Ketamine produces rapid and sustained antidepressant actions in depressed patients, but the precise cellular mechanisms underlying these effects have not been identified. Here we determined if modulation of neuronal activity in the infralimbic prefrontal cortex (IL-PFC) underlies the antidepressant and anxiolytic actions of ketamine. We found that neuronal inactivation of the IL-PFC completely blocked the antidepressant and anxiolytic effects of systemic ketamine in rodent models and that ketamine microinfusion into IL-PFC reproduced these behavioral actions of systemic ketamine. We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects and that these effects are associated with increased number and function of spine synapses of layer V pyramidal neurons. The results demonstrate that ketamine infusions or optogenetic stimulation of IL-PFC are sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to the effects of systemic ketamine administration.he NMDA receptor antagonist ketamine produces rapid and robust therapeutic responses in treatment-resistant (1, 2) as well as bipolar depressed patients (3). Preclinical studies report that ketamine also rapidly increases the number and function of spine synapses in the medial prefrontal cortex (mPFC) and that these effects are associated with rapid antidepressant behavioral responses in rodent models (4). These findings represent a major advance for the treatment of depression, although the widespread use of ketamine is limited by side effects (e.g., psychotomimetic and dissociative symptoms) and abuse potential. Further studies of the mechanisms underlying the actions of ketamine could lead to novel rapid antidepressant treatments with fewer side effects.Neuroimaging studies in humans demonstrate that ketamine increases the activity of PFC (5-7), consistent with evidence of rapid increases of glutamate transmission in rodent PFC (8, 9). In addition, depressed patients are reported to have reduced activity in the PFC (10) that is normalized with treatment (11). Rodent studies also demonstrate that long-term stress causes neuronal atrophy of mPFC neurons (12, 13) that is rapidly reversed by ketamine (14). Subregions of the mPFC, including infralimbic (IL) and prelimbic (PrL), have been implicated in diverse cognitive and emotional processes, including fear learning, extinction, and anxiety (15-18). However, the role of PFC activity in the behavioral responses to ketamine has not been examined.Here we examined the antidepressant behavioral effects of neuronal inactivation or direct infusions of ketamine into the IL-PFC and compared these effects with PrL-PFC. Using optogenetics, we also examined the antidepressant and anxiolytic effects of neuronal activation in IL-PFC and determined the impact on pyramidal cell spine number and function to assess long-term neuroplasticity. Methods and MaterialsAnimals, Surgery Microinfusions, and Optical Stimulation. Adult male Spra...

Background Two subtypes of sigma (σ) receptors, σ1 and σ2, can be pharmacologically distinguished, and each may be involved in substance-abuse disorders. σ-receptor antagonists block cocaine place conditioning and σ-receptor agonists are self-administered in rats that previously self-administered cocaine. Self-administration has been related to increased dopamine (DA) neurotransmission for different drug classes. Actions of σ-receptor agonists on mesolimbic DA have not been fully characterized. Methods Receptor-binding studies assessed affinities of different σ-receptor ligands for σ-receptor subtypes, and for the DA transporter; effects on DA transmission in the rat nucleus accumbens shell were assessed using in-vivo microdialysis. Results Cocaine (0.1–1.0 mg/kg i.v.), the non-selective σ1/2-receptor agonist DTG (1.0–5.6 mg/kg i.v.), and the selective σ1-receptor agonist PRE-084 (0.32–10 mg/kg i.v.) dose-dependently increased DA, with maxima of about 275, 150, and 160%, respectively. DTG-induced stimulation of DA was antagonized by the nonselective σ1/2-receptor antagonist, BD 1008 (10 mg/kg i.p.), and by the preferential σ2-receptor antagonist SN79 (1–3 mg/kg i.p.), but not by the preferential σ1-receptor antagonist, BD 1063 (10–30 mg/kg i.p.). Neither PRE-084 nor cocaine was antagonized by either BD1063 or BD1008. Conclusions Stimulation of DA by σ-receptor agonists in a brain area involved in the reinforcing effects of cocaine was demonstrated. The effects appear to be mediated by σ2-receptors rather than σ1-receptors. However σ-receptors are not likely involved in mediating the acute cocaine- and PRE-084-induced stimulation of DA transmission. Different mechanisms might underlie the dopaminergic and reinforcing effects of σ-receptor agonists suggesting a dopamine-independent reinforcing pathway that may contribute to substance-abuse disorders.

