The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose-response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.

The purpose of the present study was to develop an animal model of nicotine self-administration that more closely approximates the conditions of human nicotine use than do existing models. In most nicotine self-administration models, rats acquire self-administration during brief daily sessions in which rapid injections of a relatively high dose of the drug, 0.03 mg/kg, serve as the reinforcer. The present study examined nicotine self-administration in rats that acquired the behavior while having virtually unlimited access to injections of a relatively low dose of the drug; the rats did not have any prior operant training or shaping. Under these conditions, rats readily acquire nicotine self-administration at doses at least as low as 0.00375 mg/kg per injection, and they self-administer throughout the active portion of their light cycle. The daily nicotine intake of rats, which ranged from 0.18 to 1.38 mg/kg per day, appears to be comparable to that of human smokers.

A hallmark of the GABA projection neurons of the substantia nigra pars reticulata (SNr), a key basal ganglia output nucleus, is its depolarized membrane potential and rapid spontaneous spikes that encode the basal ganglia output. Parkinsonian movement disorders are often associated with abnormalities in SNr GABA neuron firing intensity and/or pattern. A fundamental question remains regarding the molecular identity of the ion channels that drive these neurons to a depolarized membrane potential. We show here that SNr GABA projection neurons selectively express type 3 canonical transient receptor potential (TRPC3) channels. These channels are tonically active and mediate an inward, Na ϩ -dependent current, leading to a substantial depolarization in these neurons. Inhibition of TRPC3 channels induces hyperpolarization, decreases firing frequency, and increases firing irregularity. These data demonstrate that TRPC3 channels play important roles in ensuring the appropriate firing intensity and pattern in SNr GABA projection neurons that are crucial to movement control.

As most human tobacco use begins during adolescence and ongoing development of the adolescent central nervous system could affect acquisition of nicotine self-administration (SA), our established rat SA procedure was modified to study adolescent acquisition of SA with prolonged access to nicotine (23 h/day). Postnatal age 43-45 female Lewis rats, without prior shaping, conditioning, or food deprivation, were housed in operant chambers equipped with two levers; pressing the active lever triggered an i.v. injection of nicotine. By the 10th day of SA, rats receiving 7.5, 15, 30, or 60 mg/kg/injection nicotine (free base) obtained 23716, 5078, 6578, or 4875 injections (mean7SE), respectively. In the 30 mg/kg/injection group, active : inactive ratio was greater than 2 after SA day 4; 92% of injections occurred during the 12-h active (dark) phase of the light cycle. Main effects (analysis of variance) were shown for day and lever (ie active vs inactive) (po0.001). Adolescent males showed similar dose-dependent nicotine SA. With the increasing workload imposed by raising the fixed ratio (FR), less nicotine was self-administered at FR 5 and 7 compared to FR 1 and 3. In comparison to adult females selfadministering 30 mg/kg/injection of nicotine at FR 1, adolescents acquired nicotine SA at an accelerated rate (po0.05) and received a greater number of injections (po0.05) by day 10. In conclusion, when given prolonged access to the drug, both female and male adolescent Lewis rats rapidly acquire nicotine SA within the dosage range and FR constraints previously observed in adult Lewis rats. However, adolescent females acquired the behavior more rapidly and attained higher levels of stable nicotine SA than adults.

Substantia nigra pars reticulata (SNr) is a key basal ganglia output nucleus critical for movement control. Its γ-aminobutyric acid (GABA)-containing projection neurons intermingle with nigral dopamine (DA) neuron dendrites. Here we show that SNr GABA neurons co-express dopamine D1 and D5 receptor mRNAs and also mRNA for TRPC3 channels. Dopamine induced an inward current in these neurons and increased their firing frequency. These effects were mimicked by D1-like agonists, blocked by a D1-like antagonist. D1-like receptor blockade reduced SNr GABA neuron firing frequency and increased their firing irregularity. These D1-like effects were absent in D1 or D5 receptor knockout mice and inhibited by intracellularly applied D1 or D5 receptor antibody. These D1-like effects were also inhibited when the tonically active TRPC3 channels were inhibited by intracellularly applied TRPC3 channel antibody. Furthermore, stimulation of DA neurons induced a direct inward current in SNr GABA neurons that was sensitive to D1-like blockade. Manipulation of DA neuron activity and DA release and inhibition of dopamine reuptake affected SNr GABA neuron activity in a D1-like receptor-dependent manner. Taken together, our findings indicate that dendritically released dopamine tonically excites SNr GABA neurons via D1-D5 receptor co-activation that enhances constitutively active TRPC3 channels, forming an ultra-short SNc→SNr dopamine pathway that regulates the firing intensity and pattern of these basal ganglia output neurons.