Current Neuropharmacology - Volume 3, Issue 2, 2005

Despite the fact that more people seek treatment for cannabis-related disorders than for any other illicit substance-related disorder in the U.S., there are no medications approved for the treatment of these disorders. Similarly, more than half of those meeting criteria for a cocaine use disorder seek treatment. Yet, after two decades of intense medications development research efforts, there remains no approved cocaine pharmacotherapy. This paper reviews data from recent research investigations that may be relevant for the development of pharmacotherapies for cannabis- and cocaine-related disorders. Included in the discussion are findings from studies that have assessed the ability of medications to ameliorate cannabis- and cocaine-related abstinence symptoms in laboratory animals and human research participants. Data from studies that have investigated the effects of pharmacological agents on response to cannabis and cocaine are also reviewed because these data may provide information critical for informing relapse prevention medication development efforts. The majority of published studies evaluating cannabis pharmacotherapies have focused on decreasing withdrawal symptoms: a growing number of medications reduce symptoms in laboratory animals, but the majority of these findings have not been replicated in humans. Fewer studies have assessed the effects of potential cannabis treatment medications on cannabinoid-related reinforcing effects. In laboratory animals, only one has shown promise, while in humans, no medication has been demonstrated to alter marijuana self-administration behavior. Numerous medications have been examined for treating cocaine use disorders; in general, none have proven effective. Some medications, however, have demonstrated utility within subpopulations of cocaine-dependent individuals, suggesting that like psychosocial treatment, pharmacotherapy may need to be tailored to the individual.

The rostromedial medulla, including the nucleus gigantocellularis (NGC) and magnocellularis (NMC), plays a role as a relay nucleus for both the sensory and motor systems. The NGC / NMC is important in the modulation of somatic and visceral activities. Electrophysiological and pharmacological studies have shown that the NGC / NMC is involved in nociception, locomotion, regulation of basal muscle tone, sleep, as well as cardiovascular and pulmonary activities. Pharmacological and electrical stimulation of the NGC / NMC can produce opposite effects on physiological functions: analgesia or hyperalgesia, and suppression or facilitation of motor activity, depending on the subgroups of neurons activated and the states of the sleep-wake cycle at the time of stimulation. Sensory inputs including noxious and innocuous stimuli converge on the NGC / NMC. The NGC / NMC also plays a role as a relay nucleus, which sends sensory information to the higher centers. The NGC / NMC receives projections from the supra-bulbar motor facilitatory and inhibitory areas, and plays an important role in the regulation of motor activity. Pharmacologically, neurons in the NGC / NMC contribute to opioid, glutamate, GABA, acetylcholine, dopamine, substance P, neurotensin, hypocretin (orexin), and cannabinoid mediated sensory and motor activities, as well as cardiovascular and pulmonary functions. In this review, we will discuss the neuronal morphology, physiological functions and pharmacological characterization of the rostromedial medulla. We will consider the evidence that dysfunction of the NGC / NMC is a factor in a number of neurological diseases, including Parkinson's disease, restless legs syndrome, periodic leg movement, REM sleep behavior disorder, amyotrophic lateral sclerosis and narcolepsy.

The pharmacological basis of changes in human behaviour and associated cortical reorganization remains poorly understood. Different paradigms have been introduced to alter motor and somatosensory skills in humans. The underlying changes in synaptic efficacy can be modulated by pharmacological agents acting to gate synaptic plasticity. Non-invasive imaging techniques offer the possibility to assess parallel changes in cortical processing. Cellular studies suggest that there might be only few, but very basic mechanisms that control regulation of synaptic transmission. In particular, the γ-aminobutyric acid (GABA) and the N-methyl-D-aspartic acid (NMDA) receptor, a specific subtype of the glutamatergic receptors, are thought to be crucial in synaptic plasticity. Thus, the application of benzodiazepines facilitating the binding of GABA on GABA(A) receptors, and NMDA receptor blockers, were found to prevent learning and associated cortical reorganization. While there are many approaches to block plastic processes, less is known about drugs, which enhance learning and cortical plasticity. Growing evidence from human studies support the suggestion that learning is subject to amplification by amphetamine. Amphetamine however acts non-specific by increasing centrally the levels of dopamine, serotonin, and noradrenaline. Thus, first approaches that intend to scrutinize the apparently ubiquitous role of only one of these neurotransmitter systems used more specifically acting pharmacological agents. In this review we focus on studies that aimed to investigate the pharmacology of the motor and somatosensory system. First, we introduce standards for testing potential effects of a substance. Then, we focus on biochemical mechanisms of learning, before discussing different motor and somatosensory paradigms which were introduced to elicit changes in cortical excitability or organization in animals and humans. Emphasis is placed on the role of inhibitory and excitatory pharmacological agents acting to gate synaptic plasticity in healthy subjects and patients. It is concluded that future studies that investigate the interaction between artificially modulated receptor activity and specific patterns of behaviour in various neurological disorders may help to improve our understanding of how to support recovery of motor and somatosensory function pharmacologically.

Opioids produce a number of acute effects, notably antinociception and euphoria, whereas chronic use produces tolerance and dependence. Mu opioid receptors (MOR) mediate opioid antinociception and reinforcement and are distributed throughout the CNS in regions consistent with their acute effects, including striatum, thalamus, amygdala, periaqueductal gray (PAG), locus coeruleus (LC), and spinal cord. G-protein-coupled receptor (GPCR) adaptation involves G-protein-coupled receptor kinase (GRK)-mediated receptor phosphorylation with subsequent β-arrestin binding, which uncouples GPCRs from G-protein activation. β-arrestin binding can initiate receptor endocytosis, leading to subsequent degradation or recycling of GPCRs. These processes are reflected experimentally by desensitization (loss of functional response) and downregulation (loss of receptor binding sites). Evaluation of MOR levels following chronic opioid treatment has indicated that MOR downregulation is not required for the expression of tolerance and dependence. In contrast, evaluation of post-receptor events has revealed region-dependent alterations in MOR-G-protein coupling and subsequent effector activity. For example, MOR-mediated G-protein activity and inhibition of adenylyl cyclase are generally decreased in brainstem nuclei following chronic morphine administration, whereas no changes are found in striatum. Similarly, tolerance develops to MOR-mediated potassium channel activation in regions that include LC and PAG. Chronic opioid-mediated effects on adenylyl cyclase affect downstream signaling via regulation of cAMP dependent protein kinase (PKA) and cAMP response element binding protein (CREB), both of which are altered in LC, nucleus accumbens (NAC) and amygdala, regions that might contribute to motivational and physiological signs of withdrawal. Possible explanations for regional differences in MOR adaptation include region-specific co-localization of MOR with signaling proteins and differential distribution of MOR splice variants or oligomers. Moreover, the finding that regional differences exist in neuroadaptation suggests that behavioral adaptations to chronic opioid administration will vary based on the functional neuroanatomy of the MOR system.

Hypoxia, which is a lowered physiological oxygen tension, is an important biological signal as well as a component of many diseases. In central nervous system, hypoxia is associated with brain injury following the ischemic stroke. Recent studies indicate that hypoxia may not only induce a direct neuronal damage, but it may also initiate inflammatory responses by activating microglia. Toxic inflammatory mediators produced by activated microglia under hypoxic conditions exacerbate the neuronal injury during cerebral ischemia. Pharmacological inhibition of hypoxic activation of microglia may prove to be neuroprotective against ischemic stroke.