The prefrontal cortex (PFC) is a site for working memory and part of a brain reward circuit. Our studies examined the involvement of the medial PFC (mPFC) in the effects of abused drugs such as alcohol (ETOH), cocaine (COC) or Δ9-tetrahydrocannabinol (Δ9-THC) on the performance of 5-s, 1-h or 4-h delayed tasks in an 8-arm radial maze. Male Wistar rats (250 - 300 g) with bilateral cannulas implanted in the mPFC (B: 2.5 mm A, +/- 1 mm L, 2.7 mm V) received intraperitoneal (IP, 5 min for ETOH or COC or 30 min before session for Δ9-THC) or intracortical [IC, 5 min for ETOH, COC or Δ9-THC or 15 min before session for naltrexone (NTX) or haloperidol(HAL)] drug administration. ETOH IC (32 - 180 μg) disrupted 5-s and 1-h delay performance in a dose-dependent manner, whereas ETOH IP (0.18 - 1.8 g/kg) tended to impair the performance of 1-h delayed task. The disruptive effects of ETOH IC (100 μg) on 1-h delayed task was blocked by NTX IC (56 μg). COC IP (1 - 18 mg/kg) impaired 5-s and 1-h delay performance in a dose...

The endocannabinoid signaling (ECS) pathway plays a central role in regulating fetal neurogenesis and neural circuit formation. Dysregulations of this signaling cascade in the neurogenic phase of human neocortex development, often due to marijuana consu...

Within the ventral tegmental area (VTA) dopamine (DA) signaling mediates reward prediction, pleasure, and motivation. DA cells are regulated by neighboring inhibitory GABA cells, which express glutamic acid decarboxylase 67 (GAD67). Using whole-cell ele...

Increasing use of cannabis makes the search for medications to reduce cannabis abuse extremely important. Here, we show that homomeric α7 nicotinic receptors are novel molecular entities that could be targeted in the development of new drugs for the treatment of cannabis dependence. In rats, systemic administration of the selective α7 nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA), but not the selective heteromeric non-α7 nicotinic acetylcholine receptor antagonist dihydrobetaerythroidine, (1) antagonized the discriminative effects of δ-9-tetrahydrocannabinol (THC), the main active ingredient in cannabis, (2) reduced intravenous self-administration of the synthetic cannabinoid CB1 receptor agonist WIN55,212-2 [( R )-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone, mesylate salt], and (3) decreased THC-induced dopamine elevations in the shell of the nucleus accumbens. Altogether, our results indicate that blockade of α7 ni...

Functional cannabinoid-opioid interactions have been demonstrated in reward and relapse. Here we studied the effect of prenatal exposure to Δ9-tetrahydrocannabinol (THC) on the vulnerability for heroin reinforcement in adulthood. Pregnant Long Evans rats were exposed daily to THC (0.15 mg/kg iv) from gestational day 5 to post-natal day 2; adult males offspring were then trained to self-administer heroin (30 µg/kg/infusion). After stable self-administration was acquired, we determined the between-session dose-response (7.5-100 µg/kg/inf) curve, the consequence of exposure to a mild stress (1-day food deprivation) on heroin intake and the effect of different non-contingent, non-reinforced drug primings on heroin-seeking reinstatement following extinction. The results indicate that both groups had similar rates of responding during acquisition. However, THC-exposed rats exhibited a higher rate of responding to lower (7.5-15 µg/kg/inf) heroin doses compared to vehicle-exposed animals, while both groups respond...

With many communities affected by the opioid crisis, it has become of paramount importance to explore methods of pain management outside of treatments with opioids. One alternative that has seen a recent surge in interest is the cannabis- and related ph...

Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana, exerts complex actions on modulatory neurotransmitters involved in attention and cognition. Though it is known that these effects are mediated via the cannabinoid (CB1) receptor, the precise pharmacological and anatomical mechanisms underlying these effects are poorly understood. Several of the cognitive and autonomic functions affected by cannabinoid administration are modulated by the noradrenergic brainstem nucleus locus coeruleus (LC) and its efferent projections to the frontal cortex (FC). Previous research performed in our laboratory has demonstrated that systemic administration of cannabinoid agonists alters norepinephrine (NE) release in the frontal cortex in a dose-dependent manner. Direct effects on noradrenergic neurons are supported by our previous electron microscopy studies showing that the receptor is present within somatodendritic processes in the LC. To further elucidate sites of action of cannabinoids in the coe...

The legalization of cannabis and shifting cultural attitudes have driven an increase in cannabis use and the proliferation of vapor delivery devices. The DSM-V recognizes “cannabis use disorder” under the umbrella of substance use disorders, but its neural mechanisms require greater clarity ([

The effects of marijuana on brain reward pathways, including the nucleus accumbens (NAc), may contribute to its addictive potential. Within the NAc, both the acute presynaptic inhibitory effects of cannabinoids, and the role of endogenous cannabinoids in the establishment of long-term depression (LTD) at glutamatergic synapses, have been described. However, changes in synaptic function following repeated cannabinoid exposure have not been investigated. Electrophysiological recordings were performed in rat brain slices prepared 24h following a 7 day treatment with a vehicle solution, delta-9-tetrahydrocannabinol (Δ9-THC, 10 mg/kg), or the cannabinoid agonist WIN55,212-2 (10 mg/kg). Glutamatergic postsynaptic potentials in the NAc were inhibited by WIN55,212-2 in slices from vehicle-treated animals (EC50 = 143 nM). Concentration-response curves were significantly shifted to the right in slices obtained from both chronic WIN55,212-2-treated animals (EC50 = 1.2 μM), and from rats chronically treated with Δ9-TH...

The effect of cannabinoid receptor ligands including 2-arachidonylglycerol, anandamide, methanandamide, Δ9-THC, WIN 55,212-2 and CP 55,940 on the function of homomeric α7 nicotinic ACh receptors expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp technique. The endogenous cannabinoid receptor ligands 2-arachidonylglycerol, anandamide and methanandamide inhibited currents evoked with ACh (100 μM). The inhibitory effects of all endogenous ligands tested developed gradually, reaching maximum within 20 to 30 min and was fully reversible following 10 to 30 min of washout. The IC50 values for 2-arachidonylglycerol, anandamide and methanandamide were 110, 218 nM and 103 nM, respectively. In contrast, the synthetic cannabinoid receptor agonists CP 55,940 and WIN 55,212-2, and the active ingredient of marijuana, Δ9-THC, inhibited these currents only at much higher concentrations (1 μM to 100 μM). The inhibition of α7-mediated currents by 2-arachidonylglycerol was non-competitive and ...