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Post-traumatic stress disorder (PTSD) is an anxiety disorder of considerable prevalence in individuals who have experienced a traumatic event. Studies of the neural substrate of this disorder have focused on the role of areas such as the hippocampus, the amygdala and the medial prefrontal cortex. We show that the ventral tegmental area (VTA), which directly modulates these areas, is part of this circuitry. Using a rat model of PTSD, we show that a brief but intense foot shock followed by three brief reminders can cause long-term behavioral changes as shown by anxiety-like, nociception, and touch-sensitivity tests. We show that an intraperitoneal injection of a dopamine (DA) antagonist or a bilateral inactivation of the VTA administered immediately before the traumatic event decrease the occurrence or intensity of these behavioral changes. Furthermore, we show that there is a significant decrease of baseline VTA dopaminergic but not GABAergic cell firing rates 2 weeks after trauma. Our data suggest that VTA DA neurons undergo long-term physiological changes after trauma and that this brain area is a crucial part of the circuits involved in PTSD symptomatology.

The CB(1) cannabinoid receptor is implicated in the rewarding properties of many drugs of abuse, including cocaine. While CB(1) receptor involvement in the acute rewarding properties of cocaine is controversial, CB(1) antagonists such as SR141716 (rimonabant) have clearly been found to prevent cue- and cocaine-elicited reinstatement of cocaine self-administration in rodents. Here we demonstrate the novel involvement of CB(1) receptors in the maintenance of behavioral sensitization to cocaine in C57BL/6 mice. Consistent with previous reports, the induction of locomotor sensitization following repeated daily cocaine was not prevented by systemic pretreatment of either rimonabant, Delta(9)-tetrahydrocannabinol (THC), or a 1:1 mixture of THC and cannabidiol (CBD). In contrast, established cocaine sensitization was markedly disrupted following subchronic treatment with rimonabant alone. This effect was notably context-dependent, in that rimonabant did not diminish established cocaine sensitization if delivered in the home cage, but only if the rimonabant-injected mice were exposed to activity chambers previously paired with cocaine. These findings are consistent with CB(1) receptor involvement in conditioned cocaine-seeking behaviors, and further suggest that endocannabinoid (eCB)-mediated synaptic plasticity may act specifically within drug-paired environments to maintain cocaine-directed behavioral responses.

Recreational abuse of toluene-containing volatile inhalants by adolescents is a significant public health problem. The mechanisms underlying the abuse potential of such substances remain unclear, but could involve increased activity in mesoaccumbal dopamine (DA) afferents innervating the nucleus accumbens (ACB). Here, using in vitro electrophysiology, we show that application of behaviorally relevant concentrations of toluene directly stimulates DA neurons in the ventral tegmental area (VTA), but not surrounding midbrain regions. Toluene stimulation of VTA neurons persists when synaptic transmission is reduced. Moreover, unlike non-DA neurons, the magnitude of VTA DA neuron firing does not decline during longer exposures designed to emulate 'huffing'. Using dual-probe in vivo microdialysis, we show that perfusion of toluene directly into the VTA increases DA concentrations in the VTA (somatodendritic release) and its terminal projection site, the ACB. These results provide the first demonstration that even brief exposure to toluene increases action potential drive onto mesoaccumbal VTA DA neurons, thereby enhancing DA release in the ACB. The finding that toluene stimulates mesoaccumbal neurotransmission by activating VTA DA neurons directly (independently of transynaptic inputs) provide insights into the neural substrates that may contribute to the initiation and pathophysiology of toluene abuse.

The effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, on cocaine self-administration were investigated. Forty-six male Wistar rats were trained to intravenously self-administer four unit doses of cocaine (0.19, 0.38, 0.75 and 1.5 mg/kg per injection) on a progressive-ratio schedule of reinforcement. The effects of increasing doses of MK-801 (0.05, 0.1, 0.15 and 0.2 mg/kg, IP, 30 min before test sessions) on breaking point (BP) for cocaine self-administration were investigated. The results showed that pretreatment with MK-801 produced effects on cocaine BPs that fit on an inverted-U function. That is, the 0.05 and 0.1 mg/kg doses of MK-801 produced no effect or a small enhancement of BPs across all doses of cocaine, respectively. The 0.15 mg/kg dose of MK-801 produced a significant treatment effect characterized by increased BPs, relative to baseline BPs, across all doses of cocaine. The 0.2 mg/kg dose of MK-801 produced a nonsignificant decrease in BPs across most doses of cocaine. The dose-dependent effects on cocaine BPs after pretreatment with MK-801 suggest that MK-801 can potentiate, and at higher doses attenuate, the rewarding effects of self-administered cocaine.

FOOT-SHOCK induced stress promotes a five to sixfold increase in β-endorphin plasma levels. Similar increases were also found for ACTH plasma levels. In the hypothalamus, foot-shock induced stress promotes a decrease of β-endorphin assayed by radioimmunoassays. These data suggest that physiological increases in plasma β-endorphin levels induced by stress do not result in elevated levels of brain β-endorphin.