. For example, use of illicit opiates is associated with an increased risk of hepatitis C infection, HIV infection, and other medical consequences, e.g., an overdose. The NIDA Medications Development Program has had success in developing, with pharmaceutical partners, levomethadyl acetate, buprenorphine, and buprenorphine/naloxone for opiate dependence. Moreover, several marketed medications have shown promise in reducing cocaine use. Of interest, these medications likely operate through diverse neurochemical mechanisms, suggesting that combination therapy may be a rational next step that could increase treatment gains further in cocaine-dependent patients. The Medications Development Program has also identified multiple neuronal mechanisms that are altered by chronic administration of drugs of abuse. Advances in neuroscience have identified changes in conditioned cueing, drug priming, stress-induced increases in drug intake, and reduced frontal inhibitory mechanisms as all being possible for the development of, maintenance of, and possible relapse to, addiction. Potential medications that modulate these mechanisms are highlighted.

Chronic nicotine administration has been reported to increase acoustic startle response (ASR) amplitude in rats, which has been offered as evidence that some dosages of nicotine can enhance attention. The present experiments examined effects of acutely administered nicotine on amplitude and pre-pulse inhibition (PPI) of acoustic startle in rats. PPI, the decrease in ASR amplitude by a stimulus preceding the startle-eliciting event, reflects pre-attentive neural processes underlying sensory gating. Nicotine had a biphasic dose effect on startle amplitude, with increases at lower dosages (0.01 mg/kg) and decreases at higher dosages (0.5-5.0 mg/kg SC). Lower dosages of nicotine (0.001-0.01 mg/kg) increased PPI and the increase at 0.001 mg/kg occurred independently of changes in ASR amplitude. These results confirm that increases in PPI are not dependent upon changes in ASR amplitude. Results are consistent with nicotine's enhancements of performance on cognitive tasks in humans and are the first reported use of the PPI paradigm to model such effects. These findings indicate that ASR paradigms are useful to study effects of nicotine.

Cigarette smokers report that one reason for smoking is that smoking helps them cope with stress, but there is conflicting evidence as to whether nicotine reduces physiological and behavioral responses to stress. The acoustic startle reflex amplitude, pre-pulse inhibition, and habituation of the reflex provide quantifiable measures of behavioral reactivity that may be sensitive to stress-induced changes that are altered by nicotine. In the present experiment, rats classified as high and low reactors according to baseline startle amplitudes were administered nicotine (6 or 12 mg/kg/day) or saline by osmotic minipump for 11 days. On day 11, animals were acutely stressed by restraint or observation of restraint of conspecifics prior to startle measurement. Nicotine and stress each independently increased acoustic startle amplitude and amount of pre-pulse inhibition, but in combination, the effect of restraint stress and 12 mg/kg nicotine were indistinguishable from saline-treated, non-stressed controls. In contrast, the 6 mg/kg nicotine dose enhanced effects of both restraint and observation stressors on startle amplitude and pre-pulse inhibition. Animals classified as highly reactive prior to treatment were more responsive to nicotine, stress, and the combination, suggesting that initial reactivity is an important determinant of drug and stress effects. Results indicate that nicotine can both reduce and enhance stress effects on reflex amplitude and pre-pulse inhibition depending upon nicotine dose, stressor, and individual differences in reactivity.

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The chronic and relapsing nature of addiction presents unique challenges for ensuring the safety of a potential medication. A patient may use cocaine, for example, while taking the medication or take more medication than prescribed. Thus, a potential medication must be safe and not exacerbate the effects of other substance use disorders. The US Food and Drug Administration has established guidelines recommending safety studies to investigate potential undesirable pharmacodynamic effects of a substance in relation to exposure in the therapeutic range and above. Hence, we assessed the interaction between this selective dopamine D 3 receptor antagonist and cocaine on hemodynamics and cardiac function in freely-moving, telemetered dogs before conducting a clinical trial. GSK598809 increased the hemodynamic effect of cocaine in this model. Thus, the increase in blood pressure after intravenous cocaine was greater in animals that had been pretreated with GSK598809 compared with vehicle. This finding suggests that GSK598809 in particular, and perhaps dopamine D 3 receptor antagonists as a class, may produce unacceptable cardiovascular risks as medications to treat cocaine use disorder.

The acoustic startle reflex was used to measure changes in sensorimotor reactivity in response to nicotine administration and cessation. Male rats received saline, 6 mg/kg/day or 12 mg/kg/day nicotine delivered subcutaneously by osmotic minipumps. The pumps delivered their contents during a 10-day period of implantation, after which time they were explanted. Animals were tested for startle reflex amplitudes using two levels of white noise bursts prior to pump implantation, on days 1 and 7 of nicotine or saline administration, and on several days following drug cessation. Nicotine produced a dose-dependent increase in startle amplitude during the period of administration that decreased during cessation. Results are interpreted in terms of nicotine's actions to enhance attentional processes.