The endocannabinoid system has been implicated in the development of synaptic plasticity induced by several drugs abused by humans, including cocaine. However, there remains some debate about the involvement of cannabinoid receptors/ligands in cocaine-induced plasticity and corresponding behavioral actions. Here we show that a single cocaine injection in Swiss-Webster mice produces behavioral and neurochemical alterations that are under the control of the endocannabinoid system. This plasticity may be the initial basis for changes in brain processes leading from recreational use of cocaine to its abuse and ultimately to dependence. Locomotor activity was monitored with photo-beam cell detectors, and accumbens shell/core microdialysate DA levels were monitored by HPLC with electrochemical detection. Development of single-trial cocaine-induced behavioral sensitization, measured as increased distance traveled in sensitized mice compared to control mice, was paralleled by a larger stimulation of extracellular dopamine (DA) levels in the core but not the shell of the nucleus accumbens. Both the behavioral and neurochemical effects were reversed by CB1 receptor blockade produced by rimonabant pretreatments. Further, both behavioral and neurochemical cocaine sensitization were facilitated by pharmacological blockade of endocannabinoid metabolism, achieved by inhibiting the fatty acid amide hydrolase enzyme. In conclusion, our results suggest that a single unconditioned exposure to cocaine produces sensitization through neuronal alterations that require regionally specific release of endocannabinoids. Further, the present results suggest that endocannabinoids play a primary role from the earliest stage of cocaine use, mediating the inception of long-term brain-adaptive responses, shaping central pathways, and likely increasing vulnerability to stimulant abuse disorders.

Rationale Dopamine transporter (DAT) conformation plays a role in the effectiveness of cocaine-like and other DAT-inhibitors. Cocaine-like stimulants are intolerant to DAT conformation changes having decreased potency in cells transfected with DAT constructs that face the cytosol compared to wild-type DAT. In contrast, analogs of benztropine (BZT) are among compounds that are less affected by DAT conformational change. Methods We compared the displacement of radioligand binding to various mammalian CNS sites, acute stimulation of accumbens shell dopamine levels, and place-conditioning in rats among cocaine and four BZT analogs with Cl-substitutions on the diphenyl-ether system including two with carboalkoxy substitutions at the 2-position of the tropane ring. Results Binding assays confirmed high-affinity and selectivity for the DAT with the BZT analogs which also produced significant stimulation of mesolimbic dopamine efflux. Because BZT analogs produced temporal patterns of extracellular dopamine levels different from those by cocaine (3-10 mg/kg, IP), the place conditioning produced by BZT analogs and cocaine was compared at doses and times at which both the increase in dopamine levels and rates of increase were similar to those produced by an effective dose of cocaine. Despite this equilibration, none of the BZT analogs tested produced significant place conditioning. Conclusions The present results extend previous findings suggesting that cocaine-like actions are dependent on a binding equilibrium that favors the outward conformational state of the DAT. In contrast BZT analogs with reduced dependence on DAT conformation have reduced cocaine-like behavioral effects and may prove useful in development of medications for stimulant abuse.

Depression is a chronic, debilitating, and common illness. Currently available pharmacotherapies can be helpful but have several major drawbacks, including substantial rates of low or no response and a long therapeutic time lag. In pursuit of better treatment options, recent research has focussed on rapid-acting antidepressants, including the N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonist ketamine, which affects a range of signaling pathways in ways that are distinct from the mechanisms of typical antidepressants. Because ketamine and similar drugs hold the promise of dramatically improving treatment options for depressed patients, there has been considerable interest in developing new ways to understand how these compounds affect the brain. Here, we review the current understanding of how rapid-acting antidepressants function, including their effects on neuronal signaling pathways and neural circuits, and the research techniques being used to address these questions.

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